tag:blogger.com,1999:blog-52018900677876059012024-03-13T09:40:22.445-07:00Celsion (Nasdaq: CLSN)Your one-stop source for in-depth analysis and extensive scientific literature for Celsion Corporation (Nasdaq: CLSN).
Please note that the contents of the blog represent my own personal opinions and are in no way affiliated with Celsion.Magicsiahttp://www.blogger.com/profile/06200209295387415335noreply@blogger.comBlogger41125tag:blogger.com,1999:blog-5201890067787605901.post-75868192856976850822013-02-02T09:56:00.002-08:002013-02-03T10:06:48.543-08:00Debate Comes to a Swift End: Bears Win, ThermoDox Fails in Phase III HEAT Study<br />
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After months of anticipation (years for many of us longs),
and a January 2013 that brought with it many nail-biting days of anticipation
and some crazy trading days and events (Brean downgrade, Hisun developments),
earlier this week Celsion reported that ThermoDox failed to meet the primary
endpoint of achieving at least a 33% improvement in progression-free survival
(PFS). Of course, it's a very unfortunate outcome for the company, and one,
that in my opinion, puts the nail in the coffin for Celsion. I was clearly wrong in my bull thesis here, though I did do the very best I personally could possibly do in terms of research and highlighting risks. It just was not enough to compel me to take a net bearish position, and clearly, I was wrong here. <o:p></o:p></div>
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We heard on the conference call an extremely depressed,
downbeat management team. We know from CEO Mike Tardugno that the trial
<b><i>"wasn't close"</i></b>, though we did hear that the reported hazard ratio for
the trial was "below 1.0", but they did not give us anything tangible
(note, these had to be pried from management during the Q&A). A
"modest benefit" was seen, per the CEO, and my guess is that the HR
was around .90, falling way short of the 33% hurdle to meet the primary
endpoint goal in progression-free survival. Management said the control arm did
better than their expectations, and after I pressed them during the Q&A to
say by how much, the approximate (unofficial, please note) median PFS of the
control arm was ~20% better than the expected 12 months, or around 14.4 months.
Let’s say ThermoDox did 10% better, that places the treatment arm at around
15.8 months, absolutely dismal results. Many of you recall my "#15v25" prediction for the HEAT trial. It appears I was actually near spot on with the "15" side of the equation given what we know about the control arm, I only wish for the sake of patients, investors, and company management, the 25 component came true. I have noticed that some media outlets
are reporting that the control arm did better than the ThermoDox arm, which, in
fairness, is simply not true. Still, it's a moot point altogether since
ThermoDox failed to show any meaningful clinical benefit, and in fact, I question
why this trial was not halted for futility at the first interim analysis back
in November of 2011. <o:p></o:p>Recall CEO Tardugno mentioning the chances of that were "de minimis" at the time, how on earth could he have known that at the time with such certainty if the trial turned out to be an utter failure?</div>
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One might ask what next for Celsion, perhaps there are
subsets of data worth exploring, etc? To be brutally honest, as my friend <a href="https://twitter.com/TrondHildahl" target="_blank">@trondhildahl</a> mentioned as well, I heard absolutely
nothing on the call to make me think there may be any glimpse of hope in the
HEAT dataset. Per my question on the call, we know distant progression, the
biggest threat facing the study in my opinion as I have said 100’s of times, was higher than “expected”,
though we never knew what they expected for distant or local progression. If
local progression, at least, looked good for the ThermoDox arm, management
would have volunteered that data, I have no doubt. Local, distant, even across
both 3-5cm and 5-7cm groups, probably looked poor. Still, the "geek" in me is curious to see the full data set to see the actual complete ablation rates, adverse events, etc., and I hope that data is made available as soon as possible.</div>
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<b>Why the trial likely failed (hat being tipped to bears):</b></div>
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<ol>
<li>Doxorubicin has always had modest response rates in HCC, despite being widely used in TACE and deb-TACE regimens. It was hypothesized by bulls that given sufficient concentrations and synergies with heat, efficacy could be significantly enhanced. We now know this did not happen, at least in the adjuvant setting, for tx naive HCC patients with 3-7cm lesions it didn't. </li>
<li>Doxorubicin concentrations may not have been enough and sustained for an ample amount of time, undermining the above</li>
<li>Distant progression jeopardized the trial, and from the CEO's comments on the call, I have no doubts that was a primary factor for the trial failing. This was probably due to ThermoDox not having a potent enough of a local impact to prevent some of the distant metastases emanating from the original ablation site. </li>
</ol>
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In hindsight as well, SA author Quoth the Raven also <a href="http://seekingalpha.com/article/1149231-celsion-s-bad-beat-4-tells-that-longs-missed?source=google_news" target="_blank">does point out a few "tells"</a> that longs did not interpret as caution. Firstly, the supposed "bear raid" and the downgrade by Brean, secondly the Cowen conference cancellation which Jeff Church told me was due to board meeting conflict (that might be true still, who knows), thirdly results being delayed until the last day, and the Feuerstein-Ratain rule, which was discussed frequently leading up to the results. The ever increasing short interest, high cost to borrow, and seemingly absent institutional interest were also some additional tells that I will tack on to the list. Oh, the beauty of hindsight.</div>
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<b>So, what next for Celsion? I told many of you that I would be as objective as possible, so here are my thoughts:</b></div>
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<ol>
<li>ABLATE trial is very unlikely to move forward. That trial has local progression at 1 year as the primary endpoint, but from what I heard on the call, ThermoDox likely had very little effect on local progression.</li>
<li>RCW Dignity Phase II study can be moved forward, but unless earlier line patients are selected, this will not complete enrollment for quite some time, perhaps as late as mid-2014. Even then, moving earlier line is no guarantee, since we have no evidence that ThermoDox works in early line RCW patients (for example, as the first chemo or prior to radiation). </li>
<li>HIFU bone metastases Phase II study with Philips may move forward (and was expected to enroll first patient in early 2013 from prior guidance), but even if this moves forward and shows benefit, HIFU itself still has a huge adoption curve, and the commercial prospects of this indication would be not be realized for quite some time. </li>
<li>LTSL platform is in jeopardy altogether given the above, particularly since we know from recent presentations that improvements are being made very rapidly in terms of other heat sensitive liposomes. For example, we know that while early stage still, some liposomes are being developed that are much more stable than ThermoDox, and release doxorubicin contents more efficiently. The ideal liposome would be 100% stable at body temperature (which ThermoDox is not), and release contents via some form of trigger, be it heat or some other source such as sound. Point is, the platform altogether might be in jeopardy given the aforementioned. </li>
<li>I see bankruptcy in the very near future Celsion, and they would be wise to sell off rights to LTSL docetaxel and carboplatin for whatever they can get for it. HEAT was validation for the entire platform, and that failed miserably. Remember, it is not like they have that much time left from a patent perspective either (2021), and the above mentioned docetaxel and carboplatin LTSL products are still in preclinical stages.</li>
</ol>
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The only wildcard that can possibly save Celsion as they stutter forward is if overall survival data somehow shows a significant benefit for the ThermoDox arm, which is highly, highly unlikely. That said, much to my amazement, the company questioned whether or not they would even follow patients in the HEAT study for overall survival, they alluded to that both in the PR and on the call. Though yes, this would be an added "cost" for the company when they clearly will have cash issues in the very immediate future, I have to say I was quite infuriated by this, as they owe it the medical community to follow these patients and report robust data from the largest study ever conducted in intermediate HCC using RFA. There is an overall lack of data in this space, and the least, the very least they could do to assist future research is to get crystal clear data from this study to pass on to the medical community. </div>
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Overall, I am obviously disappointed by the HEAT outcome. But what I am proud of, from a personal growth perspective, is the experience this gave me. What started out as an investment very quickly turned into so much more, not a love story with the company, but a personal mission to cover the company and it's developments as unbiased and objectively as I could, while sharing everything I came across with the public. In that journey, I came across and met a diverse group of people, from highly respected journalists, company management (whom I have spoken to and interacted with many times), highly experienced traders, and made many friends along the road. I remained an open book in this process, never was anonymous, and completely transparent. I also went out of my way to point out risks, I mentioned that repeatedly to people, including some family and friends who bought CLSN as well. In the minutes prior to the closing bell on January 30th, I recall urging people to assess their risk tolerance and take something off the table if they were not comfortable holding. I can hold my head up knowing that I tried, and did my best. I said before this was always about the "process", and I wouldn't have changed a thing about <i><b>how</b></i> the story was covered. </div>
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I guess this is how the story ends, and you can expect me to end coverage of Celsion from this day moving forward. Regardless of the outcome, I was going to move all my funds back to my Vanguard indices, so from a personal investing perspective, I am not going to be playing with biotechs anymore. That said, I may, <i><b>MAY</b></i>, continue to blog about other companies, if a compelling story comes along, and if I have the time and energy for it. I wish you all the very best, and want to thank each and every one of you who took the time to visit my blog and interacted with me in a number of different forums. I am just humbled by the amount of support and visits my blog received during my coverage, and for that, I thank you all greatly. Please do stay in touch. </div>
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Best,<br />
Siavoche</div>
<br />Magicsiahttp://www.blogger.com/profile/06200209295387415335noreply@blogger.com5tag:blogger.com,1999:blog-5201890067787605901.post-17157309781161667952013-01-17T06:40:00.002-08:002013-01-20T20:10:44.931-08:00[UPDATED] Brean Murray Timing Suspect, Logic Flawed, as New Downgrade and $1 PT Causes Further Drama I guess nothing about this upcoming Phase III data release for Celsion will be "conventional", far from it. Before moving on to the Brean news, I want to make a couple comments with respect to the antics from yesterday. I am not a Wall Street person per se, and perhaps I am a bit young and naive, <i><b>but I hope that ALL BULLS AND BEARS agree with me in saying that what we saw yesterday as far as trading activity for Celsion was highly suspicious, and smells of blatant manipulation.</b></i> Regardless of the outcome of the trial, for whatever it's worth, I personally call on the SEC to investigate thoroughly what happened yesterday. After years of research, I hate to see the most pivotal outcome in this company's history get tarnished with traders conducting blatant manipulation. Regardless of what side you are on, I hope you agree with my views here, as we have seen this countless times in biotech ahead of binary events. <a href="http://investorshub.advfn.com/boards/read_msg.aspx?message_id=83521129" target="_blank">One interesting note on ihub</a> from a poster <i>speculated</i> on what may have happened yesterday, it is worth a read.<br />
<br />
With yesterday's antics behind us, today we woke up to a downgrade from Brean Murray's Jon Aschoff, dropping his target price from $7 to $1. While I do not have access to the report, <a href="http://www.thestreet.com/story/11815497/1/celsion-downgraded-right-in-front-of-all-important-study-results.html" target="_blank">Adam Feuerstein reported the news earlier this AM</a> and included the verbiage from Jon Aschoff. I tweeted earlier as well that the "gloves are off" at this juncture, so let me be a bit blunt here:<br />
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<ol>
<li><i><b>The sheer timing of this "downgrade" is highly, highly suspect given HEAT data being just around the corner.</b></i> Note that I do NOT view the Roth report issued yesterday in the same vain, since that report was primarily meant to be "coverage" of what happened during the irregular trading yesterday, not necessarily a sudden shift in their fundamental view of Celsion (which, incidentally, with a $10 price target, I think should be re-thought). Adam Feuerstein himself tweeted earlier as well that Aschoff's timing was "stupid", despite Adam's own belief ThermoDox will fail. I suppose this is nothing new for Jon Aschoff, as he had a <a href="http://www.cnbc.com/id/30245189/Analyst_Eats_Dendreon_Crow" target="_blank">similar situation pan out with Dendreon</a> a few years ago. The bottom line is, for Aschoff to have a sudden change in heart, fundamentally, regarding Celsion, with data near is very suspect.</li>
<li><i style="font-weight: bold;">Aschoff's piece is missing facts, and his logic is highly questionable. </i>Let me preface this by saying even the staunchest of bears, and you ALL know I have sought and "battled" many of them over the years, believe that for ThermoDox to hit it's accelerated endpoint in progression-free survival, itself, would be a HUGE accomplishment. In fact, I have said it before as well, PFS is almost an "unfair" endpoint for ThermoDox, yet one in which I think ThermoDox will handily show clinical benefit by reducing most local and <i>some</i> distant progressions. No bear I have come across believes there would be a sell-off on news of positive PFS data, to the contrary, the consensus is a 100-200% gain from today's current market cap. PFS aside, I have discussed before, and the company and KOLs have confirmed numerous times, patients in the HEAT trial will not only potentially receive up to 2 ablations to achieve an<i><b> initial</b></i> complete ablation, but will likely receive multiple RFA treatments <i><b>post-progression</b></i>, according to their randomized protocol.<br /><br />So, all that aside, let's read verbatim what he wrote, and my comments are in <b><span style="color: red;">[red brackets]</span></b>:<br /><br /><i>"We are downgrading Celsion to Sell from Buy due to robust share price strength prior to a highly binary event in 1Q13 that, in our view, will define whether or not the company remains viable thereafter. Recent share price strength places the valuation at a level where we expect more downside from negative results than sustainable upside from positive results </i><span style="color: red;"><b>[so, if trial succeeds, they don't see any upside, and if trial fails, magnitude on downside is much larger than increase if positive. FINE, but read carefully, he is generically speaking about either outcome, not saying one way or another which will happen]</b></span><i>. We question the sustainability of a positive valuation inflection upon the potential showing of a progression free survival (PFS) benefit due to the need to show at least a clinically meaningful overall survival (OS) benefit thereafter, which after only a single administration of one active therapy (RFA) versus two active therapies (RFA and ThermoDox), appears more difficult than benefiting PFS, given the introduction of any additional therapy between progression and death </i><b><span style="color: red;">[Again, factually incorrect, he assumes patients won't receive any additional doses of ThermoDox post progression, which is simply untrue. Even if they don't, and progression times are significantly extended with even one dose of ThermoDox, PFS we know is already a strong surrogate for survival in HCC]</span></b><i>. Despite the HEAT trial's SPA, meeting the PFS primary endpoint is not a shoe-in for approval without at the very least a strong numerical OS advantage for those treated with ThermoDox </i><b><span style="color: red;">[FINE, once again. But OS is a secondary endpoint, I believe Aschoff is forgetting that PFS is an accelerated endpoint here. The big problem here, for his own sake, is his implicit assumption that PFS will be positive, and once again, even the "bearest" of bears believe hitting PFS itself would be both meaningful clinically, and catapult Celsion from a valuation perspective. And furthermore, Aschoff KNEW OF THE TRIAL PROTOCOL upon initiating coverage, didn't he? Why does he suddenly believe that PFS is a big issue, <a href="https://skydrive.live.com/redir?resid=D5139E805024FD7C!657&authkey=!APxI6sJLNgl2zmE" target="_blank">when Aschoff never raised this before in his earlier report</a> from Feb 16, 2012?]</span></b><i> ."</i></li>
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<b><span style="color: blue;">The bottom line is, if you believe a positive <i><u>PFS</u> </i>outcome, which he implicitly assumes, warrants a $1 price target, then by all means listen to Aschoff. </span></b><br />
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As my friend <a href="https://twitter.com/BioRunUp" target="_blank">@biorunup</a> tweeted earlier today as well, "data is the great equalizer", and I agree, data will end this debate once and for all. Best of luck to you.<br />
<br />
Best,<br />
Siavoche<br />
<br />
<b><span style="color: lime;">[UPDATE TO ARTICLE 1/17, 7:46 PM PT] </span></b><br />
Just to give you some more color highlighting why Brean Murray's report today was extremely suspect and a demonstration of very questionable logic/rationale, consider the following direct quotes from his first report, which I linked above. Now, call me crazy, but one would think to change one's opinion on something, in general, requires one to re-visit the original crux of one's opinion, right? What is particularly baffling to me is that nothing in his report today, not even close, conflicted with these primary drivers for his original bull thesis. <b><u>MOST BAFFLING to me is that his concerns over PFS as the HEAT primary endpoint, the crux of his argument today, was never once mentioned, <i>not even as a minor risk</i>, in his original repor</u></b>t. That, my dear friends, tells me something is terribly wrong about today's report, because a study's primary endpoint would be one of the very first things anybody conducting DD would give thought to, especially a supposed "analyst". I do not buy that it suddenly dawned on him to look askance on PFS, literally days before top-line data. Let's have a look at some other glaring inconsistencies not addressed in today's report:<br />
<br />
-<i>"The Phase 3 ThermoDox trial should read out in 4Q12, and we are expecting a positive PFS outcome."</i><br />
<span style="color: red;"><b>Question--> </b></span>Has that changed from today's new downgrade? <span style="color: red;"><b>No, it's actually</b><i style="font-weight: bold;"> reinforced, </i><b>date aside.<i> </i></b></span><br />
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-<i>"We believe ThermoDox will be broadly adopted once it's approved."</i><br />
<span style="color: red;"><b>Question--> </b></span>Has that changed from today's new downgrade? <b><span style="color: red;">No</span></b><br />
<br />
-<i>"We believe the potential end-markets for ThermoDox use are significant."</i><br />
<span style="color: red;"><b>Question--> </b></span>Has that changed from today's new downgrade? <span style="color: red;"><b>No</b></span><br />
<br />
-<i>"Celsion is carefully monitoring the Phase 3 ThermoDox trial to avoid common pitfalls."</i><br />
<span style="color: red;"><b>Question--> </b></span>Has that changed from today's new downgrade? <span style="color: red;"><b>No</b></span><br />
<br />
-<i>"We further believe that a positive <b><u>PFS result</u></b> would likely rapidly attract an ex-US partner"</i><br />
<span style="color: red;"><b>Question--> </b></span>Has that changed from today's new downgrade? <span style="color: red;"><b>No,</b></span> and this is my favorite one. I suppose <b><u>PFS</u></b> is valuable enough to attract an ex-US partner, yet, that same Ex-US partner, with much greater understanding of the regulatory environment, would do so knowing regulatory agencies would want OS rather than PFS for approval? Nevermind that such an Ex-US partnership itself would be another major catalyst for the company's valuation. There are so many things just simply wrong with the logic and rationale for a $1 PT here it is hard to believe.<br />
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Good luck to all longs,<br />
Siavoche<br />
<br />Magicsiahttp://www.blogger.com/profile/06200209295387415335noreply@blogger.com2tag:blogger.com,1999:blog-5201890067787605901.post-79918544684065751272013-01-16T12:37:00.000-08:002013-01-26T08:22:55.469-08:00"Flash Crash" Causes Concern for Celsion Investors, Roth Issues New ReportI did not anticipate having any new blog posts until final data, but today's actions prompted me to give my blog viewers a quick update on a couple fronts.<br />
<ol>
<li>A T7 halt was issued when shares of Celsion plummeted to an intraday low of 6.17. Flyonthewall issued this <a href="http://finance.yahoo.com/news/celsion-trading-halted-single-stock-183631835.html" target="_blank">brief note</a> as well. I reached out to management directly asking what had happened, and the response from Greg Weaver, Celsion CFO, was <b style="font-style: italic;">"We have no further information right now, and are in contact with nasdaq and trading desks to sort it out." </b> Celsion CEO also subsequently provided a brief, general follow-up saying <i><b>"fundamentals here are strong and have not changed...Company remains on track." </b></i>Nobody can be sure of what happened (leak, bear raid, whatever), but the responses from Celsion management do give me some reassurance.</li>
<li>Obviously lost in this news, Roth Capital issued a new report as well today, and the link is provided below. From the report, the author states: </li>
<li style="display: inline !important;"><i><b>"In short, management has <i><b></b></i></b></i></li>
<li style="display: inline !important;"><i><b><i><b>indicated that all is status quo in finalizing the HEAT data readout and <span style="color: red;"><u>that </u></span></b></i></b></i></li>
<i><b><i><b>
<li style="display: inline !important;"><span style="color: red;"><u>nothing has leaked out</u></span>. </li>
</b></i><i><b>Nasdaq has indicated its belief that the intraday drop was driven primarily by retail and some short interest pressure coming through. Recall that the stock performance has been strong and sustainable as of late as investors have been making bets on HEAT. Other feedback we received from investors was that if it was a leak or institutional selling, the negative stock pressure would have been sustained."</b></i></b></i></ol>
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I remain extremely confident in a positive HEAT outcome, despite the craziness we observed today. Fingers are crossed, wishing management, shareholders, and most importantly, potential future patients, the best of luck as we near data release.<br />
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Best,<br />
SiavocheMagicsiahttp://www.blogger.com/profile/06200209295387415335noreply@blogger.com4tag:blogger.com,1999:blog-5201890067787605901.post-75091836094184209122012-11-13T16:53:00.002-08:002012-11-13T22:33:17.255-08:00"We have never been so well positioned"— Michael Tardugno, Celsion Q3 conference callWhile I was unable to listen live and participate in the Q3 conference call, after listening to the replay, I was extremely impressed with the tone and confidence exuded by management during the call. Of course, most investors already received the news they wanted to hear in the press release last Friday (380 realized, or projected to be realized, and data due in January), still, the company provided updates on a few fronts worth noting. For the most part, yesterday's call was a strong reiteration of many of the things management has said before.<br />
<br />
A <a href="http://seekingalpha.com/article/1001421-celsion-s-ceo-discusses-q3-2012-results-earnings-call-transcript?source=yahoo" target="_blank">transcript from Seeking Alpha can be found here</a>, but note that there are some egregious mistakes made throughout the transcript. As an example, in some places, Greg Weaver's name is used in place of Dr. Borys, so please re-read this carefully. Even better, I encourage you to listen to<a href="http://public.viavid.com/index.php?id=102314" target="_blank"> the replay, linked here</a>.<br />
<ul>
<li>CEO described ThermoDox as a drug that could potentially "extend life and perhaps provide a cure" for those with HCC. The "C" word is not one to be used lightly, so those are some pretty strong words. That said, bulls shouldn't get too excited over this, since RFA by itself is meant to be a "curative" treatment. We know most patients will recur even with ThermoDox, so it is really a question of how long progression is delayed. Remember, HCC is the result of underlying liver disease, the manifestation of which is in a lesion. </li>
<li>Regulatory support for ThermoDox and the HEAT study again strongly re-emphasized...per the CEO, "they [regulators] get it."</li>
<li>Re-affirmation that it is the company's expectation that the control arm in the HEAT study will have a 12 month median PFS time, and OS ~30M. Per the CEO, "outcome statistics have remained constant since we began research in HCC over 6 years ago." The expectations of the performance of the control arm will forever be debated until top-line data is finally released, but management has never once qualified or stepped back from that 12 month number. For what it is worth, I personally think PFS will come in around 15-16 months, with OS up closer towards 40 months. As some of you know, many (including Mangrove Partners' Nathaniel August and several others) have tried "modeling" the HEAT study using enrollment data and events recorded at the interim analysis date and now for 380. According to some, if the control arm is truly 12 months, the separation in the curves could be fairly large due to <i>unconfirmed guesses/estimates </i>by many that the pooled median for the entire trial is in the 20-25 month range. I try not to speculate at all in this area (everything is purely just that, speculation based on fancy excel spreadsheets), as it is not an area of expertise of mine nor do I think such models carry much utility given all the variables that need to be accounted for. Sorry for the digression on this point. </li>
<li>Stressed the importance of data quality, exhibited by frequent checks and reviews of data timeliness, concordance/discordance, and audits of their CROs...again, a theme we have heard before from the company, "no surprises." With a radiologic endpoint such as PFS, the importance of data quality is critical. Shareholders can be confident, in my strong opinion, that Dr. Borys and Celsion management have placed data quality as perhaps the highest priority in executing the HEAT study. </li>
<li>Payer/market access research reveals potential pricing is at the "top of the charts" for ThermoDox. "Top of the charts" in my opinion likely means a price $25,000-$50,000 per dose. Being able to speak to this given that I have some background in this area, you can bet that Celsion conducted this market research (through a consultancy) with medical and pharmacy directors from various public and private payers. </li>
<li>Half day meeting (in what was supposed to be a 1 hour meeting) with Chinese sFDA recently conducted. The fact that China will accept an NDA without the need for a reference application <i><b>is a significant development, make no mistake</b></i>. This approach in China was largely due to the company's partnership with Hisun, which the company has mentioned before, would afford them regulatory pathway benefits in the country. We are already seeing the fruits of their investment in that partnership (see <a href="http://www.accenture.com/SiteCollectionDocuments/PDF/Accenture-Launching-Successful-Products-China-Pharmaceutical-Market.pdf" target="_blank">here</a> and <a href="http://files.shareholder.com/downloads/SCLN/0x0x580139/c80f370b-5555-444c-8617-821ab3ab4722/China_Regulatory_and_Commercialization_Backgrounder_final__062512.pdf" target="_blank">here</a> for good primers on drug approvals in China). Now, I will point out, approval is one thing, reimbursement is another, same as is the case in Europe, so that remains to be seen in China. </li>
<li>In reference to Hisun, while Jeff Church has mentioned before that Hisun has a relationship with Pfizer (this was noted in the Celsion Hisun PR as well), I found it interesting that he also called out their relationship with Eli Lilly, a first if my memory serves me right. </li>
<li>Started the rolling NDA process using a common technical document (CTD). In Q&A, noted that first 2 modules can be filed at the time of top-line data release in January assuming the FDA allows rolling submission (I don't see why this is even a question, should be a given as a function of fast-track). The company expects to file in the US and EMA in same time-frame as previously guided, then China shortly thereafter. </li>
<li>ABLATE is underway in 4 locations, recruitment being limited to preserve cash. Will ramp up after HEAT study.</li>
<li>Company will be announcing additional research collaborations for HIFU in combination with ThermoDox...."I can tell you now there will be others", something that has been telegraphed before by the CEO on prior calls as it relates to HIFU research partnerships. </li>
<li><b><i>No current plans to raise cash before HEAT topline results.</i></b> Once again, re-stated several times. I have been telling many publicly that it was my firm belief the company would not raise cash ahead of the top-line data, and this appears to be set in stone at this point. </li>
<li>$22.7M in cash to end the quarter (partly due to $4M from warrants). Company has an additional $5M loan that can be drawn from Oxford assuming a positive HEAT study. Per the CFO, "emphasizes the wise use of cash and cost controls and our ability to make cash and by extension our equity work as hard as possible"</li>
<li>HEAT study designed to show statistical <b><i>and </i></b>clinical significance per Dr. Borys. With regard to OS, CEO said that "survival trends" might be available at the time of FDA approval, which is expected for end of 2013 at the earliest. Previously, the company said mid-2014 for OS data, <i><b>perhaps this timeline has changed</b></i>. Further adding to this, Dr. Borys said they "have very high confidence" in confirming OS assuming assuming positive PFS data, largely a function of the company's strong belief that PFS in the HCC setting is an especially strong predictor of survival. </li>
<li>Philips phase II study to begin in "early 2013". It is worth pointing out in honesty this does represent a slip on management's original timeline to have first patient enrolled by the end of 2012. I'll give them a pass on it, mainly because the fault could be with Philips for all we know, and secondly, because I want their attention on HEAT anyways. </li>
<li>Per the Q&A, priority review will be conditioned upon the outcome of a pre-NDA meeting with the FDA. This is interesting, as management has slightly changed their tone from priority review being a "given" as a function of fast-track, to being "conditioned" on the pre-NDA outcome.</li>
<li>Licensing interest remains very high, but management basically reconfirmed that they won't sign any license deals until data is released in January, at which point, the company would be "entertaining multiple term sheets". Its been a while since management has promised a large second deal, but they "expect our [their] patience to pay off" when it's all said and done. I personally think a licensing deal will RAPIDLY follow announcement of top-line results with a major big pharma company seeking aggressive expansion in emerging markets. As I have said before, ThermoDox presents the best of both worlds for big pharma, a very attractive oncology asset in China, and one which will receive considerable off-label attention in the developed regions of the world for CRLM. </li>
<li>Company is definitely considering commercializing the US market on their own, which is nothing new. I think the company will in fact retain the US market for themselves (or do some form of co-marketing agreement as mentioned on the call). </li>
<li>In response to one of the questions posed to management about the extent of data that would be released in the top-line data PR, the company reiterated that they will be seeking publication in a major medical journal, and of course, will be limited in the amount of data they can,or would want to disclose, before peer-review. Expect median PFS times in both arms and a hazard ratio to go along with it, nothing more. </li>
<li>A fellow shareholder (<a href="https://twitter.com/TrondHildahl" target="_blank">Trond Hildahl</a>, whose name SA butchered on the transcript!) asked a question which danced around a topic I was hoping to ask management re: the number of RFA treatments performed within the first month/month and half following initial treatment. Management simply said that RFA is repeatable, which it is, and ThermoDox does not change that. What Trond's question was getting it is the number of RFA treatments necessary to achieve technical success, or an <i>initial</i> complete ablation. I will boldly predict that there will be some significant differences here between the 3-5 and 5-7cm lesions in BOTH arms in terms of technical success, while I expect ThermoDox to slightly improve complete ablation rates. The 3-5cm group will likely have an 80% complete ablation rate after 1 treatment, and that number will go up to ~95% following the second treatment to achieve a complete ablation within that first month and half per protocol. I expect the ThermoDox arm might achieve closer to 97-98% complete ablation rates in the 3-5cm group. The balance of these patients are considered treatment failures, and immediately have PFS events at time = 0. The 5-7cm group will likely have a 65% complete ablation rate initially, and this number will likely go as high as 80-85% in the control arm with the second treatment per protocol, again, with the balance being immediate treatment failures. So, yes, between 15 and 20% of control arm patients in the 5-7cm <i><b>will immediately event</b></i> at time = 0 in my opinion. In the ThermoDox arm, I would be really happy to see complete ablation rates ~90% in this cohort after 2 initial attempts. By the way, these numbers were not just pulled out of thin air, please review for yourself some of the literature on my blog for support of this.<br />So, that gets at Trond's question. My question is including both these initial treatments to achieve technical success, how many RFA's are patients receiving POST-PROGRESSION in both arms? Again, this becomes a critical, critical driver in the derivation of revenue estimates for ThermoDox, and one that all analysts have overlooked for some reason. While I want management to speak to this for the HEAT study in particular themselves, I would expect patients receive at least 2-3 RFAs during their entire course of treatment, some as many as 5 or 6 in total. Keep in mind, not all patients will remain eligible for curative treatments such as RFA following progression, some immediately would go to TACE or Nexavar. The <i>specific patterns of progression</i> exhibited in each arm is something I anxiously await to see in the full data set presented for publication. </li>
</ul>
<div>
I definitely digressed more than usual here, but hopefully it was helpful in some ways. I also had some questions that I was hoping to get answered on the call yesterday (like the average # RFA question above), and to that end, I have reached to management to see if they could give me 15-20 minutes to discuss some of the questions I posted. Should I get that opportunity, I will update this post with what I hear. </div>
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<br /></div>
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After a lot thinking, researching, interacting with other shareholders, physicians, Celsion management, questioning my own thoughts, and actively soliciting opposing views, I continue to come to the same conclusion when it is all said and done: <i><b><span style="color: blue;">Celsion will unveil a new standard of care for 1st line intermediate HCC come January. </span></b></i></div>
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<br /></div>
<div>
Best,<br />
Siavoche<br />
#15vs25</div>
Magicsiahttp://www.blogger.com/profile/06200209295387415335noreply@blogger.com5tag:blogger.com,1999:blog-5201890067787605901.post-33905850423511328312012-11-09T06:53:00.002-08:002012-11-09T16:24:34.790-08:00UPDATED- Celsion Pleasantly Surprises Investors with 380+ PFS Event Confirmation, Final Data Targeted for January. Griffin Securities Reiterates $18 PTNeedless to say, today's PR was quite a surprise and I think the market liked what they heard. I don't have much to say here other than to re-post the <a href="http://finance.yahoo.com/news/celsion-announces-phase-iii-heat-130000661.html" target="_blank">PR</a> and highlight some key areas for investors. This is significant since I was under the strong impression that management had no intentions of PR'ing the 380+, exactly as they did <a href="http://celsion.blogspot.com/2011/09/dont-bank-on-190-pfs-event-press.html" target="_blank">prior to the interim analysis last November</a>. You can bet the final number of events will be well over 380 just to be extra safe, I would count on 400 events or so being the final count.<br />
<br />
<b><u>My own takeaways from the PR:</u></b><br />
<ol>
<li>Management listens to investors, I have said this before as well. I can bet this is not necessarily what they wanted to do (who knows, maybe they had intentions of under-promising and over-delivering on this topic as well, as they have been doing for much of 2012 to be honest), but they knew it would be received well by the investor community. </li>
<li>The company absolutely will not be raising money, period. For a development stage biotech facing life and death here, this is a major, MAJOR sign of confidence. HEAT failure means bankruptcy before the end of 2013. If they wanted to, management could have easily issued 10M shares when the stock was 5 or 6, and had plenty of cushion for several years to come. The fact that they did not, in my humble opinion, speaks volumes about their own sense of confidence in the HEAT study, and reaffirms that they are actively keeping in mind delivering maximum value to shareholders.</li>
<li>Data will be out in January, plain and simple. It's very possible data could be out before opex (10 weeks from now takes us right to op ex), but that is pushing it given the holidays, etc. Of note, the PR did say that they "project" that 380+ has been realized, so it is very likely this has not yet been confirmed per se, but that is likely a formality at this point. </li>
</ol>
<b><u>From today's PR (emphasis, colors mine):</u></b><br />
<br />
LAWRENCEVILLE, NJ--(Marketwire - Nov 9, 2012) - Celsion Corporation ( NASDAQ : CLSN ), a leading oncology drug development company, today announced that it<i><b><span style="color: blue;"> projects </span></b></i>that <i><b><span style="color: blue;">a minimum of 380 events of progression have been realized</span></b></i> in the Company's pivotal, Phase III HEAT Study, a multinational, double-blind, placebo-controlled, pivotal study of ThermoDox® in combination with radiofrequency ablation (RFA) for the treatment of hepatocellular carcinoma (HCC), also known as primary liver cancer. According to protocol, 380 events of progression, subject to confirmation by the Study's independent Data Monitoring Committee (DMC), trigger the data collection process, unblinding and final analysis of the results by the DMC. Progression Free Survival (PFS) is the HEAT Study's primary endpoint. The HEAT Study has been granted Special Protocol Assessment by the FDA. Following DMC review, the Company plans to disclose top line results, <i><b><span style="color: blue;">an announcement that is expected to occur in January 2013</span></b></i>.<br />
<br />
"The HEAT Study addresses a significant and growing global unmet medical need in oncology, primary liver cancer. With a positive outcome, ThermoDox® will become the most important 1st line therapy for patients with non-resectable disease," said Michael H. Tardugno, Celsion's President and Chief Executive Officer. "The positive implications of this study, for patients and their families, the healthcare community, our investors and employees, cannot be overestimated."<br />
<br />
Mr. Tardugno added: "We enter this transformative period from a position of financial strength, having taken ThermoDox® through to pivotal data while maintaining full worldwide rights outside of Japan, a minimal number of shares outstanding and a strong balance sheet." The Company ended the second quarter of 2012 with $24 million in cash, subsequently supplemented by $4.7 million in option and warrant exercises. Celsion also has available to draw an additional $5 million from a $10 million loan facility with Oxford Finance LLC and Horizon Technology Finance Corporation, pending positive data from the Phase III HEAT Study. "Consistent with our previous guidance, <span style="color: blue;"><i><b>we have no plans to raise additional capital before disclosing top line data from the HEAT Study which, if positive, will vastly expand the Company's strategic and financing options."</b></i></span><br />
<span style="color: blue;"><i><b><br /></b></i></span>
Just moments after this PR, a note was issued by Keith Markey from Griffin Securities re-affirming their $18 price target on the stock. Now, I have brought this up before, but even though Griffin has the highest price target on the stock, I will boldly say they are most accurately capturing ThermoDox' true valuation compared to the other analysts from Rodman (formerly I suppose at this point), Brean Murray, and Roth Capital. Keep in mind this valuation from Dr. Markey STILL does NOT include any revenue from the RCW indication, but it does include off-label colorectal liver mets revenue. <a href="http://celsion.blogspot.com/2012/09/the-importance-of-phase-ii-ablate-study.html" target="_blank">As I have mentioned here</a>, it is my strong belief that off-label use for colorectal liver mets will be a given if the HEAT trial succeeds. Another factor to be aware of, Dr. Markey is being conservative by only assuming one treatment per patient based on an incidence model, and does not reflect that many patients will receive as many as 5 RFAs potentially through their course of treatment (more likely, between 2-3). So, again, while his target price is high, it is still a very realistic one. I thank Keith again for allowing me to post his note here for my blog viewers.
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<br />
I am excited, and looking forward to Monday's Q3 conference call and the Lazard Conference presentation as well. As mentioned, I will be updating<a href="http://celsion.blogspot.com/2012/10/questions-for-celsion-management-during.html" target="_blank"> my list of questions for management ahead of the Monday call</a> as well.<br />
<br />
Best,<br />
Siavoche<br />
#15vs25<br />
<br />Magicsiahttp://www.blogger.com/profile/06200209295387415335noreply@blogger.com4tag:blogger.com,1999:blog-5201890067787605901.post-50475016387424283222012-10-24T19:43:00.000-07:002012-10-24T19:49:47.290-07:00Guest Author Post: Celsion and the Risks of Clinical Trials- By Phil Kobierowski (@philkobi) Several weeks ago, <a href="http://celsion.blogspot.com/2012/09/invitation-for-guest-authors-regarding.html" target="_blank">I invited viewers of my blog/twitter-verse to submit articles</a> representing "rational bear views" for Celsion. Some have questioned why I am doing this, and the answer is very simple and straight-forward. From my <a href="http://celsion.blogspot.com/2011/07/welcome-quick-intro.html" target="_blank">very first blog post</a>, I made clear that this would be a forum to provide investors with as much information as possible regarding Celsion, and to share with you resources/research that have guided my own investment rationale. I have never been one to shy away from potential bear views, and have used them, in fact, to help with my own due diligence. Why have I historically brought up concerns over PFS as the endpoint in the HEAT study, intrahepatic distant spread vs local progression, competition with TACE, etc? These were entirely guided by me second guessing my own views of ThermoDox and the HEAT study, and because of it frankly, I think it has given me an even greater confidence and comfort in my investment rationale (see my <a href="http://celsion.blogspot.com/2012/06/celsion-bulls-and-bears-balancing.html" target="_blank">bulls/bears article</a> for more on this). Separate from the above, I am also thankful for the many tweets/feedback I have received regarding my blog, including from the likes of Adam Feuerstein (and Celsion management for that matter), for being an "informative" site, and in some cases, <i>the</i> site to look at for Celsion. That is truly humbling and means the most to me, primarily because I never envisioned this blog to be a tool for "pumping", never, EVER, despite my own personal, long bias. To that end, an "informative" site needs to convey all angles, and while I have made every effort on my part to do that, I wanted to open the doors for you to express your opinions as well using this blog as a platform to reach other Celsion investors/stakeholders. Transparency and objectivity mean everything in biotech investing, literally, so this is an exercise I am proud of doing.<br />
<br />
Sorry for the long introduction, I'll jump straight into my first guest author blog post from Phil Kobierowski (@philkobi on twitter). I don't know Phil personally, but have exchanged several tweets with him over the last several months. It did not take long for me to realize that he is both an intelligent and very respectful guy, and I am pleased to share with you his "bear views" on Celsion. Note, his disclosure is listed at the bottom of the post.<br />
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<div style="text-align: center;">
<b style="background-color: white;"><span style="color: #cc0000; font-size: large;">Celsion and the Risks of Clinical Trials</span></b></div>
<span style="background-color: white;"><span style="color: #cc0000; font-size: large;">By: Phil Kobierowski, <a href="https://twitter.com/PhilKobi" target="_blank">@philkobi</a> (celsion.blogspot.com guest author)</span></span><br />
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As we near the results of the pivotal, long-awaited, Phase III
"HEAT" clinical trial for Celsion Corp’s ThermoDox, optimistic
investors might want to take a step back and consider why they are holding shares
of Celsion (CLSN) and evaluate the potential risks associated with clinical
trials. <br />
<br />
<o:p></o:p></div>
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The HEAT trial is Celsion’s double-blinded, placebo
controlled Phase III trial for the treatment of primary liver cancer, or hepatocellular
carcinoma (HCC). Here are <b><u>five reasons</u></b>
that would dampen my enthusiasm regarding the upcoming HEAT trial results that
are expected to be announced around December 2012:</div>
<ol>
<li>The first item worth noting is that I should have been
writing this almost two years ago. What
that means is that Celsion management has been notorious in missing their
forecasted milestones.<br /><br />The HEAT trial seemed to start well. On <a href="http://investor.celsion.com/releasedetail.cfm?ReleaseID=336556" target="_blank">a press release</a><b> </b>issued September 24, 2008 "Celsion reports that site initiation and
patient enrollment are tracking well against its most recent projections." This led to their <a href="http://investor.celsion.com/releasedetail.cfm?ReleaseID=469443" target="_blank">forecast</a><b> </b>19 months later in May 13, 2010 that predicted the trial ending a year and a
half before Celsion’s current December 2012 forecast: "Celsion expects the
study could be completed by the middle of 2011, and pending positive data, a
New Drug Application would be submitted to the FDA before the end of
2011". <a href="http://investor.celsion.com/releasedetail.cfm?ReleaseID=410326" target="_blank">September 21, 2009</a>, is another example of HEAT trial delays, this time regarding patient enrollment
completion: "We expect to complete enrollment in the spring of 2010." Then, in an August 24, 2010 <a href="http://investor.celsion.com/releasedetail.cfm?ReleaseID=501947" target="_blank">press release</a>,
we see Celsion’s expected enrollment completion pushed-back over half a year:
"With nearly 70% of patients enrolled in the trial, Celsion is targeting
to complete patient enrollment by year end 2010." When did full enrollment finally happen? July 2011 for the <i>initial</i> target enrollment of 600, and May 2012 year for the full target
of 700.<br /><br />Granted, if the HEAT results are solid, these delays are a
moot point. Delays in clinical trial
completion are not rare and certainly not proof of problems with the
trial. Nonetheless, if Celsion
management has significantly missed their forecasting of how the HEAT trial
would progress, what other parts of the trial might they be missing or will be
a surprise to investors? For example, is
the control arm of the trial significantly exceeding Celsion’s expectations
when compared to the ThermoDox arm?</li>
<li>The noticeably low market cap of Celsion has long been a
mystery, for me at least. Despite the share price tripling from June to
September of this year (followed by the recent pullback), the current $145
market cap is paltry for a company with a promising, late-stage product that is
a potential first-line standard of care treatment for a major cancer.<br /><br />Is this a hidden opportunity, or is there a hidden,
unpublicized reason for this? Has the
aforementioned timeline delay in the HEAT trial’s completion caused a lack of
credibility with, or lack of interest from, investors? After so many years of developing ThermoDox,
medical conference and Wall St road show presentations, etc, it's hard to think
that the low market cap is due to the market being really unaware of Celsion. So what is the reason? The voice in my head (one of them at least)
brings to mind to adage: “if you don't know who is being set-up as the dupe at
the poker game, then it's you”. I’m just
sayin’…</li>
<li>There is a shortage of evidence supporting the efficacy of
ThermoDox. Celsion's Phase I clinical trial
for ThermoDox in liver cancer showed very promising results, no doubt, with a
very compelling dose-response correlation. But with only 7 of the 20 patients enrolled in
the entire trial (plus 4 who were censored from results) who were diagnosed
with HCC (the HEAT trial indication), and with the lack of a Phase II trial
because Celsion moved from their Phase I right to the Phase III HEAT, well, … you
get the point.<br /><br />Some could argue that Celsion’s <a href="http://investor.celsion.com/releasedetail.cfm?ReleaseID=710275" target="_blank">recently released</a> DIGNITY Phase I trial results (using ThermoDox for the treatment of recurrent
chest wall breast cancer – another of several indications being considered for ThermoDox)
looked encouraging, and therefore, would be reconfirming of ThermoDox’s’s
potential. But, there is really no way
to compare the results of the small, 11 patient group in the DIGNITY trial - who
were all previously treated with harsh chemotherapy and/or radiation treatments
- to those in the 700 patient HEAT trial where ThermoDox is a front-line, induction
therapy. Further, the trials are
conducted on completely different indications and are evaluated by very
different endpoints. It is just 2 totally
different situations.</li>
<li>The HEAT trial is
only 80% powered for its endpoint of a 33% improvement in progression free
survival (PFS) over the control arm. This
means that even if ThermoDox could produce such a 33% PFS improvement if used as
a global standard of care, and the HEAT clinical trial procedures, protocols,
etc, have no glitches; there is still a 20% chance that the HEAT trial is not
powered sufficiently to demonstrate that its primary endpoint is met.<br /><br />Granted, if ThermoDox’s actually efficacy far exceeds this 33%
PFS improvement (as it very well may) then the powering of the trial becomes
less of an issue. But, there is still an
unavoidable element of random luck involved and the potential of a steep drop
in share price if things don’t work out.<br /><br />Further, the HEAT trial is being conducted in 79 different,
globally located, clinical sites, of which only nine are in the United States. The administration of radio frequency
ablation (RFA) is a key component in both the ThermoDox arm and the control arm
in all the study sites of the HEAT trial. (Both arms use RFA to burn cancer tumors, the
heat of which triggers the injected ThermoDox – which is technically a
temperature sensitive liposome that encapsulates doxorubicin – a common
chemotherapeutic agent, to release its chemotherapeutic payload at the tumor
site.) The effectiveness of RFA may
significantly be determined by the skill and practice of the individual
interventional radiologist performing the RFA in the HEAT trial, who are located in,
and have been trained, from all parts of the globe. Considering this, and that ThermoDox may have
little effect on any cancer cells located away from the ablated tumor(s), it
becomes evident that there are many elements that will affect the results of
the HEAT trial, perhaps negatively, that have nothing to do with ThermoDox.</li>
<li>Will the unique
requirements for administering ThermoDox restrict its adoption? ThermoDox is not a cure, but only a treatment
that hopes to post-pone the recurrence of cancer by several months longer than current
treatments (such as RFA alone). As
mentioned above, ThermoDox is administered in conjunction with a heat source;
RFA in the case of the HEAT trail.
ThermoDox is injected intravenously (IV), then 30 minutes after the IV,
the RFA procedure must be initiated. Any
period outside this 30 minute window reduces the optimal pharmacokinetics, and
thus the effectiveness, of ThermoDox.<br /><br />One under-publicized concern is the extra logistical effort required
coordinate this: two different procedures, conducted at two different locations
by two different staffs at a hospital or oncology center. All within a very tight timeframe. The <a href="http://celsion.com/files/BreastCancerRecurrence_v2-final-09-24-2012.pdf" target="_blank">poster presentation</a> of the aforementioned DIGNITY trial acknowledges this challenge with ThermoDox:
"CHALLENGES - Infusion of
cytotoxic agent in chemotherapy suite followed by transfer to radiologic
oncology to administer hyperthermia." Such a challenge is seemingly manageable in a
clinical trial setting where there are just a few patients and where it is
possible to get simultaneous coordination from all needed medical staffs. But how
will this translate as a standard of care, where care centers are large, understaffed,
and unexpected delays are the norm? </li>
</ol>
</div>
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For the sake of Celsion, its investors, and most importantly for the benefit of the tens of thousands of patients that could benefit from such a potentially beneficial treatment as ThermoDox, we should all hope for positive data results from the HEAT trial. And I acknowledge there are many reasons (that I have not discussed here) to believe that it may. But that should not preclude each investor from objectively assessing the risks inherent to any investment.<br />
<i><b><br />Disclosure: I am a long-term Celsion shareholder with no plans to initiate a net short position.</b></i></div>
Magicsiahttp://www.blogger.com/profile/06200209295387415335noreply@blogger.com30tag:blogger.com,1999:blog-5201890067787605901.post-40493689687278200332012-10-18T16:42:00.003-07:002012-11-11T12:13:43.931-08:00Questions for Celsion Management During Upcoming Q3 CC<b><span style="color: red;">[NOTE: LIST WILL BE UPDATED AS CC APPROACHES]</span></b> As per usual, I have a laundry list of questions for Celsion management during the upcoming conference call (likely mid-Nov, tbd for now). Especially since this will likely be the last time we hear management until the much anticipated top-line results from the HEAT study are announced, I pulled out all the stops in terms of questions for the company. Many of these are very "forward-looking" if you will, and are only relevant if ThermoDox succeeds (who cares if patients were treated on an outpatient basis versus inpatient if the study fails, right?), at the same time, these are geared towards getting investors thinking about the challenges that may come down the road from a competitive/marketing perspective assuming ThermoDox passes this <i><b>critical</b></i> upcoming test.<br />
<ol>
<li><strike><span style="color: #cccccc;">Has 380 PFS events been confirmed, triggering data analysis?</span></strike></li>
<ul>
<li><strike><span style="color: #cccccc;">Can we still expect DATA by end of the year?</span></strike></li>
</ul>
<li><span style="color: red;"><b>***</b>[NEWLY ADDED]</span> There is a clear consensus amongst journalists and analysts that a successful HEAT trial will immediately march the stock upwards to the $500M+ mkt cap range. Why do you think that despite being a late stage oncology company with a 1st line therapy for one of the largest unaddressed cancers, Wall Street places such a low valuation on the company? Does the company have any comments on this?</li>
<li>Without speculating about the treatment arm, how surprised would the company be, especially given <i><b>the firm and repeated stance of a 12 month estimate for the control arm</b></i>, if the control arm came in 50% greater than the 12 month estimate the company provided, or 18 months? Given that control arms of clinical trials can, <i>and often do</i>, outperform "historical controls", how likely is this in the HEAT study, particularly when the focus is around a procedure in RFA that is <u>highly</u> influenced by operator skill and experience?</li>
<ul>
<li>***We know that the HEAT trial sites are some of the best and most reputable sites in the world with significant experience with RFA. For this same reason, is it fair to say that a real possibility exists for the control arm to significantly outperform the 12 month PFS guidance the company has provided? If not, why?</li>
</ul>
<li>Can we assume that most HEAT patients are in the 3-5cm cohort? What proportion of patients roughly are in each cohort?</li>
<li>I read in an analyst report that 90% of patients in the HEAT trial are Child-Pugh A, can you confirm this? Clearly, there is a big difference in outcomes between A versus B patients.</li>
<li>Can you tell us how many RFA treatments a typical patient has received in the HEAT study, approximately? As you know, <i><u>every analyst</u> </i>covering the stock has assumed only 1 RFA treatment per patient, which we know with certainty fails to accurately reflect the number of RFA treatments patients receive throughout their overall HCC treatment.</li>
<li>On your RCW poster presented at ESMO, the company highlighted what I like to call a "logistical" challenge for getting the timing of ThermoDox aligned with hyperthermia treatment, specifically, <i>"infusion of cytotoxic agent in chemotherapy suite followed by transfer to radiologic oncology to administer hyperthermia."</i> How has this noted challenge played out in the HEAT study specifically, and how do you expect this to play out in the <i><b>real world</b></i>? What implications does this have for how the company educates and targets future customers?</li>
<li><span style="color: red;">[NEWLY ADDED]</span> The company clearly made some assumptions when designing the HEAT study, such as the hypothesized effect ThermoDox would have in reducing local and intrahepatic distant spread. What assumptions did the company make in terms of ThermoDox' ability to reduce intrahepatic distant spread, both within the same liver segment, and in other liver segments? As an aside, I personally expect ThermoDox to reduce at least 80% of "true" local progression, but struggle in assigning a number in terms of hypothesized reduction in intrahepatic distant spread. Again, and again as I have stated, this will make all the difference in the world in terms of yielding great results versus <i>spectacular</i> results when it comes to PFS in particular. </li>
<li>***Just to confirm, were most patients treated in an outpatient versus inpatient setting? Within outpatient treated patients, what was the distribution between physician offices versus hospital outpatient settings? What percentage of patients, if any, in the HEAT study required any sort of post-treatment observation?</li>
<li><span style="color: red; font-style: italic; font-weight: bold;">***</span><span style="color: red;">[NEWLY ADDED]</span><span style="color: red; font-style: italic; font-weight: bold;"> </span>Can you comment on the average number of RFA treatments (factoring in those who will need additional RFA for technical success within the first month as well as downstream post-progression RFA treatments) a typical patient has received in the HEAT study right up until they no longer are eligible for RFA? Some clarity on this would be greatly appreciated, as you know, most analysts are assuming one, single, treatment per patient, which from my understanding, grossly underestimates the number of RFAs a typical patient receives as part of their treatment for HCC. Perhaps even more importantly, this significantly underestimates the revenue estimates analysts are placing on ThermoDox. </li>
<li><span style="color: red;">[NEWLY ADDED]</span> It is a given that the ThermoDox arm, by definition, will have more adverse events than the RFA-only arm, as a function of the known side-effect profile of doxorubicin. Clearly given all the DMC reviews, these side-effects have been managed appropriately and are relatively minor. That being said, does the company expect any challenges/pushback from clinicians in the real-world with respect to managing side-effects for this population following RFA/ThermoDox?<span style="color: red;"> </span></li>
<li><span style="color: red; font-style: italic; font-weight: bold;">***</span><span style="color: red;">[NEWLY ADDED]</span> If the HEAT study comes close, but ultimately, fails to hit its PFS endpoint in January, would the company still make a case to seek approval? In that scenario, how important does the yet to be mature OS become?</li>
<li><b>***</b>Let's assume ThermoDox is on the market. If I am a physician about to treat a patient with a 7 cm lesion not amenable to transplantation or resection, tell me exactly why I should use RFA plus ThermoDox as opposed to doxorubicin eluting beads (DEB)-TACE followed by RFA alone?<i><b> What is the specific point of differentiation here?</b></i> (to answer my own question for starters, TACE is another cumbersome procedure)</li>
<li>What do you expect the bridging study in Japan to look like from a trial design perspective? The company said differences in "SOC" lead to the decision to halt enrollment. Well, what differences in SOC will be reflected in this new bridging study?</li>
<li>What would success in the HEAT study mean in terms of potential success in the ongoing ABLATE study? In that context, how does the local progression only primary endpoint in the ABLATE trial affect that trial's chances for success?</li>
<li>At the FUS foundation 3rd symposium, some data was presented around a novel thermosensitive liposome with some suggested improvements over Celsion's LTSL in terms of serum stability. Elsewhere, we have seen some data for a "HaT" liposome with apparently much greater serum stability than ThermoDox and improved release dynamics (more than happy to send you the papers). Granted, these products are several years away from clinical application, nowhere near ThermoDox, but how does the company view these newer thermosensitive liposomes? By the same token, do these products present opportunities for the company in terms of next steps for clinical development?</li>
</ol>
<div>
I intend to send all of these to management personally ahead of the call <span style="color: red;"><b>[Already sent earlier draft to management, resent updated list 11/11/2012]</b></span>. Again, many of these questions are simply not important for the task at hand: making sure ThermoDox hits its PFS endpoint. That is really all that matters here. But, nevertheless, I want these items to stay top of mind for investors/management. </div>
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<br /></div>
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Best,</div>
<div>
Siavoche</div>
Magicsiahttp://www.blogger.com/profile/06200209295387415335noreply@blogger.com5tag:blogger.com,1999:blog-5201890067787605901.post-89333837633546931242012-10-14T16:30:00.002-07:002012-10-14T17:23:01.007-07:00FUS Foundation 3rd Symposium Kicks Off: Relevant Highlights for Celsion Investors to NoteToday marks the official kick-off of the<a href="http://www.fusfoundation.org/Symposium-2012/focused-ultrasound-2012" target="_blank"> Focused Ultrasound Foundation's (FUS) 3rd international symposium taking place from October 14-17th</a>. The FUS foundation really has been the academic vehicle pushing for the adoption of high-intensity focused ultrasound, and its many applications, both in research and clinical settings. This is relevant for Celsion investors because as many of you know, HIFU truly represents the optimal heating modality with which to pair with temperature-sensitive liposomes such as Celsion's ThermoDox. Celsion has 3 ongoing HIFU clinical programs underway, the most advanced of which is the planned Phase II study examining Philips' Sonalleve MRI-HIFU with ThermoDox for the pain palliation of bone metastases. Other trials include an early stage pancreatic cancer study looking at HIFU and ThermoDox in collaboration with the University of Washington, and a study at Oxford University (currently pending IRB approval) in liver metastases using ultrasound-guided HIFU plus ThermoDox.<br />
<br />
The below program includes all the abstracts and poster sessions for the FUS symposium, and while the entire program is extremely interesting from the perspective of seeing HIFU's clinical utility mature across many indications, I would draw interested Celsion stakeholders to the following pages:<br />
<br />
<ul>
<li><i><span style="color: blue;">Page 54 - Differences in Intratumoral Distribution of Doxorubicin Releeased from Temperature-Sensitive Liposomes During Hyperthermia, Ablation and Combined Treatment:</span></i> Highlights the effect of different heating modalities on the release of doxorubicin from ThermoDox (presumably, though cannot confirm) using HIFU. Of interest for future clinical applications using ThermoDox is the finding that a combination of ablative and mild-hyperthermia are optimal to enhance drug delivery.</li>
<li><i><span style="color: blue;">Page 55 - Ultrasound-Triggered Release of Doxorubicin from Thermosensitive Liposomes Modified with Poly Copolymers for Cancer Therapy:</span></i> Demonstrates a next generation temperature sensitive liposome with a more responsive drug release profile than the comparator "temperature-sensitive liposome (TSL)" product, presumably ThermoDox. This is still very early stage, so from a competitive standpoint, it is not clear how this could affect ThermoDox.</li>
<li><i><span style="color: blue;">Page 85 - Phase II Trial Design of MRI-Guided High Intensity Focused Ultrasound and Lyso-thermosensitive Liposomal Doxorubicin for Palliation of Painful Bone Metastases: </span></i>This is not new, as I have talked about this before, but this will be a nice forum for Celsion to discuss their planned joint PII with Philips. The proof of concept of using MRI-HIFU for bone metastases in general was highlighted on Pages 80-82 (page 80 shows outcome of a multi-center PIII trial amongst patients for whom radiation therapy was contraindicated)</li>
<li><i><span style="color: blue;">Page 91 - HIFU Ablation for Hepatocellular Carcinoma: Updated Applications:</span></i> While this presentation does not address temperature sensitive liposomes in any direct manner, it is nevertheless important since it establishes the use of HIFU, along with HIFU in combination with TACE, for the treatment of HCC. <a href="http://celsion.blogspot.com/2012/03/hifu-for-bone-metastases-brief-overview.html" target="_blank">As I mentioned before</a>, it is important for HIFU to establish itself on its own two feet before future applications with ThermoDox begin to take off. The same type of proof was required for radiofrequency ablation for HCC, which is now considered a standard of care in its own right. This is a great step in that direction for the use of HIFU for HCC.</li>
<li><i><span style="color: blue;">Page 92 - Magnetic Resonance guided Focused Ultrasound (MRgFUS) Treatment of Primary Pancreatic and Hepatic Cancer: Preliminary Experience in Tumor Control: </span></i>Same as above, except this goes one step further and examines the use of HIFU for pancreatic cancer as well.</li>
<li><i><span style="color: blue;">Page 93 - MR-Guided Focused Ultrasound Induced Hyperthermia for Enhancing Drug Delivery in a Pancreatic Cancer Mouse Model: </span></i>Note that one of the authors of this study is Joo-Ha Hwang from the University of Washington, and Philips/FUS funded this work. I would venture to say this is directly related to the aforementioned pancreatic cancer HIFU study Celsion announced earlier this year. Using Philips' Sonalleve MRI-HIFU, the study demonstrated strong proof of concept for local drug release from ThermoDox (again, presumably) in a pancreatic cancer mouse model.</li>
<li><i><span style="color: blue;">Page 102 - MRI-HIFU Drug Paintbrush: Large Volume, Conformal Mild Hyperthermia with MRI-HIFU Used to Trigger and Monitor Release from Image-Able, Temperature-Sensitive Liposomes:</span></i> Clearly, this is my favorite potential application of ThermoDox, and it involves Celsion's next generation "4 lipid" version of ThermoDox in which an imaging agent would be combined with the drug to monitor in real-time, uptake of drug using MRI-HIFU. The study shows that lesions of variable shapes can be targeted with MRI-HIFU, and drug release from the "image-able" liposome can be well characterized. This application of ThermDox gets me most excited, I have to say.</li>
<li><i><span style="color: blue;">Page 104- Targeted Drug Delivery By Focused Ultrasound Mediated Hyperthermia Combined with Temperature Sensitive Liposomes: </span></i>Again, this is presumably speaking about ThermoDox, and this somewhat ties back to Page 54 from the above. Using a mathematical model, this study demonstrated that hyperthermia followed by ablative temperatures yielded much more drug from the liposome (40%) compared to mild hyperthermia alone. This has implications for future clinical applications to <i><u>optimize the delivery of hyperthermia</u></i> for use with ThermoDox. </li>
</ul>
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Again, there are a lot of other interesting pieces of data being presented this week pertaining to HIFU, and I only meant to highlight a select few. While my attention remains focused on the HEAT study, it is nevertheless encouraging to see Celsion's technology being used in various applications with HIFU. Let's see how the market reacts to any potential "buzz" coming out of the FUS Foundation 3rd Symposium.<br />
<br />
Best,<br />
Siavoche<br />
<br />Magicsiahttp://www.blogger.com/profile/06200209295387415335noreply@blogger.com0tag:blogger.com,1999:blog-5201890067787605901.post-60308943821893897882012-09-25T20:12:00.003-07:002012-09-25T22:06:39.339-07:00The Importance of the Phase II ABLATE Study for Understanding ThermoDox's Market PotentialLet me just make one quick point before I even begin discussing the Phase II ABLATE study for patients with colorectal liver metastases (CRLM): Celsion is banking everything on the Phase III HEAT study, so all of this goes out the window in the <i>(dare I say unlikely)</i> event that the HEAT study fails to hit its PFS endpoint. Rightly so, the focus should be on the HEAT study, and every investor should focus their attention on the impending Q4 PIII data coming out of it. I think its important to preface the article this way, as it should tell you how high the stakes really are for Celsion as we come down home stretch.<br />
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<div>
Now, on to the article.<br />
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Celsion <a href="http://investor.celsion.com/releasedetail.cfm?ReleaseID=648067" target="_blank">initiated the Phase II ABLATE</a> study in February, with <a href="http://celsion.blogspot.com/2012/03/interview-with-celsion-investigator-dr.html" target="_blank">Dr. Steven Libutti</a> as principal lead investigator. As of right now, I am not sure how many patients have been enrolled in the study, but we do know that management has made clear they have been deliberately slow in recruiting patients/expanding sites to conserve resources for in anticipation of a successful HEAT trial and commercial preparations. The study, randomized and double-blind in the same manner as the HEAT study, seeks to enroll up to 88 patients with colorectal metastases to the liver (CRLM). That said, this study does have some salient distinctions (<a href="http://clinicaltrials.gov/ct2/show/NCT01464593" target="_blank">clinicaltrials.gov link here</a>):<br />
<ol>
<li>The primary endpoint is local recurrence within 1 cm of the ablation site at 1 year (the <i><b>ideal</b></i> endpoint for ThermoDox)</li>
<li>The inclusion criteria allows for patients to have tumors as small as 2 cm. Some of you might recall I questioned the company on this decision on a prior conference call, since local recurrence from what I have read is not a significant problem in patients with lesions under 3 cm. Dr. Borys responded that physician input during the design phase of the study lead to this, as clinicians are still not satisfied with local recurrence outcomes in CRLM patients even for lesions as low as 2 cm, suggesting that the literature might over-estimate clinician ability to control smaller CRLM. Either way, the good news is that this means a larger patient pool to enroll from, and presumably, faster enrollment. </li>
</ol>
I have said it before and will say it again, initiation of this trial before HEAT results was a<i> very precocious move</i> by management for several reasons. <b>Firstly</b> and most importantly, it is an indirect signal of the confidence that management has in the ongoing HEAT study, since the effect ThermoDox will have in this setting is very similar to that in HCC (more to come on this below). <b>Secondly</b>, it leverages the experience the company has from the Phase I study, in which more than half had metastases to the liver rather than HCC (8 with CRLM). <b>Thirdly</b>, from a timing perspective, date from the ABLATE study is expected around the time ThermoDox hopefully receives FDA approval, so the medical community will have yet additional data supporting the product's broad potential in indications outside of HCC right when the product is expected to hit the marketplace.<br />
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I will boldly say that the analysts who have covered Celsion, with the exception of Keith Markey from Griffin, are significantly undervaluing the company by excluding the colorectal metastases indication<i><b> (yes, only Griffin has included off-label CRLM in their valuation of Celsion)</b></i>. I have characterized the off-label potential in CRLM before as an "inevitable reality" assuming the HEAT study shows success. So, why am I so excited over this market for Celsion?<br />
<ul>
<li><b><span style="color: blue;">Big market, VERY big market:</span> </b>Yes, the colorectal liver metastases population is a very large one, but one that needs to be carefully examined in order to identify real-world patients who would be candidates for ThermoDox. Let's start from the top looking at all colorectal cancer patients. In the US, the incidence is 141K cases, <a href="http://www.ejcancer.info/article/S0959-8049(09)00926-5/abstract" target="_blank">Europe 436K cases</a>, and 811K cases rest of world, so ~1.4M cases globally.<br /><br />
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<br />From that, we have to be very careful how we arrive at the number of patients who would be eligible for local treatment for liver metastases. As I have mentioned before, the key is to arrive at patients who have <i><u>confined</u></i> liver metastases. While a significant number of patients will eventually develop metastases to the liver (50-75% in total, 25% at diagnosis), local treatment will likely not be used to treat the liver if the disease has metastasized to other parts of the body. However, in total, we can confidently say that ~25-30% of patients will have confined liver mets (refer to the articles below).<br /><br />The next step is to squarely identify the proportion of these patients who would receive the gold standard treatment, surgery. Recent advances have allowed a solid ~25% of this population to be eligible for surgery to remove their hepatic tumors, leaving us with <b>~18-23%</b> eligible for some form of <i><u>non-surgical</u></i> treatment such as RFA, microwave ablation, cryoablation, etc.<br /> <iframe frameborder="0" height="120" scrolling="no" src="https://skydrive.live.com/embed?cid=D5139E805024FD7C&resid=D5139E805024FD7C%21229&authkey=APwCnssbmWsj9BU" width="98"></iframe>
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<br /> You can do the math on 18-23% of 1.4M global cases. Just looking at the US and EU, that is ~120K patients who <b><u>realistically</u></b> (not pie in the sky numbers) are eligible for RFA every year.<br /><br />As a point of comparison, looking at HCC <i>just in the US and EU</i>, there are ~65K patients, of which 25% are initially eligible for RFA (underestimates the true number of RFA patients though, since patients who undergo surgery very often undergo RFA at some point in their prognosis as well, but lets be conservative), leaving us with 15K eligible HCC patients. <i><b>As you can see, in the Western world, there are <u>8x more</u> (120K vs 15K) CRLM patients than HCC patients who are squarely candidates for RFA treatment.</b></i></li>
<li><b><span style="color: blue;">Unlike HCC, CRLM market is in geographies where Celsion is expected to have <i>greatest</i> pricing power for ThermoDox:</span></b> The focus above on the US and EU was done on purpose, again, mainly because these will be regions in which Celsion will have the most pricing power for ThermoDox. The population of HCC patients in China is significant, but pricing and reimbursement there is the wild card, whereas in the US and EU, this is relatively straightforward (assuming Celsion and their future partners can successfully navigate the health economic "exercises" necessary in the EU, up to $30K per administration would not be out of question depending on the strength of the data). From a commercial perspective, make no mistake that potential license partners are keenly aware of this "favorable" patient distribution reality in the CRLM indication.</li>
<li><b><span style="color: blue;">Should the HEAT trial show positive data, savvy investors will know immediately that the ABLATE study, too, will be poised for success:</span></b> I've alluded to this a few times before, but if ThermoDox can improve PFS in HCC (likely mainly be reducing local and <i>related</i> distant recurrence), you can be fairly certain ThermoDox will have similar activity in colorectal liver metastases. Actually, scratch that, you can be 99% certain that ThermoDox would hit its endpoint focused entirely on local progression in the CRLM population.<br /><br />From all the different papers I have seen and amassed on my blog, it is crystal clear to me that the approach and process for treatment of an HCC lesion versus a CRLM lesion are identical. In fact, many papers simply lump these two populations together for the purposes of determining local control using RFA. Of course, treatment of the originating colon cancer necessitates an entirely different approach, so again, I am only talking about the treatment of the liver tumor burden.</li>
<li><b><span style="color: blue;">Experience with 700 patient HEAT trial plus 88 patient ABLATE study will preclude the need for a registrational PIII CRLM trial:</span></b> My suspicion is that Celsion management has zero plans to conduct a registrational PIII CRLM trial, simply because the value-add of doing so would be minimal. As outlined above, treatment of localized CRLM and HCC via RFA are very similar. And successful completion of both the HEAT and ABLATE trials will mean 788 total liver cancer patients, treated in a robust, randomized and double-blind manner. The only other liver-focused trials we are likely to see will be those focused on other heating modalities (such as HIFU) or those eventually focused on the 4 lipid platform combined with an imaging agent, further down the road.</li>
<li><span style="color: blue;"><b>ABLATE trial is more than enough to drive inevitable off-label use (at least in the US):</b></span> In part related to the above point, it is obvious to all familiar with pharma and the US health care system that off-label use can be more than secured with PII data. In fact, 50-75% of <i><b>all</b></i> chemotherapy utilization is prescribed off-label. In addition to cancer-specific state mandates to cover off-label drugs which are present in most states, Medicare reimburses for off-label use if peer-reviewed data supports its use (inevitable for positive ABLATE data by itself, specific journals are listed in the JOP article below) <b><u>or</u></b> as long as the drug is listed in one of four compendia:</li>
</ul>
<ol>
<li>The American Hospital Formulary Service – Drug Information (AHFS-DI) </li>
<li>Elsevier Gold Standard’s Clinical Pharmacology </li>
<li>The National Comprehensive Cancer Networks’ Drug Information & Biologics Compendium NCCN </li>
<li>Thomson Micromedex’s DrugDex<br /><br />Granted, it is not automatic that a drug gets compendia listing, but I think it is very safe to say the trial design of the ABLATE study will quickly translate into compendia listing, assuming positive data of course. See the below references, the one from <i>Formulary</i> is a great read on this topic.</li>
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<ul>
<li><span style="color: blue;"><b>Same physician targets as for HCC, interventional radiologists:</b></span> This may be one of the most important reasons why off-label use in CRLM will be inevitable for ThermoDox. Aside from the fact that an RFA treatment session is nearly identical for an HCC and CRLM patient, remember, we are dealing with the exact same physician target audience: interventional radiologists. So, while the referral source of patients are likely to be different (hepatologists versus gastroenterologists), the same interventional radiologist will be conducting the RFA and injecting the ThermoDox. So, this is not like other drugs where off-label use is being driven by an entirely different prescribing physician base. From the perspective of "marketing" and physician education, you can see how straight-forward this will be for Celsion, especially given all of the above. </li>
</ul>
</div>
<div>
Again, investors' focus should be on the HEAT study, but I maintain that this small 88 patient trial in CRLM patients will go a very long way for Celsion valuation. You can bet the company will significantly ramp enrollment in the trial once positive HEAT data is collected, and a robust CRLM data set along with positive HEAT data gives potential big pharma the best of both worlds: A vast HCC market in emerging market China, and an <i><b>equal number</b></i> of off-label patient candidates between the US and EU. Like I said, the stakes are very high with the impending HEAT data.<br />
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Best,<br />
Siavoche</div>
Magicsiahttp://www.blogger.com/profile/06200209295387415335noreply@blogger.com0tag:blogger.com,1999:blog-5201890067787605901.post-6196416557561679402012-09-21T16:52:00.000-07:002012-09-21T16:52:08.943-07:00Invitation for Guest Authors Regarding Celsion, Seeking Rational Bear ViewsFor those of you who follow me on twitter (@magicsia), you may have seen earlier today the following tweets:<br />
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<a href="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEg6gLIiF6tx0z5hPIWk3a17xVjUogpAhoIgchOqB3Y-upcYQ1PQG7m6f_NQVyvLps6B9bKjcgM0aoegdXkTKZzskYjytu7AQTdc98aRpm2qwMGWQwZ8vdjXfK44grj-tdHhxROaR7S0S0-5/s1600/Tweets.bmp" imageanchor="1" style="margin-left: 1em; margin-right: 1em;"><img border="0" height="325" src="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEg6gLIiF6tx0z5hPIWk3a17xVjUogpAhoIgchOqB3Y-upcYQ1PQG7m6f_NQVyvLps6B9bKjcgM0aoegdXkTKZzskYjytu7AQTdc98aRpm2qwMGWQwZ8vdjXfK44grj-tdHhxROaR7S0S0-5/s400/Tweets.bmp" width="400" /></a></div>
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I meant every word in this series of tweets, and I would like to formally "open up" my blog to those of you who would like to "guest author" thoughts or ideas around Celsion. I am not necessarily seeking "positive" articles on Celsion, to the contrary, I want my blog to serve as a forum to communicate <i><b>well-articulated, researched, and thought-provoking "bearish" views on Celsion</b></i>. No name calling or ad hominem attacks, but rather, rational views on ThermoDox, the HEAT study, or anything else Celsion-related. Perhaps you want to reference articles listed on the blog as well, that would be all the more better.<br />
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As you have seen before, I have laid out <a href="http://celsion.blogspot.com/2012/06/celsion-bulls-and-bears-balancing.html" target="_blank">bull and bear views</a> on the company several different times, and have reminded you that my DD is guided by trying to prove myself wrong. Hence, the bear view is always on my mind.<br />
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The blog has continued to attract new visitors and interested stakeholders in the company, and for that, I thank you. If this site will continue to be a source of DD for new investors, then I have an obligation make sure both sides are heard as loudly and clearly as possible. And for that, the doors are open to you. Please either tweet me, email me or reply on a comment below if you would like to guest author a post. This won't be the wild west, so there will be a quick editorial "process", if you will. Hopefully, between now and final HEAT data, we can have a couple "bear" views posted for myself, and viewers, to react to. <i><b>I encourage it, and I envision forwarding such views on to management for their reaction as well. </b></i><br />
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As always, let me know your thoughts, have a great weekend.<br />
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Best,<br />
SiavocheMagicsiahttp://www.blogger.com/profile/06200209295387415335noreply@blogger.com0tag:blogger.com,1999:blog-5201890067787605901.post-8333320038666518362012-09-14T07:10:00.002-07:002012-09-14T07:10:56.342-07:00Final HEAT DMC Meeting Results in Expected Unanimous Recommendation to Continue, 380 PFS Still Projected for Q4This morning, investors woke up to a highly <a href="http://finance.yahoo.com/news/celsion-announces-independent-data-monitoring-120000315.html" target="_blank">anticipated press release</a> from Celsion in regards to the outcome of their regularly planned, independent Data Monitoring Committee (DMC) routine safety review for patients in the HEAT study. This was one of 7 (maybe 8, I lost count to be honest) such reviews conducted by the DMC throughout the duration of the trial, so what made <i>this one</i> so important? Management has mentioned in prior calls that they would update the investor community if the timing for 380 PFS events, originally estimated for "Q4" with data to follow (also in Q4) changed significantly following this DMC review.<br />
<br />
So, what did we get in the press release?<br />
<br />
<b><i>"Celsion reconfirmed that 380 PFS events are projected to occur in the fourth quarter of 2012, with top line results announced following DMC review and confirmation."</i></b><div>
<b><i><br /></i></b></div>
<div>
<b>Couple things to note about this wording from the PR:</b></div>
<div>
<ol>
<li>The guidance has <i>NOT</i> changed, this is the same thing we have heard for some time now. I take that as being status quo. Celsion CEO has stated numerous times that the company's "best guess" for top-line data is in Q4, so my assumption is they are expecting 380 PFS to be confirmed early to mid Q4, just enough time for the 8-12 week process of compiling and tabulating the data.</li>
<li>Some might suggest the wording "opens the door" for data to bleed into 2013. It certainly IS possible, especially if 380 PFS is not confirmed until late December, as an example. </li>
</ol>
<div>
Beyond this DMC PR, I know many (voiced loudly by many I interact with on twitter) WILL want to know exactly when 380 PFS is eventually confirmed in Q4. Perhaps this will be something the company speaks to during the Q3 quarterly call (likely in early November) and reiterates in upcoming SEC filings. Not for myself (still long my original shares, holding thru data, makes no difference to me), but for the sake of traders who want to plan and execute their trading strategies leading up to final data, I also do hope the company gives some more clarity on when the 380 has been confirmed. Not to worry, all of this really is a "timing" game. Worst case scenario, 380 PFS occurs on New Year's eve, and we get data in February.</div>
<div>
</div>
<div>
The outcome of the HEAT study looms, and as Adam Feuerstein points out today in <a href="http://www.thestreet.com/story/11700415/1/biotech-stock-mailbag-navidea-celsion-raptor-and-threshold.html?puc=yahoo&cm_ven=YAHOO" target="_blank">his latest mailbag</a>, Celsion is either "uncared" for or "unknown" to Wall Street. As I have said before (one of several reasons Celsion was attractive to me in the first place), I suspect the latter, but we will ultimately have to wait for final data to make that determination. </div>
<div>
<br /></div>
<div>
Best,<br />Siavoche</div>
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Magicsiahttp://www.blogger.com/profile/06200209295387415335noreply@blogger.com4tag:blogger.com,1999:blog-5201890067787605901.post-56320760421422844282012-08-16T20:49:00.001-07:002012-08-18T11:33:41.456-07:00Celsion Energizes Investor Community with Q2 Update, Griffin Securities Raises Price Target to $18Well, here we are again with the stock back to near $4. I think it is safe to say the Q2 quarterly call was one of the best calls the company has hosted to date, with management providing a clear and enthusiastic update to investors. Many of the questions I submitted were also incorporated into the company's prepared remarks (thank you management). At a high-level, here were the takeaways:<br />
<ul>
<li>Reiteration that 380 PFS events are projected in Q4, with data to follow. The company continues to use 380 PFS and final data interchangeably, nevertheless, I personally expect <u>DATA</u> by the end of 2012.</li>
<li>DMC is meeting mid-September, at which point, they will provide an update to management regarding confirmed PFS and OS events. If the timeline for 380 PFS events changes following this, the company will let the investment community know. My guess is that we will get an update on events in the PR the company will issue after the DMC outcome. </li>
<li>Twice, <i>and firmly</i>, the company said they have no plans for equity financing before final HEAT data. This was significant given the recent <a href="http://investor.celsion.com/secfiling.cfm?filingID=1437749-12-8319&CIK=749647" target="_blank">$75M shelf</a> filed that got investors nervous. The company added that the timing of the shelf was done to avoid potential review by the SEC if done near the time of final data. I know we have to take company comments with a grain of salt, but I absolutely did get the sense that they truly have zero plans to do a raise pre-data.</li>
<li>Company alluded to additional partnerships for conducting clinical research with HIFU. Outside of Philips, the other big name in this space is Israel-based Insightec (20% owned by GE). </li>
<li>Assuming positive data, NDA in the US and MAA for Europe are expected to be filed around the same time (my guess, by May/June of next year)</li>
<li>Celsion CEO reiterated that outcomes data for the population being studied in the HEAT study have remained the same, again reiterating an expectation for a 12 month PFS median in the control arm, and median OS of 30 months. (My personal guess is that the HEAT control arm will come in at ~16 months median PFS)</li>
<li>Company does not anticipate being in competition with Nexavar, even if STORM trial shows positive data as an adjuvant therapy</li>
<li>When data is presented (from analyst question, seemingly taken right off of my list of questions!), company will present PFS data for sure, but other data (such as complete ablation rates, local/distant recurrence, etc.) is likely to be preserved for publication. OS trends may be highlighted in the final data PR as well. </li>
<li>Celsion CEO noted that a key Chinese KOL in ablative techniques will be updating her publication to include data from the HEAT study. Per the CEO, this individual is a global authority on RFA. </li>
</ul>
<div>
There was a lot more, but these are the highlights that come to mind. I absolutely recommend anybody with an interest in the company to listen to this call, and I have embedded it here for your convenience:</div>
<iframe frameborder="0" height="120" scrolling="no" src="https://skydrive.live.com/embed?cid=D5139E805024FD7C&resid=D5139E805024FD7C%21946&authkey=AGrDFw5FhbLlw64" width="98"></iframe>
<br />
<div>
Outside of the conference call, today, the investment community woke up to a boosted price target from Griffin Securities analyst Keith Markey. The upgrade from a $10 target to $18 seemed to open a lot of eyes. From the second I heard of this in the morning, I suspected the primary change in the valuation was pricing, and indeed, Keith assumed a $20K per patient per year for the US, up from $9K <i><b>(Keith kindly sent me the report, thank you Keith)</b></i>. The RCW indication was removed entirely, but colorectal liver mets revenue from off-label use is assumed. Outside of the $20K price per patient per year assumed for China (I think pricing in China will be no more than half of what it is in the US to be honest), his assumptions (share capture, etc.) are quite conservative.<br />
<br />
Moreover, I confirmed with him via email that he is only assuming 1 RFA per patient per year, which itself is a conservative number. Why? At a minimum, I can almost guarantee that roughly 15% of patients will require a second ablation within the first month to achieve a "complete" ablation, or technical success. Also, if ThermoDox is working as good as I suspect it is, patients hopefully won't require another RFA until progression well beyond 1 year, but still, some patients will recur within the first year and remain eligible for RFA. Thus, for modeling purposes, taken together, I would assume 1.5 RFAs per patient per year. That said, it certainly does not hurt to err on the side of conservatism. </div>
<div>
<br />
See below for a link to the report (again, thank you Keith):<br />
<iframe frameborder="0" height="120" scrolling="no" src="https://skydrive.live.com/embed?cid=D5139E805024FD7C&resid=D5139E805024FD7C%21945&authkey=AB15QwrLbliaF9A" width="98"></iframe>
<br />
With September right around the corner, and Q4 looming, we approach the outcome of the HEAT study, something I have personally looked forward to for a very, very long time (and, having come across a <a href="https://skydrive.live.com/redir?resid=D5139E805024FD7C!934" target="_blank">recent report by Dr. Lencioni</a> highlighting that distant recurrences occurring within the first 2 years may be more closely related to the original lesion than I originally suspected, I am now even more confident in a positive trial outcome). Bull or bear, place your "bets", this binary event is well within reach now.<br />
<br />
Best,<br />
Siavoche</div>
Magicsiahttp://www.blogger.com/profile/06200209295387415335noreply@blogger.com0tag:blogger.com,1999:blog-5201890067787605901.post-6137076940502622022012-08-09T14:20:00.001-07:002012-08-09T14:20:33.598-07:00Upcoming Q2 Conference Call: Questions for Celsion Management<br />
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As we near the <a href="http://investor.celsion.com/releasedetail.cfm?ReleaseID=698228" target="_blank">Q2 conference call next week</a>, in what has become a
ritual it seems, I have devised some questions to relay to Celsion management
ahead of the call, both for them to address during their prepared remarks, or for shareholders to follow-up
on during the Q&A session. It is worth mentioning again that Celsion management, coming from the CEO directly, has<i> invited</i> such questions ahead of conference calls. As I also mentioned before, I maintain frequent communication with other
Celsion shareholders who I deeply respect, and the questions below represent our
collective thoughts<i><b> (thank you fellow shareholders, you know who you are)</b></i>:<o:p></o:p></div>
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<ul>
<li>With Q4 right around the corner, and event rate projections
relatively clear at this point, can the company still confirm DATA, not 380 PFS
events, will be due by end of 2012?</li>
<li>Although it has been asked before, it <i>still </i>bears asking
again: have any new studies or data come up that make you question the
historical guidance for 11-12 months median PFS for the RFA-only arm?</li>
<li>What level of detail can we expect in terms of data when
top-line results are finally revealed? In addition to median PFS times and
hazard ratios for the whole trial, can we expect:</li>
<ul>
<li>Average tumor size for the trial?</li>
<li>Complete ablation rates for both arms?</li>
<li>Rates of local versus distant recurrence <i>(MOST interesting
for me personally)</i>?</li>
<li>OS events and trends to date?</li>
<li>Side effects/Adverse events?</li>
<li>Break-out of data for 3-5 versus 5-7 cm groups?</li>
</ul>
<li>Is the next DMC meeting still scheduled for mid-September?</li>
<ul>
<li>Is it the company’s expectation that 380+ confirmed PFS
events will have been reached by the time this meeting occurs?</li>
</ul>
<li>I have asked before about the average lesion size in the
HEAT study, and I know the company did not want to yet report this data. Can
you at the least give us a sense for the % proportion of patients in the 3-5
cohort versus 5-7 cohort? Is it safe to say the vast majority are in the 3-5
group, or are they evenly split?</li>
<li>What timeline can the company provide for when the full 372+
OS data would be made available?</li>
<li>Do you believe Yakult will be able to work on a new Japanese
trial with the data available from top-line?
Or will they need to wait until all (including greater-matured OS) data
is available?</li>
<li>Ongoing Phase II colorectal liver metastases ABLATE
study: Can the company report current
enrollment in this trial (and number treated, if different)?</li>
<li>The company will eventually have 3 ongoing HIFU studies with
ThermoDox, one in Pancreatic cancer at University of Washington, one for liver
metastases at Oxford, and the PII w/Philips for bone metastases.</li>
<ul>
<li>Pancreatic HIFU trial: As I understood from the press
release, this will start with preclinical work in animal models, not human
patients. Can you provide additional color on the types of questions that will
be explored during these studies? Is it possible that future trials in humans
involve ThermoDox plus other agents, such as gemcitabine?</li>
<li>Liver metastases HIFU trial: What phase study will this be,
how many patients, will this look at metastases from any primary site or
specified sites (colorectal, melanoma, etc.), expected timeline for completion
and what primary endpoint? Will this have the same primary/secondary endpoints
as the ongoing ABLATE study in CRLM?</li>
</ul>
<li>Have there been any updates from potential licensing
partners? Is the company still leaning towards keeping rights to the US market?</li>
<li>Does the company have any updated views on potential pricing
of ThermoDox®?</li>
<li>Does the company expect cash burn to increase following
top-line data due to NDA preparation?</li>
<li>Will an MAA in Europe be pursued concurrently to the NDA in
the US, or after the NDA?</li>
<li>As the company is likely well aware, obtaining European
marketing authorization is one thing, but reimbursement is a local, country by
country game. A common theme throughout Europe is having health economic data
to support reimbursement. Has the company proactively thought about/started developing such data for ThermoDox®?</li>
<li>I have assumed that upon NDA submission and acceptance, a
priority review of 6 months is essentially guaranteed from the FDA as a
function of fast-track status. Can the company confirm that this is the case?</li>
<li>Per Onyx’ recent conference call, it appears data from the
adjuvant Nexavar trial following resection or ablation won’t be available until
2014. What competitive threat does the company perceive from early line use of
Nexavar in the adjuvant setting?</li>
</ul>
<div>
I look forward to what should be a very interesting call, as there have been new developments on a couple fronts (Philips HIFU PII, RCW abstract acceptance at ESMO, etc.), and I expect we will get some more color on the HEAT study. As a reminder, it is scheduled for this coming Tuesday, the 14th, at 11AM ET/8AM PT. </div>
<div>
<br /></div>
<div>
Best,<br />
Siavoche</div>
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</div>Magicsiahttp://www.blogger.com/profile/06200209295387415335noreply@blogger.com0tag:blogger.com,1999:blog-5201890067787605901.post-84274250043536417342012-06-21T12:46:00.002-07:002012-06-30T14:14:47.074-07:00Celsion Bulls and Bears: Balancing Investor Views Heading into Final HEAT DataThere appears to be a resurgence of interest in Celsion at the moment. Perhaps some new investors have stumbled upon my blog as of late, learning about Celsion via the recently conducted <a href="https://skydrive.live.com/#cid=D5139E805024FD7C&id=D5139E805024FD7C%21874" target="_blank">interview CEO Michael Tardugno had with Reuters</a> or after reading <a href="http://www.celsion.com/letter.cfm" target="_blank">the newly released CEO letter</a> on the corporate website.<br />
<table align="center" cellpadding="0" cellspacing="0" class="tr-caption-container" style="margin-left: auto; margin-right: auto; text-align: center;"><tbody>
<tr><td style="text-align: center;"><a href="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEj4mY_YxX14JmHQaNqTdC9LyBBoSjFF8B0GmSMqSoSx6m7_-uIpKDV_Jfokzvt4fFMMTmOyZLQyNUgXjMr2DTRxDVOkn1iHNUkzFNxoTGWIkR-eqZuRzkjmzwtd3iDpRjELJyf8ZHs8bLw8/s1600/CLSN+June+2012.jpg" imageanchor="1" style="margin-left: auto; margin-right: auto;"><img border="0" height="215" src="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEj4mY_YxX14JmHQaNqTdC9LyBBoSjFF8B0GmSMqSoSx6m7_-uIpKDV_Jfokzvt4fFMMTmOyZLQyNUgXjMr2DTRxDVOkn1iHNUkzFNxoTGWIkR-eqZuRzkjmzwtd3iDpRjELJyf8ZHs8bLw8/s400/CLSN+June+2012.jpg" width="400" /></a></td></tr>
<tr><td class="tr-caption" style="text-align: center;">Celsion- June 2012</td></tr>
</tbody></table>
<span style="background-color: white;">As I have said in my very first blog post and reiterated during subsequent posts/tweets, I am very optimistic and confident in the potential of ThermoDox®, and this is what shaped my initial investment in Celsion. That being the case, I would caution any investor who simply seeks out data/opinions reinforcing their own personal opinions, and this is even more important in pharma/biotech investing. Thus, my approach has been to challenge my investment thesis from day one, “prove myself wrong”, if you will, and this has given rise to a solid appreciation for some of the “bearish” views that some might have on Celsion.</span><br />
<br />
Rather than a high-level bulls/bears piece, I thought I would get very specific, and look at this from multiple perspectives. Again, arming investors with as much information as possible has been the intent from day one with my blog. With that said, the table below summarizes this assessment:<br />
<div>
<br /></div>
<div>
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<b><span style="color: white; font-size: large;">"Bullish Views"<o:p></o:p></span></b></div>
</td>
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<b><span style="color: white;"><span style="font-size: large;">"Bearish Views"</span><o:p></o:p></span></b></div>
</td>
</tr>
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<div style="text-align: center;">
<b><span style="line-height: 115%;"><span style="color: blue;">General</span><o:p></o:p></span></b></div>
</div>
Very low market cap for a late-stage Phase III oncology company, "dirt cheap". <br />
<br />
Sufficient cash on hand until mid-2013, reiterated multiple times by the company. Low burn rate of $5M/quarter. <br />
<br />
Very low/negligible debt<br />
<br />
Analyst targets several multiples of current price <br />
<a href="https://skydrive.live.com/redir?resid=D5139E805024FD7C!875&authkey=!AORPOMNYj3rE5u4" target="_blank">(click here for a comparative review of Griffin Securities, Rodman & Renshaw, Brean Murray and Roth Capital analyst reports)</a><br />
<br />
Recent large investment stake by Orbimed Advisors<br />
<br />
Steady and consistent insider buying, not a single insider sale.<br />
<br />
Positive HEAT trial outcome should fetch anywhere from 250M-600M (in my humble opinion) market cap valuation<br />
<br />
Apparent sentiment shift post-ASCO, reflected in recent strength in stock price<br />
<br />
Strong management team, company <i>encourages </i>questions from shareholders (I can <i>personally</i> attest to this)<br />
<br />
<span style="color: red;"><b>6/29/2012 Update--> </b></span><a href="http://www.celsion.com/releasedetail.cfm?ReleaseID=687405" target="_blank">$10M loan agreement announced </a>(first $5M tranch now, second $5M only after positive HEAT data), in my opinion, <i>completely eliminates</i> nagging dilution concerns pre-data, a major positive for shareholders. Total of 102,740 warrants issued as part of this deal. </td>
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<div style="text-align: center;">
<b><span style="line-height: 115%;"><span style="color: blue;">General</span><o:p></o:p></span></b></div>
</div>
Wall Street may be pricing Celsion appropriately given the level of risk in the HEAT trial, "efficient markets" at work?<br />
<br />
The <a href="http://jnci.oxfordjournals.org/content/early/2011/09/26/jnci.djr375.full" target="_blank">"Feuerstein-Ratain Rule"</a>, might it be at play here?<br />
<br />
Admittedly out of necessity, company was trigger happy to raise money in 2011, sometimes at unfavorable prices (<b><i>Note to Celsion--></i></b> If you repeatedly insist you have enough cash on hand, don't be surprised if shareholders get upset if another raise is made pre-data).<br />
<br />
Large-scale recent exits by Mangrove and Ayer capital, large institutional holders.<br />
<br />
Institutional ownership remains relatively low (~15%, though I suspect that will change nearing data)<br />
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<div style="text-align: center;">
<b><span style="line-height: 115%;"><span style="color: blue;">ThermoDox® as an Asset / LTSL Pipeline</span><o:p></o:p></span></b></div>
</div>
ThermoDox® enjoys every available regulatory advantage available (SPA, orphan designation, fast-track, accelerated endpoint, priority review)<br />
<br />
A “pipeline within a product”, ThermoDox® has demonstrated clinical potential in multiple indications, including liver mets and recurrent chest wall breast cancer. Pancreatic cancer and bone metastases to be examined further downstream. <br />
<br />
Company specifically targeting high-unmet need areas within oncology<br />
<br />
Platform can be triggered by all available approved sources of hyperthermia (RFA, Microwave, HIFU), "heat is heat is heat." HIFU adoption in particular is inevitable given completely non-invasive approach, ability to monitor temperatures in real-time marries this technology to ThermoDox®<br />
<br />
Platform focus is on established chemotherapeutics, limiting risk and accelerating approval process (505b2)<br />
<br />
Patent protection to 2021 and 2024, respectively, for 3 lipid and 4 lipid Needham family patents<br />
<br />
Fully paid off patent, licensed from Duke<br />
<br />
Other pipeline products include docetaxel and carboplatin, as well as combining agents for real-time monitoring<br />
<br />
Use of hyperthermia growing in oncology regardless of ThermoDox®, this trend clearly bodes well for Celsion.</td><td style="border-bottom: solid windowtext 1.0pt; border-left: none; border-right: solid windowtext 1.0pt; border-top: none; height: 115.3pt; mso-border-alt: solid windowtext .5pt; mso-border-left-alt: solid #FFC000 2.25pt; mso-border-left-alt: solid #FFC000 2.25pt; mso-border-top-alt: solid windowtext .5pt; padding: 0in 5.4pt 0in 5.4pt; width: 358.2pt;" valign="top" width="478"><div class="MsoNormal" style="line-height: 115%; margin-bottom: .0001pt; margin-bottom: 0in;">
<div style="text-align: center;">
<b><span style="line-height: 115%;"><span style="color: blue;">ThermoDox® as an Asset / LTSL Pipeline</span><o:p></o:p></span></b></div>
</div>
Celsion essentially banking everything on ThermoDox®, only <i><b>late-stage</b></i> asset<br />
<br />
Colorectal liver metastases (CRLM) trial <i>deliberately</i> slow to enroll patients, recurrent chest wall (RCW) will not be enrolled until end of 2013 earliest.<br />
<br />
All platform products limited to indications where hyperthermia is already part of SOC, places finite parameters around market size. Adoption of microwave and HIFU still slow in the US.<br />
<br />
Liposomes accumulate in the liver, thus, while ThermoDox® ideal for liver applications, accumulation outside of liver largely dependent upon leaky tumor vasculature. <br />
<br />
Improving delivery of old chemos not as "sexy" as new molecular entities, and in my opinion, payers not as willing to accept significant price premiums for them either.<br />
<br />
Docetaxel and carboplatin pipeline products still very early stage, years away from the market<br />
<br />
Modest (~5%) royalty due to Duke</td>
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<div style="text-align: center;">
<b><span style="line-height: 115%;"><span style="color: blue;">HEAT Study and Outcome</span><o:p></o:p></span></b></div>
</div>
Phase III predicated on a Phase I trial demonstrating strong dose response relationship, particularly in patients who had failed multiple lines of therapy<br />
<br />
Robust trial design using PFS as an accelerated endpoint, and OS as secondary confirmatory endpoint<br />
<br />
Overwhelming majority of literature (please do look for yourself on my blog) points to local recurrence originating precisely where ThermoDox® activates via RFA sub-lethal zone<br />
<br />
Largest study in intermediate stage HCC, data from HEAT study will be "bullet-proof" and widely accepted by regulatory authorities. Succeed or fail, this trial will be a major contribution to the medical literature.<br />
<br />
Company and Chief Medical Officer in particular continue to stress importance of data quality, particularly given the radiologic PFS endpoint.<br />
<br />
Builds off of an existing standard of care for unresectable HCC in radiofrequency ablation (RFA), synergy potential very evident. <br />
<br />
Study has cleared multiple DMC reviews for safety, all unanimous recommendations to continue. ThermoDox® likely very safe. No protocol changes since trial initiated.<br />
<br />
Successful interim efficacy analysis completed November 2011, key endorsement that efficacy on the right track.<br />
<br />
According to the recent CEO letter, Celsion's anticipated timing of 380 PFS events (an event that will be PR'd, my guess sometime in early Q4) is "reasonably consistent with the assumptions that we made in constructing the HEAT study"<br />
<br />
Initiation of the CRLM trial (granted that trial is purely looking at local progression) <i><b>before</b></i> HEAT data can be viewed as a sign of confidence, mechanism of action for ThermoDox's proposed efficacy exactly the same. Further, recurrence patterns are very similar between CRLM and HCC, in fact, CRLM tougher to treat in general. <br />
<br />
Fair to say company has maintained a very close working relationship with the FDA, company prides itself on sharing this relationship with investors.<br />
<br />
Company lead investigators, all prominent KOLs, <a href="http://celsion.blogspot.com/2012/06/dr-ronnie-poon-heat-lead-investigator.html">continue to express optimism</a> about ThermoDox® and ongoing HEAT study.<br />
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<b><span style="line-height: 115%;"><span style="color: blue;">HEAT Study and Outcome</span><o:p></o:p></span></b></div>
</div>
Phase I study small (24 patients), most patients were not HCC, progression times largely incomparable to established literature. No Phase II conducted.<br />
<br />
PFS<i> not</i> the "ideal" endpoint for a drug with a predominant local effect such as ThermoDox®, it simply is not. Implicit assumption of the trial is that local progression (and technical failures) will account for a sufficient number of events such that ThermoDox® can make an impact. Distant intrahepatic progression outside of ThermoDox®' "reach" <i>remains the biggest threat</i> jeopardizing the trial's outcome, something I have mentioned repeatedly.<br />
<br />
Trial did not include microwave ablation, which is also emerging alongside RFA as another ablative approach for HCC and liver mets.<br />
<br />
Enrollment paused/halted in Japan due to differences in SOC (bridging study to commence after HEAT results, partner Yakult still very much engaged, however)<br />
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<b><span style="color: blue;">Competition
and Commercialization</span><o:p></o:p></b></div>
</div>
A good analog to point to for commercialization success is Doxil, another liposomal encapsulation of doxorubicin. <br />
<br />
Very large potential patient population in initial HCC indication. Current HCC treatment paradigm is very unclear, HEAT study will add tremendous clarity and confidence to medical community about RFA's potential in combination with ThermoDox®<br />
<br />
1st line therapy in HCC and liver metastases, limited competition.<br />
<br />
Aggressive pricing potential given expected outpatient, rather than inpatient, utilization<br />
<br />
Attractive licensing asset (J&J and Merck marketed Doxil/Caelyx, now solely J&J), ThermoDox® is a "green-light" into emerging markets for big pharma<br />
<br />
Attractive deal in place for Japan with Yakult-Honsha<br />
<br />
Significant milestone achieved with signing of Chinese manufacturing partner Hisun (in many ways, <a href="http://celsion.blogspot.com/2012/05/celsion-secures-strategic-china.html" target="_blank">this is much more</a> than simply a manufacturing agreement)<br />
<br />
Significant (and I would argue, <i>natural</i>) off-label potential with CRLM, especially given strong HCC data<br />
<br />
Adoption facilitated by ease of incorporation into existing SOC, simple intravenous (IV) infusion <br />
(This is clearly <i><b>not</b></i> Delcath's ChemoSAT system)<br />
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<div style="text-align: center;">
<b><span style="color: blue;">Competition
and Commercialization</span><o:p></o:p></b></div>
</div>
Most HCC patients are in China, difficult market for pricing, penetration, and IP protection. Entry into Japan, another key market with relatively flexible pricing potential, delayed by at least 1-1.5 years relative to US/EU.<br />
<br />
RFA alone + TACE also being used for similar tumor sizes, early stage Sorafenib might also be source of competition.<br />
<br />
Pricing too aggressively can lead to restrictions from payers (prior authorizations, step edits, etc), payers beginning to scrutinize medical benefit oncologics more closely in general. Aggressive pricing very problematic in fixed reimbursement, inpatient settings. Company should consider not only the obvious Nexavar and Doxil as pricing analogs, but also, TACE, doxorubicin-eluting beads (DEBDOX), Therasphere, SIR-spheres, and RFA itself, all as potential analogs to base pricing on. <br />
<br />
Matter of necessity for Celsion to secure a large partner to commercialize Ex-US, no licensing deals outside of Japan yet<br />
<br />
Impact of IV drug administration <i>within interventional radiology suite</i> will likely require some physician education, particularly to ensure compliance with optimal "timing" of administration and heat source</td>
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</div>
<br />
So what does all of this give you? Why should you care? Plain and simple, if you are bullish, be mindful of some of the potential bear views, and if you are bearish, know that a compelling bull case can be made to invest in Celsion. <i><b>You all know where I ultimately stand on this</b></i>, <a href="http://celsion.blogspot.com/2011/09/thermodox-in-hcc-science-points-to-heat.html" target="_blank">I think the HEAT trial will succeed</a>, despite the risks I point out inherent in the trial, and ThermoDox<span style="background-color: white; font-size: 13px; line-height: 14px;">®</span><span style="background-color: white;"> will very rapidly make its way as a first-line standard of care for unresectable HCC patients not eligible for transplantation. </span><i style="background-color: white;"><b>More importantly</b></i><span style="background-color: white;">, I do think the management team is well aware of some of the “bear concerns” I have raised, and I am optimistic about their confidence in ensuring they are addressed/mitigated to the extent possible.</span><br />
<br />
Risks remain, as they do with every biotech, and for that, I encourage everyone to continue their DD. At the same time, I would challenge investors to identify a company with a better risk/reward than Celsion. The market, dare I say, is beginning to take notice of the company's potential.<br />
<br />
As always, please let me know if you have any questions or comments.<br />
<br />
Best,<br />
SiavocheMagicsiahttp://www.blogger.com/profile/06200209295387415335noreply@blogger.com0tag:blogger.com,1999:blog-5201890067787605901.post-9208841517638706402012-06-04T10:23:00.001-07:002012-06-04T10:23:40.710-07:00Dr. Ronnie Poon, HEAT Lead Investigator, Discusses HCC, Outlines Potential of ThermoDoxReleased coincident to this year's ASCO conference, I was excited to see <a href="http://finance.yahoo.com/news/celsion-announces-webcast-interview-featuring-155700471.html" target="_blank">another investigator interview recording made available by Celsion today</a>. As many of you recall, Rodman & Renshaw's Dr. Reni Benjamin conducted a similar interview a few months back with Dr. Steven Libutti (who leads the ABLATE Phase II study), <a href="http://celsion.blogspot.com/2012/03/interview-with-celsion-investigator-dr.html">which I commented on as well</a>.<br />
<br />
Arguably, this is an even more impactful interview (not to discount Dr. Libutti, of course) since it involves Dr. Ronnie Poon, a lead Co-PI in the HEAT study, and one of the most well-respected liver cancer physicians in the world. Of note, Dr. Ronnie Poon is based in China, which is by far the biggest potential market for ThermoDox in HCC, and he has personally treated "15 or 16" patients in the HEAT study according to the interview. Of course, Dr. Poon also lead the Phase I study as well.<br />
<br />
I like how these interviews have been conducted, as they are not meant to be "advertising" for Celsion and ThermoDox. Rather, Dr. Benjamin asked Dr. Poon to discuss the typical treatment HCC patients receive, and from that very broad context, how ThermoDox might play a role in the treatment paradigm alongside resection, transplantation, transarterial approaches, and later stage treatments such as Nexavar. Below are some of the highlights of the discussion, but I highly recommend you listen for yourself (see below, I embedded it here as well).<br />
<ul>
<li>True global incidence of HCC likely underestimated, 750,000 cited in most sources, but this is likely an underestimation, 55% of which are in China. </li>
<li>Surgery and transplantation are the best treatments for HCC larger than 3cm, but very few patients are eligible for such treatment. Dr. Poon mentioned that in reality, only 2% of patients end up with transplantation, and 20-25% get resection.</li>
<li>Transarterial treatments such as TACE and deb-TACE are used for patients with very large tumors, 5-6 lesions in number.</li>
<li>Ideally, RFA should take the place of surgery because of the extensive time and invasive nature of surgery. Ablation has similar efficacy to surgery for tumors <3cm (<a href="http://abstract.asco.org/AbstView_114_96270.html" target="_blank">some data does challenge what he said though</a>, but it's a moot point since few patients are eligible for surgery anyways).</li>
<li>Approximately 30% of HCC patients are eligible for RFA on first diagnosis, and Dr. Poon without ambiguity emphasized that RFA is indeed today's SOC for early/intermediate stage disease. Interestingly, Dr. Poon emphasized that among the 20-25% of patients getting surgical resection, 70% of those will develop recurrence and will inevitably receive treatment with RFA as well. Taking it all together, 40-45% of patients are eligible for RFA. </li>
<li>Dr. Poon mentioned that incomplete ablation and recurrence around the tumor margins are common issues in lesions >3cm, again, something I have reiterated many times, and this serves as the rationale for ThermoDox.</li>
<li>Dr. Poon emphasized that local control can be improved by ThermoDox' proposed mechanism of action, in which high concentrations of chemo are released in the margins surrounding the tumor in the so-called, thermal zone, or sub-lethal temperature zone, where there are micrometastases present that cannot be seen using imaging techniques.</li>
<li>Regular doxorubicin suffers from very high toxicity, ThermoDox is "definitely a safe drug", with side effects that are "not clinically significant"</li>
<li>Dose response seen in Phase I was the rationale for jumping straight to Phase III. Dr. Poon mentioned that initially, there were "some issues" in working with the FDA to design the Phase III trial, primarily around the use of OS versus PFS as the study's primary endpoint. However, Dr. Poon emphasized that PFS is a clinically appropriate endpoint for intermediate stage patients. He later added that the trial was "designed as good as it can be"</li>
<li>There will be a "lot of expectations for the results of this trial", according to Dr. Poon, primarily because the HEAT study is the largest intermediate stage trial conducted and there are very few, if any, other trials looking at this line of therapy (versus late stage, for example, which he mentions a lot of companies are looking at). </li>
<li>High quality trial sites selected in the HEAT study should help to reduce site to site variation in data</li>
<li>Theoretically, a patient could get 6 or 7 administrations of ThermoDox before they hit the doxorubicin dose ceiling. Dr. Poon emphasizes that a typical patient might get 2-4 RFA treatments in their course of treatment. </li>
<li>Even a 20-25% improvement in PFS in this population is meaningful, according to Dr. Poon. Recall that the HEAT study needs to show a 33% improvement.</li>
<li>As an adjunct to RFA, Dr. Poon highlighted that ThermoDox can be readily incorporated into standard practice, suggesting a rapid pace of adoption assuming positive data and approval of course. Simplicity and familiarity of doxorubicin should accelerate adoption, but education will still be needed to time the administration of the drug and beginning the RFA procedure to take advantage of the PK/PD profile of ThermoDox.</li>
<li>One area where I will take issue with Dr. Poon is in how he described heat plus non-heat sensitive Doxil. While immediate release of chemo is indeed not seen with heat plus Doxil (as would be expected), he did not mention that there is some literature suggesting that RFA + Doxil increases the tumor necrosis volume. I was surprised he did not bring this up.</li>
<li>An interesting area Dr. Poon suddenly veered into was around the topic of pricing, suggesting that price could be a barrier for some patients. However, Dr. Poon was quick to highlight the relatively high price of an often used analog for ThermoDox (Nexavar, a poor analog if you ask me in all honesty).</li>
</ul>
<div>
These were just the salient points brought up, again, I do recommend investors listen for themselves:</div>
<iframe frameborder="0" height="120" scrolling="no" src="https://skydrive.live.com/embed?cid=D5139E805024FD7C&resid=D5139E805024FD7C%21836&authkey=AGC1QVZCuuhf0yg" width="98"></iframe><br />
<div>
Looking broadly at these "meet the investigator" interviews Celsion has coordinated, I have to applaud them for doing so. Again, these are extremely well-known, world renowned physicians, so I can't think of much more they can do to generate interest for ThermoDox. Speaking for myself, I very much do appreciate hearing firsthand from highly respected clinicians in the field.</div>
<div>
<br />
The data will ultimately tell the story...you can be sure that the eyes of the interventional/surgical oncology world will be glued to the outcome of the HEAT study, hopefully due by end of year (the inevitable PR of 380 confirmed PFS events triggering the 6-10 week "countdown" will give us much more clarity as to timing). As this year's ASCO winds down, I am already looking forward to ASCO 2013.<br />
<br />
Best,<br />
Siavoche</div>Magicsiahttp://www.blogger.com/profile/06200209295387415335noreply@blogger.com4tag:blogger.com,1999:blog-5201890067787605901.post-86496330672395770792012-05-15T22:25:00.002-07:002012-11-12T20:10:08.015-08:00"The message today is momentum" — Michael Tardugno, Q1 2012 Conference CallI highly recommend everyone to listen to today's Q1 conference call, it was particularly detailed and the company sounded rather upbeat (link can be found <a href="http://viavid.net/dce.aspx?sid=00009785" target="_blank">here</a>). Highlights from today's 2012 Q1 conference call (generally only highlighting what is unique and new):<br />
<br />
<ul>
<li>Moving forward with branding and payer research, conducting market research with key stakeholders</li>
<li>NDA submission process--Engaged KOLs and moving forward with selection of a CRO with FDA portal access and using a common technical document approach as a basis for NDA and MAA filings.</li>
<li>Multimodality approach is the future for a number of cancers, hyperthermia being a key component.</li>
<li>On track for 700 patients by the end of Q2</li>
<li>Approximately $2M to be paid to Hisun only after technical success (3 registration batches) and after unblinding of data. Registration batches expected to be completed "next year"</li>
<li>Yakult remains enthusiastic and that initiation of bridging study will commence after successful HEAT data</li>
<li>Ended first quarter with $24.6M dollars, sufficient to fund through Q3 of 2013. </li>
<li>Phase 2 RCW will recruit 40 patients</li>
<li>CRLM, RCW, bone mets, and pancreatic cancer trials will "give the oncology a community a snapshot of the broad potential of ThermoDox while it's approval is being considered"</li>
<li>Securing multiple manufacturers important for supply continuity. Hisun has recently invested significantly in expanding capacity in China.</li>
<li>Next DMC meeting likely in September (DMC meetings are every 3-4 months roughly every 100 patients)</li>
<li>Progression and event rates are "substantially following what they consider consistent with a successful trial"</li>
<li>Approval for ThermoDox in HCC as early as end of 2013</li>
<li>sFDA China regulatory review period could be "cut by half" from 12-15 months, due primarily to the severity and umnet need in HCC. Hisun will support the regulatory process in China. </li>
<li>Target number of patients for HIFU bone mets trial is "in the 20's"</li>
<li>No presentations at ASCO or WCIO, first data to be presented will likely be data from RCW Phase 1 trial (my question was in regards to WCIO)</li>
<li>Company cannot disclose the average lesion size in the trial (my question)</li>
<li>The company would like a business card for "Odaat enterprises" (sorry, had to...that was quite funny...for those who don't know, Odaat is the individual from this <a href="http://celsion.blogspot.com/2012/04/leading-celsion-shareholder-achieves.html" target="_blank">blog post</a>)</li>
<li>As an FYI, this was the second time I noted both Cowen (Edward Nash) and Cantor Fitzgerald (Mara Goldstein) analysts on the call. </li>
</ul>
<div>
Let me know if you have any questions or if I missed something. </div>
<div>
<br /></div>
<div>
Best,<br />
Siavoche</div>
Magicsiahttp://www.blogger.com/profile/06200209295387415335noreply@blogger.com0tag:blogger.com,1999:blog-5201890067787605901.post-78325235386023753572012-05-07T20:12:00.001-07:002012-05-07T20:17:35.023-07:00Celsion Secures Strategic China Manufacturing Agreement, CEO presents at Deutsche Bank Conference<br />
Today, investors saw a new press release from Celsion, specifically announcing that the company has entered into a long-term supply agreement with Hisun Pharmaceuticals for the manufacturing of ThermoDox in the China market. The market did not seem to pay much attention to this announcement, but I would argue this represents a key milestone along the commercialization path for ThermoDox, particularly since China represents the largest market for the company in HCC. The agreement includes the following:<br />
<ol>
<li>Tech transfer for proprietary manufacturing process, and non-dilutive funds to support that endeavor <i>(I imagine there is a lot of legal work there, IP in emerging markets <a href="http://economictimes.indiatimes.com/news/news-by-industry/healthcare/biotech/pharmaceuticals/bayer-challenges-nexavar-generic-licence-order/articleshow/13035296.cms" target="_blank">is a scary topic</a>, read about Bayer's experiences with Nexavar in India)</i></li>
<li>Production of China registration batches</li>
<li>Option for Hisun to globally manufacture ThermoDox following SFDA approval</li>
<li>Support for regulatory approval activities in China</li>
<li>An undisclosed manufacturing price that "will support high gross margins across global territories"</li>
</ol>
My own personal thought is that this agreement with Hisun gets the company one step closer to global licensing agreement with a big pharma partner. I found it quite interesting that the press release made a reference to <a href="http://www.fiercepharma.com/story/hisun-jv-inked-pfizer-eyes-other-chinese-tie-ups/2012-02-21" target="_blank">Pfizer's JV with Hisun</a>, a greater than half billion dollar agreement signed in February. According to that agreement, both companies will contribute assets to the JV. I could see how a Pfizer-Celsion deal fits very nicely into this arrangement. As I have tweeted and reiterated many times before, ThermoDox presents big pharma with a very attractive product to penetrate emerging markets, particularly China, especially given the initial indication focus on HCC. My own thoughts are that a deal will not be announced until <i>manufacturing</i> is completely squared away, and this point has been reiterated by the company before (see below).<br />
<br />
In other news, Michael Tardugno also presented at the 37th Annual Deutsche Bank Health Care Conference. There was nothing particularly new or exciting presented:<br />
<ul>
<li>Reconfirmed final data from the HEAT study would be available at the end of 2012</li>
<li>Final confirmatory OS data due 18-24 months after top-line PFS results</li>
<li>Reiterated enough cash on hand to last until Q3 of 2013, burn rate of $1.7M for next 18 months <i>(company likely has just over $20M as of right now)</i></li>
<li>Revenue potential of $500M by 2017 in HCC using 10% global share capture rate</li>
<li>Phase II RCW trial to commence patient enrollment in the second half of 2012
</li>
<li>Company working to establish "redundant manufacturing capability" from high quality sites, "which we believe would be very important to a successful high quality license with a multinational company"</li>
<li>In response to the sole Q&A question regarding business development, Mr. Tardugno said the "enthusiasm coming from our investigators [HCC] is nothing short of remarkable". He added, "We would be looking forward to firm license discussions with what we think would be a multinational partner<b><i> post data</i></b> for markets outside the US"</li>
</ul>
<div>
The last point was probably the most interesting one, as it tells me the company is really playing hard ball with potential partners. Post data, assuming success, the terms of such a licensing deal <u>exponentially</u> change in the company's favor. That said, if the company is truly not seeking a deal until end of the year, I see a cash raise likely in Q3,<a href="http://celsion.blogspot.com/2012/02/celsion-2012-anticipated-milestones-and.html" target="_blank"> as I have mentioned before</a>, hopefully in the 3-5 range. Absent a cash raise, the company will have $10M in cash by the end of 2012, and I sense they are no longer looking to "scrape the barrel" as they have done in the past. </div>
<div>
<br /></div>
<div>
It's hard to believe that we are already nearing mid-2012, and rapidly approaching final data from the HEAT study. Feel free to leave questions or comments.</div>
<div>
<br />
Best,</div>
<div>
Siavoche</div>Magicsiahttp://www.blogger.com/profile/06200209295387415335noreply@blogger.com2tag:blogger.com,1999:blog-5201890067787605901.post-29260643126128726272012-04-29T16:43:00.000-07:002012-04-29T16:43:00.887-07:00Leading Celsion Shareholder Achieves National Cancer-Fighting Accolade<div>
Dear blog visitors, this next post is one that I take great pride in making available to my readers. As many of you might recall, Mitch Landgraf <a href="http://celsion.blogspot.com/2011/09/thermodox-in-hcc-science-points-to-heat.html" target="_blank">edited my scientific deep-dive article</a> for ThermoDox a little while ago. He is one of the, in fact, THE most active cancer "fighter" I have ever seen, relentlessly raising awareness wherever he goes. I met Mitch not long after I took an initial interest in Celsion, and I am proud to call him a good friend. The following summarizes an important milestone he recently achieved, and while slightly out of scope relative to my usual articles, I nevertheless want to do my part to support Mitch and his efforts at the American Cancer Society.</div>
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A long time shareholder, cancer-fighting volunteer, and vocal supporter of Celsion's technology lead the way to a history making cancer-fighting achievement. Mitch Landgraf, a.k.a. "Odaat," is the volunteer chairperson of The American Cancer Society Relay For Life of Upper Illinois Valley event. Due to the goodness of generous donors (including Celsion shareholders), outstanding committee and team volunteers, and Mitch's passion to fight cancer, the event was successful on an historic proportion. Not only did the event break State of Illinois records, garner multiple awards and recognitions, and rank in the top 25 events for the state of Illinois, but it did so in only its second year of existence. Most astonishingly, and unprecedented in the history of Relay For Life, the Relay For Life of Upper Illinois Valley ranked 2ND IN THE NATION from over 6,500 Relay For Life events in rankings based on participant feedback surveys. The event also had more than a ten-fold increase in monies raised and number of participants, cancer survivors, youth teams, and overall teams.<br /> <br />"We raised an incredible amount of money to fight cancer on the research front and to provide 100% free services to anyone affected by cancer," said Chairperson Mitch Landgraf. "I understand, Relay is a fundraiser, I get it, but my goal was not just to fight cancer, but to heal cancer. The things those oustanding feedback surveys expressed tell me that we achieved that goal...that people were moved, healed, got to cry, to laugh, to remember, to celebrate, to share fellowship with others affected by cancer, and to stand with each other in a powerful way against this insidious disease. For me, there is no disconnect between my cancer fighting volunteerism and my investment in and support of Celsion. Talk to anyone at a Relay event who watched a loved one suffer not only from cancer but from the way treatment side effects can lead to a steady demise of the body's health and the soul's joy, and you will know what I mean. Wemust get the Celsion LTSL drug delivery model to patients on a worldwide scale. I have been unabashed in sharing my personal opinion that iLTSSL technology, especially when triggered by HIFU, represents what I believe to be the drug delivery and cancer answer. Until the (increasingly near) time that it becomes widely available, I plan to stand firm in my trench with my fellow cancer fighters, survivors, caregivers, and biotech investors to fight cancer tirelessly. It is a life-changing privilege to serve as chairperson of such a healing, powerful, hope-filled event. Together, we can defeat cancer and heal its scars, one day at a time."<br /> <br /><i><b>If you would like to help Mitch in this cause, you can make tax-deductible donations here:</b></i><br /> <br /><a href="http://main.acsevents.org/site/TR/RelayForLife/RFLFY12IL?px=10917803&pg=personal&fr_id=38398">http://main.acsevents.org/site/TR/RelayForLife/RFLFY12IL?px=10917803&pg=personal&fr_id=38398</a><br /> <br /><b><i>by clicking <u>"Donate on my behalf."</u></i></b><br /> <br />For more information about the event, photos, etc. go to <a href="http://www.relayforlife.org/upperillinoisvalleyil">www.relayforlife.org/upperillinoisvalleyil</a><div>
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(Note: Mitch wanted to make it clear that he is not a representative of Celsion or The American Cancer Society.)<div>
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Best,</div>
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Siavoche</div>Magicsiahttp://www.blogger.com/profile/06200209295387415335noreply@blogger.com1tag:blogger.com,1999:blog-5201890067787605901.post-33875382073930852912012-04-16T21:00:00.000-07:002012-04-16T21:09:41.456-07:00ThermoDox Reimbursement Deep Dive (Part 2)While this follow-up is not quite the <a href="http://celsion.blogspot.com/2011/08/thermodox-reimbursement-deep-dive-part.html" target="_blank">“Part 2” of the Reimbursement Deep Dive</a> that I had in mind (my original intent was to walk through pricing and reimbursement in the EU-5 plus China), I do nevertheless want to take the time to highlight some of the components of the “pharmacoeconomic” puzzle that Celsion management will have to consider during the commercialization process of ThermoDox. In fact, forward-thinking biotechs and pharma companies now proactively plan for pharmaceconomics and reimbursement much earlier in the commercialization life cycle, in many instances making such considerations as trials are being designed. <br />
<br />
Let me preface this by saying, boldly, that pharmacoeconomics is not entrenched in the fabric of the US health care system, though it is much more widely used and adopted in other developed countries (I personally think the US is in the stone ages in this regard, we have a lot to learn from Europe, I digress). While there have been uproars about the cost of products such as Erbitux, Avastin, and more recently, Provenge and Yervoy, for the most part, payers grudgingly cover them (particularly within oncology). Drugs might get certain utilization management restrictions in the US, but they still end up on the market. A payer might place a very expensive pharmacy benefit drug (recall the distinction I made in my first article between pharmacy versus medical benefit drugs, as this is a critical foundational piece to understanding pricing and reimbursement) on a 4th tier rather than 2nd tier, for example, and have a prior authorization, but the drug still makes it in to the market place, and is still relatively affordable by most with insurance. In contrast, in the UK, for example, the National Institutes for Health and Clinical Excellence (NICE) has a relatively rigid bar in terms of the required <a href="http://www.nice.org.uk/newsroom/features/measuringeffectivenessandcosteffectivenesstheqaly.jsp" target="_blank">cost per quality adjusted life year (QALY)</a> in order to recommend reimbursement of a particular drug. If NICE does not recommend the drug, it is technically on the market, but the government will simply not reimburse. <br />
<br />
So, what point am I trying to make? The US is much more lax about even considering "cost" in determining access decisions for drugs compared to the EU. The difference between the US and EU is that while a pharmacy and therapeutics committee (health plans have P&T committees consisting of medical and pharmacy directors who make such formulary coverage decisions, hospitals almost always have their own separate P&Ts as well) at, Aetna, for example, can place restrictions on a product, payers rarely flat out do not cover something. In Europe, it is somewhat binary, coverage or no coverage. <br />
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Alright, now that I have gotten that out of the way, what is pharmacoeconomics? At its simplest, pharmacoeconomics takes into account two key components: cost and outcomes (For those seriously interested in diving into this further, I have several references I could guide you to). The above-mentioned cost/QALY used by NICE is one commonly used metric, though there are others as well.<br />
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So, what will forward looking payers in the US and Ex-US countries consider from this perspective in evaluating ThermoDox, and what types of data must Celsion be prepared to share in such dossiers/analyses? <br />
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<b>Costs (some are incremental reductions/additions)</b> <br />
<ul>
<li>Drug price</li>
<ul>
<li>Obviously, this is the big one. We still don't know definitively where ThermoDox will be priced, and again, I hope the company is proactively studying/gauging payers to see what type of price could be "digested" for a given level of benefit. My complete wild guess is that in the US and EU, $10-$20K, while in China, it will be 1/3 to 1/5 of that cost, unless the company is willing to "skim" the Chinese market and simply target affluent, self-paying individuals and forget about getting provincial formulary coverage.</li>
</ul>
<li>Pre-RFA visit fees (if needed) </li>
<li>Pre-RFA prophylaxis (I believe this was protocol in the HEAT study)</li>
<li>Additional length of stay potentially to monitor for side effects (for inpatients)</li>
<ul>
<li>This can be significant. (Described below, every additional penny counts in the inpatient setting since reimbursement is fixed for the entire inpatient stay, you can conservatively count each additional inpatient day as an ~$2000 cost to hospitals)</li>
</ul>
<li>Drugs to treat chemotherapy-induced neutropenia (CIN)</li>
<ul>
<li>I am going to elaborate on this one a bit, because I think this is going to play into the “cost” of ThermoDox. Payers will often look at the experience of patients in clinical trials for guidance as to what to expect in the real world, although this can often be misleading for a number of reasons (topic for another discussion). I have no doubt that a good portion of patients in the HEAT study will require granulocyte colony stimulating factor (G-CSF) agents for CIN. Neulasta (once/cycle, ~$2,800 average sales price) and Neupogen (daily injections, ~$260-$414 depending on dose), marketed by Amgen, dominate the G-CSF market, but there are others as well, including biosimilar filgrastim and pegfilgrastim in the EU. These are not cheap, and payers will factor them in to the “total cost of care”, <i>costs that would otherwise not be needed for RFA alone.</i></li>
</ul>
<li>Other drugs needed to offset other chemo side effects (nausea for example) </li>
<li>RFA Procedure cost</li>
<ul>
<li>If ThermoDox patients require fewer RFA to achieve complete ablation, this would be an incremental cost reduction, however, the data will tell us the story as to complete ablation rates in both arms. Similarly, avoidance of future RFA to reduce local recurrence would be yet another potential significant source of cost reduction for ThermoDox patients. </li>
</ul>
<li>TACE avoidance (ThermoDox might preclude need for TACE in some instances) </li>
</ul>
<b>Potential Incremental Outcome Improvements </b><br />
<ul>
<li>Prolonged PFS </li>
<li>Extended OS </li>
</ul>
What complicates this story is that the above-mentioned “costs” vary by site of care. Recall in the first part of my reimbursement deep dive I highlighted that inpatient versus outpatient sites of care are very, very different for drug reimbursement, given that in the former, drugs are bundled into a DRG (flat cost) for the entire hospitalization visit. In that instance, an extended stay, ThermoDox drug price, etc., would all be “swallowed” by the hospital, as they would not be able seek reimbursement for those separately unless the DRG is modified, or under the very rare circumstance that ThermoDox would be given a new technology payment. So, in that setting, the payer could care less, but in the outpatient setting, those would all be billed separately, and the payer would have to take them into account. As I have said before, Celsion’s pricing flexibility will be significantly limited (de facto as a function of reimbursement to providers) if most utilization is going to come from inpatient versus outpatient use of ThermoDox (not good news). This is the same as what I have said before about Delcath’s ChemoSat procedure, which by definition <b><i>has</i></b> to be done on an inpatient basis. Absent a compelling clinical story, inpatient adoption of very expensive drugs relative to the total DRG payment will be difficult.<br />
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The “gist” of what I am trying to get at with this article is that sophisticated payers won’t just look at the cost of the drug when making access decisions. Compared to patients who just receive RFA alone, as you can see, payers (and hospitals) will have a wide range of incremental costs (and reductions) to consider, not the least of which is the cost of the drug itself. As I have pointed above, this incremental cost story is nothing from a pharmacoeconomic perspective without knowing the incremental outcome <b><i>benefit</i></b> (however that is defined) for ThermoDox as well. For that, standby for final phase III data, which the company has firmly guided would be on hand by end of year.<br />
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I have personally advised Celsion management, if they have not already done so, to strongly consider engaging experts in the field to carefully craft their “payer engagement” strategies and devise a crisp, articulate value proposition for ThermoDox. While US payers will welcome this (some much more than others), it is simply a matter of necessity in the EU. Furthermore, contrary to what most people think, the EU is<i> very heterogeneous</i> in terms of reimbursement (unlike most EU countries, UK and Germany have "free" pricing for example, but as you saw in the UK example, the NICE cost/QALY is the de facto price regulator. Other countries such as France, Italy and Spain have "fixed" pricing for the most part). So, admittedly, I have not done justice in fully describing the EU system. Additionally, pricing and reimbursement in China is still <i>extremely challenging</i>, due in most part to a still fledgling, third party reimbursement system that is slowly beginning to take shape in China with national health reform changes.<br />
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I hope by now the reader has a much better picture of the complexities management will face during the commercialization process of ThermoDox (hopefully, a big pharma partner will be by their side as a partner during this process)<br />
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As always, feel free to ask any questions. <br />
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Siavoche</div>Magicsiahttp://www.blogger.com/profile/06200209295387415335noreply@blogger.com0tag:blogger.com,1999:blog-5201890067787605901.post-33600974687233746702012-03-24T18:53:00.000-07:002012-03-25T09:46:33.606-07:00HIFU for Bone Metastases - Brief Overview and Implications for ThermoDoxAs many of you know, Celsion has a partnership agreement with Philips Healthcare to jointly research the use of ThermoDox in combination with Philips' high-intensity focused ultrasound device (Sonalleve) in a few different indications. The most immediate potential indication would be for the treatment of bone metastases, and by "treatment", I should qualify that to pain palliation in particular. More to come on that.<br />
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To back things up a bit, I have had quite a few links regarding Philips' HIFU technology all over my blog, but I have not really gone into much detail yet (too occupied with the HEAT trial!). With that said, let's take a brief elementary look at what HIFU is with a few key questions:<br />
<br />
<b>What is HIFU?</b><br />
As mentioned above, HIFU stands for high intensity focused ultrasound. It is a way of delivering focused energy, either to generate mild hyperthermia or high temperatures for ablation, completely non-invasively. HIFU can be conducted either via ultrasound (US), or via MRI (you may have seen the term MRI-HIFU), with the latter being inherently more precise from an imaging perspective. HIFU made <a href="http://www.tedmed.com/videos-info?name=Yoav_Medan_at_TEDMED_2011&q=updated&year=all" target="_blank">a nice splash at TEDMED 2011</a> in a presentation by Insightec's (see below) Yoav Medan.<br />
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<b>What are some potential indications HIFU is being tested/used in?</b><br />
Indications of interest for HIFU include the following:<br />
<ul>
<li>Bone metastases</li>
<li>Brain tumors</li>
<li>Epilepsy</li>
<li>Essential tremor</li>
<li>Liver tumors</li>
<li>Neuropathic pain</li>
<li>Parkinson's Disease</li>
<li>Prostate tumors</li>
<li>Uterine Fibroids</li>
</ul>
<b>Is HIFU approved in the US/EU/Ex-US? Who are the key players?</b><br />
Yes, HIFU devices are available in the US, but I think it is safe to say that "early adopters" are the ones championing its use still, and I would venture to say that most utilization is taking place for the treatment of uterine fibroids. One of the drivers behind the formation of the <a href="http://www.fusfoundation.org/" target="_blank">Focused Ultrasound Surgery Foundation </a>(highly recommend you visit this site if you are interested) is to drive use of this technology. Globally, there are a few players, but the main two you will hear about are Israel-based Insightec (GE owns 20% of the company) and Philips. Insightec's Exablate 2000 system was approved in the US in 2004 for uterine fibroids, a very common condition for women, and has received a CE mark in Europe. <a href="http://www.prnewswire.com/news-releases/insightec-submits-pre-market-application-pma-for-fda-approval-of-exablate-for-treatment-of-painful-bone-metastases-137945718.html" target="_blank">In January of this year</a>, Insightec submitted the very first oncology PMA (pre-market application, that is essentially an NDA-equivalent in device speak) for the treatment of painful bone metastases. Philips' system is not yet cleared for approval in the US, but does have CE mark in Europe, most recently for <a href="http://www.fusfoundation.org/Blog/philips-sonalleve-receives-ce-mark-for-mr-guided-focused-ultrasound-ablation-of-metastatic-bone-cancer" target="_blank">bone metastases pain palliation in April of 2011</a>. <a href="http://www.auntminnieeurope.com/index.aspx?sec=rca&sub=ecr_2011&pag=dis&itemId=604885" target="_blank">Per this article as well</a>, it is interesting to note that Philips only has 22 systems installed world-wide at the moment, though I expect we will see growth here in the years to come. Oddly enough, and usually in stark contrast to what one would expect, experts have commented that adoption of HIFU is largely being driven <a href="http://www.fusfoundation.org/Newsletter-Articles/asian-markets-are-leading-the-way-an-update-on-worldwide-focused-ultrasound-adoption" target="_blank">within the Asian markets</a>.<br />
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<b>Siavoche, you have a million journal articles on your blog. If you had to point me to a single one that gives me a great overview of HIFU, its clinical applications, and experience to date, which would it be?</b><br />
Here you go, a read I highly recommend if you are interested in HIFU.<br />
<iframe frameborder="0" height="120px" marginheight="0" marginwidth="0" scrolling="no" src="https://skydrive.live.com/embed?cid=D5139E805024FD7C&resid=D5139E805024FD7C%21242&authkey=ALmFCPhr7zdxcCA" style="background-color: #fcfcfc; padding: 0;" title="Preview" width="98px"></iframe>
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Let's take a closer look at the<i><b> bone indication</b></i> for HIFU, as this would represent the most immediate opportunity for Celsion's ThermoDox within the clinical setting alongside this novel procedure. For starters, this is a very different type of opportunity, and a more challenging one from a commercial perspective than with RFA for liver cancer. As indicated above, HIFU is still slowly gaining adoption, and ThermoDox is not even on the market yet, which stands in stark contrast to RFA, which is considered<i> the standard of care</i> for a segment of primary and metastatic liver cancer patients. So, the heating "modality" in HIFU is not as widely used, nor accepted at the moment, so again, a very different dynamic. Incidentally, RFA and cryoablation are being used increasingly for bone metastases, but that is the subject of another post.<br />
<br />
The other observation investors should note is that similar to the recurrent chest wall trials, the use of HIFU plus ThermoDox is not for treatment of the underlying disease, rather, it will be for palliative purposes. The RCW trial is looking at durable local response, which in that setting, is considered clinically meaningful. However, unlike RFA plus ThermoDox in primary liver cancer, the clinical setting for both RCW and bone metastases pain palliation is one marked by very late stage disease with patients refractory to multiple lines of treatment already.<br />
<br />
All that said, a very large proportion of patients with cancer (about 15-20%, primarily those with breast, prostate and lung cancer) develop metastases to the bone, while many have primary cancers originating in the bone. The market for the treatment of bone mets is a large one, as evidenced by Amgen's denosumab label expansion (Prolia for PMO, Xgeva for cancer indications) and a host of other competitors vying for a share of this market. A critical distinction to make is Amgen's Xgeva, for example, is only indicated for the <i>prevention</i> of bone mets (also called skeletal related events, which would be fractures resulting from such mets) rather than for palliation of pain associated with the onset of such metastases.<br />
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Typically, the standard of care for patients requiring palliation of pain from bone mets is external beam radiation therapy (EBRT), which is also a non-invasive procedure similar to HIFU. However, 20-30% of patients who undergo radiation therapy do not experience pain relief, and thus, are left with no options after that. Thus, the vast majority of studies to date with HIFU in bone mets have included patients in this setting, who have failed external beam radiation. In this setting, the primary endpoint is typically the visual analog pain score (VAS), reduction in pain medications, and local tumor control.<br />
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Before I litter you with what I would consider the cream of the crop of papers from trials conducted to date (see below, as per usual, I don't like to "cherry pick" data out, rather, I will leave it to you to read the abstract and or full report for yourself), I should also point out that there is an ongoing trial by Insightec comparing their HIFU technology head to head with external beam radiation therapy. The trial is <a href="http://clinicaltrials.gov/ct2/show/NCT01091883" target="_blank">currently enrolling patients</a>, and should have data by Q1 of 2013. This is a significant trial, in my opinion, because it effectively seeks to supplant external beam radiation therapy, which would significantly elevate the status of HIFU in bone metastases, and dramatically expand its commercial potential.<br />
<iframe frameborder="0" height="120px" marginheight="0" marginwidth="0" scrolling="no" src="https://skydrive.live.com/embed?cid=D5139E805024FD7C&resid=D5139E805024FD7C%21706&authkey=AM7Mf3cI1bz6Elc" style="background-color: #fcfcfc; padding: 0;" title="Preview" width="98px"></iframe>
<iframe frameborder="0" height="120px" marginheight="0" marginwidth="0" scrolling="no" src="https://skydrive.live.com/embed?cid=D5139E805024FD7C&resid=D5139E805024FD7C%21705&authkey=AIX45dy-dRmm_DM" style="background-color: #fcfcfc; padding: 0;" title="Preview" width="98px"></iframe>
<iframe frameborder="0" height="120px" marginheight="0" marginwidth="0" scrolling="no" src="https://skydrive.live.com/embed?cid=D5139E805024FD7C&resid=D5139E805024FD7C%21704&authkey=AD3iWmFcxMaZsUU" style="background-color: #fcfcfc; padding: 0;" title="Preview" width="98px"></iframe>
<iframe frameborder="0" height="120px" marginheight="0" marginwidth="0" scrolling="no" src="https://skydrive.live.com/embed?cid=D5139E805024FD7C&resid=D5139E805024FD7C%21709&authkey=AOxKFK8jU09bvZE" style="background-color: #fcfcfc; padding: 0;" title="Preview" width="98px"></iframe>=<br />
So where does all this leave ThermoDox? I am near the end of this article, and nary a mention yet. The reason for that is I think HIFU first needs to become entrenched as a mainstay of treatment for pain palliation in general, and then we can worry about adding additional treatments in combination with it. I try to be brutally honest with my readers, and at the moment, there is a steep adoption curve that will have to take place for HIFU <i><b>alone</b></i>, so that is where investors should keep their focus on for the time being.<br />
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Assuming HIFU takes off, which I truly think will happen (as evidenced by the significant investigator interest and trials with HIFU, not just in bone use), ThermoDox will come along for the ride and very quickly. What is interesting to note is that the vast majority of patients in the trials cited above received adjuvant and/or systemic chemotherapy, so the notion of adding ThermoDox would be a seamless transition for practitioners, particularly since the doxorubicin would be heavily concentrated locally where it would be needed most.<br />
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I will leave you with a final paper, which was very recently published online ahead of print in Radiology, another high-impact journal. The results from this animal study of ThermoDox for bone mets, in my opinion, are highly suggestive of potential clinical activity when and if the Philips/ThermoDox Phase II trial gets underway sometime by the end of the year (per Celsion, the wait is on Philips' end, as the FDA is still seeking additional safety data for Sonalleve. Remember, Sonalleve is not yet approved in the US). The results indicate that the delivery of significant concentrations of doxorubicin locally via ThermoDox is feasible (8 and 16 fold increase compared to unheated regions in marrow and muscle respectively). <br />
<iframe frameborder="0" height="120px" marginheight="0" marginwidth="0" scrolling="no" src="https://skydrive.live.com/embed?cid=D5139E805024FD7C&resid=D5139E805024FD7C%21707&authkey=AAs-ZJpu5IBIdE8" style="background-color: #fcfcfc; padding: 0;" title="Preview" width="98px"></iframe><br />
<b><span style="color: red;">(Edit: Addition 3/25)</span></b> One area that I will press the company for some clarity in the coming months is specifically what they expect the trial design of their planned Phase II with Philips to look like. All we know to date is that is going to be a phase II and focused on pain palliation, however, what I would like to know further is the following:<br />
<ul>
<li>What <b><i>line of therapy</i></b> is the trial going to be focused on? As I have outlined before, my suspicion is that its inclusion criteria will be patients who have failed EBRT.</li>
<li>Is the trial going to consist of a <b><i>single arm, or will there be a control group?</i></b></li>
<li>If there is going to be a control group, what is it going to be? HIFU plus a placebo? The problem with that is that I believe there would be specific target temperatures planned <i>a priori </i>for use with ThermoDox, whereas without ThermoDox, the goal would simply be pure ablation at high temperatures. This would make it hard to compare arms since the HIFU would not be held "constant".</li>
<li>What are the<i><b> primary and secondary endpoints? </b></i>I will venture to say, as I pointed above, VAS score will be the key measure here.</li>
<li>How many<i><b> trial sites</b></i> and in what geographies? </li>
<li><b><i>How many patients</i></b> would be enrolled? </li>
<li><b><i>How long</i></b> from the time of initiation of the trial to expected complete enrollment, and how long until final data? The good news here is that once all patients have been enrolled and treated, it will likely not take long for final data to accrue. </li>
</ul>
I will return to the HIFU topic in the future, as I left out a lot of information pertaining to the use of HIFU in liver and other solid tumors (this is really taking off in Asia). I will make no bones about one thing, however, and I have mentioned this to other fellow shareholders: If Celsion's Phase III HEAT study does<i><b> not </b></i>succeed (10%-15% chance in my opinion), even though it is an entirely different clinical setting, I think we can forget about ThermoDox in these other uses such as RCW and HIFU (simply because the company would not be in a viable position anymore in my opinion). That is also why I have not put much emphasis to date on HIFU on my blog. As we approach what I believe will, in fact, be <i><b>fantastic</b></i> final HEAT data, I think it is now time to turn our attention to these other innovative areas of use for ThermoDox.<br />
<br />
As always, feel free to leave me any questions or comments.<br />
<br />
Best,<br />
SiavocheMagicsiahttp://www.blogger.com/profile/06200209295387415335noreply@blogger.com0tag:blogger.com,1999:blog-5201890067787605901.post-62248777998110333312012-03-17T16:25:00.001-07:002012-03-17T16:26:54.763-07:00Interview with Celsion Investigator Dr. Steven LibuttiThis interview with Dr. Steven Libutti, conducted by Rodman & Renshaw's Reni Benjamin on 3/12/12, was recently posted by Celsion on their website and announced <a href="http://celsion.com/releasedetail.cfm?ReleaseID=657169" target="_blank">via a press release</a>. For those of you new to the Celsion story, I highly encourage you to listen to this in its entirety. Dr. Libutti not only touches on the promise of ThermoDox, but gives a highly informative overview of the HCC treatment paradigm, his own research interests, and future therapies on the horizon. Note that Dr. Libutti was not an investigator in the Phase III HEAT study, but will be leading the Phase II CRLM ABLATE trial.<br />
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<iframe frameborder="0" height="240px" marginheight="0" marginwidth="0" scrolling="no" src="https://skydrive.live.com/embed?cid=D5139E805024FD7C&resid=D5139E805024FD7C%21703&authkey=ADOnu-5eOAE9tTM" style="background-color: #fcfcfc; padding: 0;" title="Preview" width="320px"></iframe><br />
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Below are some of the salient highlights from this hour long interview, <i><b>specifically as they pertain to ThermoDox</b></i>:<br />
<ul><li>Margins of ablation are "main Achilles heel" for RFA </li>
<li>Temperature zone that activates ThermoDox extends "several centimeters" out from center of ablation</li>
<li>"Very reasonable safety profile"</li>
<li>"We saw interesting increases in the ablation zone, above and beyond what you would get with RF alone"</li>
<li>"PFS is an important endpoint for both HCC and metastatic liver disease"</li>
<li>"Plan is to get around 6 sites in the ABLATE trial...I believe Cleveland Clinic will be the next one"</li>
<li>"Ablative technologies like RF ablation and ThermoDox might be prime for the addition of an agent <i>after</i> the ablation to try [a la Bayer/Onyxx STORM trial] to hold the response...that is potentially an ideal use for pathway targeting therapies [i.e. like Nexavar, other TKI's, etc.]"</li>
</ul><div>It does not get any better than hearing directly from a key opinion leader in the field, particularly from someone with a specific interest in locoregional treatments of the liver such as Dr. Libutti. </div><div><br />
</div><div>Siavoche</div>Magicsiahttp://www.blogger.com/profile/06200209295387415335noreply@blogger.com2tag:blogger.com,1999:blog-5201890067787605901.post-1196112745201752212012-02-16T23:19:00.000-08:002012-02-17T10:23:31.977-08:00Quotes from the 2/13/12 BIO CEO Conference Presentation by Michael TardugnoI thought CEO Mr. Tardugno did a very good job presenting an overview of Celsion at the BIO conference earlier this week on Monday. See below for some "quotables" I pulled directly from the presentation:<br />
<br />
<div class="MsoNormal"><b><i>"We are delighted to have an audience….for a change."</i></b></div><div class="MsoNormal"><b><i><br />
</i></b></div><div class="MsoNormal"><b><i>"I want to make one comment. <u>Your company is in the best position it has been</u> since it transitioned to a development company. On the financials and fundamental perspective, the company is strong."</i></b></div><div class="MsoNormal"><b><i><br />
</i></b></div><div class="MsoNormal"><b><i>"From the beginning, we thought it was important to position our study with every potential for success."</i></b></div><div class="MsoNormal"><b><i><br />
</i></b></div><div class="MsoNormal"><b><i>"The trial is powered at 80% to show a 33% improvement. Interestingly, more than interestingly, one of the things we are quite proud of is this trial has a p value on this data set of .05."</i></b></div><div class="MsoNormal"><b><i><br />
</i></b></div><div class="MsoNormal"><b><i>"We’ve conducted ongoing meetings with the agency [FDA]. Every time we call they pick up the phone, every time we’ve asked for a meeting they’ve given us a meeting. I’d like to think that’s because of the quality of our management but I think it is, more importantly, a function of the disease we are studying and this wonderfully innovative approach that we are taking to treat tumors."</i></b></div><div class="MsoNormal"><b><i><br />
</i></b></div><div class="MsoNormal"><b><i>"The [HEAT] study has been the center of our life."</i></b></div><div class="MsoNormal"><b><i><br />
</i></b></div><div class="MsoNormal"><b><i>"We have asked the DMC to assess risk-benefit on an ongoing basis, as well as a panel of quality metrics. Given our radiologic endpoint, we wanted to make sure our data coming from our investigator sites are consistent with a quality data set that we can file with the FDA…this trial has been monitored frequently and regularly by the DMC and the most recent outcome was, in November, when we announced the successfully pre-planned interim efficacy analysis. What we expected happened, we had a unanimous recommendation from the committee to continue, meaning no evidence of futility or safety problems. <u>What was unexpected is that the DMC indicated to us that we presented them with a model for unblinding at the interim analysis that allows the company to take multiple looks at the data without any significant alpha hit. That’s unusual….on that basis we have submitted a letter to the FDA requesting within the SPA their view and support for a second interim analysis.</u> I get asked all the time when is that going to happen…frankly, we are breaking new ground here as a company, and I think even for the agency. So, we are hopeful to have an answer from the agency in the relative near term.<u> If we do, then I suspect that we could be looking at a 2<sup>nd</sup> interim efficacy analysis about the middle of the summer. </u>I want to point out that our independent statistician attached the DMC pointed out to the company, after reviewing enrollment rates and event rates, that the company could expect top-line data by the end of the year."</i></b></div><div class="MsoNormal"><b><i><br />
</i></b></div><div class="MsoNormal"><b><i>"The drug works, it simply works, there is no doubt about it."</i></b></div><div class="MsoNormal"><b><i><br />
</i></b></div><div class="MsoNormal"><b><i>"It’s on that [Phase I data] basis that we are so excited that the Phase III trial has a great chance to be successful. I want to say that to you, a great chance to be successful. When we look into the eyes and listen to the voices of our investigators who we meet with on a regular basis, we know they are interested in seeing data from this trial, and we clearly know they are interested in enrolling patients in this trial."</i></b></div><div class="MsoNormal"><b><i><br />
</i></b></div><div class="MsoNormal"><b><i>"If we make some very conservative assumptions, we are talking about capturing about 12.5% of this population, penetrating the market over a 5 year period, with some very conservative pricing assumptions, It’s a billion dollar opportunity. And that’s not just our assumptions. <u>We have had multiple multi-national companies conduct their own due diligence and they have come to the same conclusion."</u></i></b></div><div class="MsoNormal"><b><i><br />
</i></b></div><div class="MsoNormal"><b><i>"Partnering is very important to us. We have had multiple and currently have multiple partners doing diligence. What you can expect from us in terms of a license is something that not only represents value to us, but to our shareholders."</i></b></div><div class="MsoNormal"><b><i><br />
</i></b></div><div class="MsoNormal"><b><i>"We have more than 6 quarters worth of cash going forward, more than enough to see us through top-line data from the trial."</i></b></div>Magicsiahttp://www.blogger.com/profile/06200209295387415335noreply@blogger.com2tag:blogger.com,1999:blog-5201890067787605901.post-30207922228384026712012-02-04T09:54:00.000-08:002012-02-04T12:05:13.946-08:00Celsion 2012 Anticipated Milestones and Events<div class="MsoListParagraphCxSpFirst"></div><div>While it is hard to predict with any measure of confidence, below are my own estimates of potential company news releases from Celsion, and approximately when we can expect them in 2012. Note that many of these are "carryovers" from milestones that were <a href="http://celsion.blogspot.com/2011/08/what-rest-of-2011-holds-for-celsion.html" target="_blank">expected to happen in 2011</a>. The timing attached to each of these is simply a guess from my end, so do take it with a grain of salt. The wild card I see here is, of course, the Phase III HEAT SPA amendment process, as well as the timing for a potential 2nd licensing deal. At the rate things have been going from a business development perspective in the biotech world to kick off 2012, a 2nd license agreement could come any day it seems. That said, I think it will follow closely in the timeframe of the <i><b>potential</b></i> 2nd interim analysis.<br />
<br />
When I spoke to CEO Michael Tardugno just before the Christmas break, he made it very clear that the company is squarely focused on the tasks ahead of them. As is evident from this list, there are a lot of things on the company's plate. </div><ul><li><u><b>Q1 2012</b> </u></li>
<ul><li>Manufacturing of 3 registrational batches of ThermoDox complete </li>
<li>Treatment of 1st (of approx. ~90 planned total) patient in ABLATE randomized Phase II CRLM study </li>
<li>Announcement that HEAT enrollment of 200 patients in China has been completed </li>
<li>Go-forward decision for RCW Phase I/II protocol </li>
<li>Update on potential SPA amendment process for Phase III HEAT study </li>
<li>Update on Philips IND process for ThermoDox + HIFU in bone metastases</li>
<li>Key meetings: BIO CEO Conference Presentation (2/13), FY 2011 company call (mid-March) </li>
</ul></ul><div class="MsoListParagraphCxSpFirst"></div><ul><li><b><u>Q2 2012 </u></b></li>
<ul><li>Realization of sufficient PFS events (275-300 in my opinion) for <i><b>potential</b></i> 2nd interim analysis in HEAT study </li>
<li>Results from <i><b>potential</b></i> 2nd interim analysis </li>
<li>Update from Yakult-Honsha regarding new study of ThermoDox in HCC in Japan <b><span style="color: red;">(Note: Newly added after original post, how could I forget about this one?)</span></b></li>
<li>Initiation of newly expanded RCW trial (Phase I/II TBD, likely not registrational anymore) </li>
<li>Rolling NDA initiation for ThermoDox in HCC</li>
<li>Update on carboplatin preclinical work </li>
<li>Update on mystery “product #4”, and potential partner behind this initiative </li>
<li>Publication/presentation of RCW Phase I data at a selected medical conference</li>
<li>Potential 2nd licensing deal announced for all ex-US geographies, or for select ex-US regions </li>
<li>Key meetings: Q1 2012 company call, Annual Shareholders Meeting, ASCO, WCIO </li>
</ul></ul><ul><li><u><b>Q3 2012 </b></u></li>
<ul><li>Initiation of Philips/Celsion Phase II bone metastases study (although, again, I have seen some reports putting this at Q4 of 2012, no update on the company regarding this discrepancy yet) </li>
<li><i>Unfortunately, if no 2nd license deal, potential share offering at this point</i><b><span style="color: red;"> (Note: Upon second thought, moved this to Q3 from Q2)</span></b></li>
<li>Key meetings: Q2 2012 company call</li>
</ul></ul><ul><li><u><b>Q4 2012</b></u> </li>
<ul><li>If trial successfully stopped at 2nd interim analysis, NDA submission complete by this time </li>
<li>If trial did not stop at 2nd interim, or no SPA amendment granted at all, realization of 380 PFS events in HEAT study</li>
<li>Key meetings: Q3 2012 company call</li>
</ul></ul><div>I know a lot of savvy investors visit my blog, so if I missed anything, please let me know and I will update this list accordingly. </div><div><br />
</div><div>Best,</div><div>Siavoche</div>Magicsiahttp://www.blogger.com/profile/06200209295387415335noreply@blogger.com0tag:blogger.com,1999:blog-5201890067787605901.post-59871278564498557612012-01-13T19:05:00.000-08:002012-01-14T16:17:03.943-08:00Attention Stats Gurus - Is it Possible ThermoDox Hit its PFS Endpoint at the Interim?I won't even try to act like I am a statistics guru, but I want to bounce a particular journal article off my blog viewers to read. I received an email from another fellow shareholder (whose name I will not disclose) who directly influenced me to send Celsion CEO Michael Tardugno one of the several questions I recently posed to management:<br />
<br />
<b><i>It's clear from the recent CEO letter that the "no statistical penalty" verbiage from the interim PR was changed to "de minimis". I take this as reinforcing that the alpha penalty is negligible. Is the alpha spent on the next interim any less than the normal Lan-Demets because the company is able to "buy back" the alpha spent on the previous interim and redistribute it the new interim?</i></b><br />
<div><b><i><br />
</i></b></div><div>So, why, might you ask, would the DMC recommend the trial to continue even if the PFS data was strong? There could be many reasons:</div><div><ol><li>An early unblinding may have muddied the waters in China, as recall, the company continues to enroll patients in the HEAT trial in China such that a sufficient number of patients are enrolled to meet SFDA filing requirements. </li>
<li>PFS may have been strong, but there may not have been a well defined OS trend established. (though one could argue PFS and OS are strongly correlated)</li>
<li>Unblinding does present some problems in terms of OS as well, since patients in the control arm who have recurred (but remain eligible for RFA per inclusion/exclusion criteria of the trial), would be given ThermoDox. This could ultimately impact the confirmatory OS results upon realization of 372 events.</li>
<li>More generally, the DMC could not justify an early unblinding due to the risk-benefit profile established at the time, which would include number 2 above certainly.</li>
</ol><div>Anyways, the point is there may have been a myriad of reasons why the DMC may have used their judgment to recommend the HEAT trial continue even though PFS may have been strong. And for the record, even if a 2nd interim analysis is done, many of the same issues above may still apply (although I would imagine China would be fully enrolled by then).</div></div><div><br />
</div><div>The shareholder in question who I referred to above, by the way, was particularly intrigued by the CEO's comments in the initial press release that there would be "no statistical penalty" (later revised to "de minimis" penalty in the CEO letter) if a 2nd look was conducted after having received approval from the FDA via a SPA modification to do so. </div><div><br />
</div><div>I can't stress enough...the company was extremely conservative before the interim analysis in ensuring that the trial, in it's entirely, be conducted to the highest of standards, which includes not "tampering" with the original SPA. That tune has completely changed, and I would imagine that as of right now, they are in discussion with the FDA to do just that.</div><div><br />
</div><div>The paper below (Note the name of the author, Lan, as in "Lan DeMets") strikes at this precise issue in question. <b><i><u>I want to emphasize that I am by no means asserting this is indeed what happened during the interim analysis.</u></i></b> We don't know, and the company is only going off of what the DMC has recommended to them.<br />
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</div><div><iframe frameborder="0" height="120px" marginheight="0" marginwidth="0" scrolling="no" src="https://skydrive.live.com/embed?cid=D5139E805024FD7C&resid=D5139E805024FD7C%21624&authkey=AKMuQs8aUYNe3AQ" style="background-color: #fcfcfc; padding: 0;" title="Preview" width="98px"></iframe></div><div><br />
Best,<br />
Siavoche</div>Magicsiahttp://www.blogger.com/profile/06200209295387415335noreply@blogger.com0tag:blogger.com,1999:blog-5201890067787605901.post-13724126997404831122012-01-01T15:01:00.000-08:002012-01-02T12:13:41.059-08:00Some Great New Year's Reading, Quick Thoughts on ABLATEWhat a better way to start the new year than with more reading materials? :-)<br />
<br />
In all seriousness, I continue to add journals to the links at the top of my blog, and I recently came across some fantastic reads that span a few different areas of interest. A couple of these articles really dive into the "nitty gritty" of thermal ablation, and in particular, draw upon the potential synergies seen with adjuvant therapies in the "sub-lethal zone" of ablation. I have also posted a very recent review of locoregional treatments in general for HCC, and have included some articles to get your interest brewing in the ABLATE trial Celsion recently initiated, focusing on the role of RFA for colorectal liver mets. <br />
<br />
On the topic of CRLM, just keep in mind that while the population of patients with colorectal cancer is significant, and about 40-50% of them get liver mets at some point in their prognosis, it is <b><i>confined</i></b> liver mets (~25-30% of <i><u>all </u></i>patients, see the second to last reference below) where local treatment, such as RFA or surgery, would be used (this is reflected in the ABLATE trial protocol as well). This, of course, has implications for the "treatable" CRLM population with ThermoDox, impacting market potential estimates. Going even further, around 25% of that 30% are now treatable with surgery, so that leaves a little over 20% of patients that could receive some form of local treatment for colorectal liver mets (TACE, RFA, PEI, etc.), excluding surgery. Still, the numbers are significant from a market potential perspective for ThermoDox. Even if we say Celsion captures 10% at peak share capture, in the US alone, that is ~15,000 patients. Those numbers are even more important since the CRLM incidence primarily comes from the Western world, where Celsion is likely to have a more aggressive pricing strategy as well.<br />
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In regards to the ABLATE trial, I anxiously await news from the company in terms of a "first patient treated" press release, as I believe this should be imminent (in fact, this should have happened before end of 2011).<br />
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<b>Chem Physics Lipids- (in press) Synergy Lipo Thermal Ablation 2011.pdf</b><br />
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<iframe frameborder="0" height="120px" marginheight="0" marginwidth="0" scrolling="no" src="https://skydrive.live.com/embed?cid=D5139E805024FD7C&resid=D5139E805024FD7C%21594&authkey=ABBljJji7fLuYfI" style="background-color: #fcfcfc; padding: 0;" title="Preview" width="98px"></iframe><br />
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<b>Surg Oncol Clin- Basic Research in Thermal Ablation 2011.pdf</b><br />
<iframe frameborder="0" height="120px" marginheight="0" marginwidth="0" scrolling="no" src="https://skydrive.live.com/embed?cid=D5139E805024FD7C&resid=D5139E805024FD7C%21593&authkey=ABTzHnk9m4RxhrM" style="background-color: #fcfcfc; padding: 0;" title="Preview" width="98px"></iframe><br />
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<b>Can Treat Rev- Locoregional radiological Tx for HCC Which When How 2012.pdf</b><br />
<iframe frameborder="0" height="120px" marginheight="0" marginwidth="0" scrolling="no" src="https://skydrive.live.com/embed?cid=D5139E805024FD7C&resid=D5139E805024FD7C%21603&authkey=AETUUmUiFKzvx2w" style="background-color: #fcfcfc; padding: 0;" title="Preview" width="98px"></iframe><br />
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<b>J Surg Onc- RFA of CRLM Dec 2010.pdf</b><br />
<iframe frameborder="0" height="120px" marginheight="0" marginwidth="0" scrolling="no" src="https://skydrive.live.com/embed?cid=D5139E805024FD7C&resid=D5139E805024FD7C%21591&authkey=AGD_zPE0WwtXxik" style="background-color: #fcfcfc; padding: 0;" title="Preview" width="98px"></iframe><br />
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<b>J Surg Onc- Tx of CRLM Role of lap. RFA, Micr 2010.pdf</b><br />
<iframe frameborder="0" height="120px" marginheight="0" marginwidth="0" scrolling="no" src="https://skydrive.live.com/embed?cid=D5139E805024FD7C&resid=D5139E805024FD7C%21589&authkey=AEkuBLcnpoxQLJA" style="background-color: #fcfcfc; padding: 0;" title="Preview" width="98px"></iframe><br />
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<b>Cancer Control- Resection of CRLM Current Perspectives Jan 2006.pdf</b><br />
<iframe frameborder="0" height="120px" marginheight="0" marginwidth="0" scrolling="no" src="https://skydrive.live.com/embed?cid=D5139E805024FD7C&resid=D5139E805024FD7C%21587&authkey=AOcGu42zgyOmIyQ" style="background-color: #fcfcfc; padding: 0;" title="Preview" width="98px"></iframe><br />
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<b>Cancer Control- RFA of Liver Metastases Jan 2006.pdf</b><br />
<iframe frameborder="0" height="120px" marginheight="0" marginwidth="0" scrolling="no" src="https://skydrive.live.com/embed?cid=D5139E805024FD7C&resid=D5139E805024FD7C%21229&authkey=APwCnssbmWsj9BU" style="background-color: #fcfcfc; padding: 0;" title="Preview" width="98px"></iframe><br />
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<b>Int. J Surg Onc- Colorectal Liver Mets Review- Dec 2010.pdf <span style="color: red;">(Added 1/2/12)</span></b><br />
<iframe frameborder="0" height="120px" marginheight="0" marginwidth="0" scrolling="no" src="https://skydrive.live.com/embed?cid=D5139E805024FD7C&resid=D5139E805024FD7C%21605&authkey=ANgyTyn1RKCjNS8" style="background-color: #fcfcfc; padding: 0;" title="Preview" width="98px"></iframe><br />
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Enjoy the articles. I look forward to a busy 2012 for Celsion.<br />
<br />
Best,<br />
SiavocheMagicsiahttp://www.blogger.com/profile/06200209295387415335noreply@blogger.com0