Saturday, March 24, 2012

HIFU for Bone Metastases - Brief Overview and Implications for ThermoDox

As 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.

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:

What is HIFU?
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 nice splash at TEDMED 2011 in a presentation by Insightec's (see below) Yoav Medan.

What are some potential indications HIFU is being tested/used in?
Indications of interest for HIFU include the following:
  • Bone metastases
  • Brain tumors
  • Epilepsy
  • Essential tremor
  • Liver tumors
  • Neuropathic pain
  • Parkinson's Disease
  • Prostate tumors
  • Uterine Fibroids
Is HIFU approved in the US/EU/Ex-US? Who are the key players?
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 Focused Ultrasound Surgery Foundation (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. In January of this year, 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 bone metastases pain palliation in April of 2011. Per this article as well, 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 within the Asian markets.

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?
Here you go, a read I highly recommend if you are interested in HIFU.

Let's take a closer look at the bone indication 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 the standard of care 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.

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.

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 prevention 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.

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.

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 currently enrolling patients, 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.
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 alone, so that is where investors should keep their focus on for the time being.

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.

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).

(Edit: Addition 3/25) 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:
  • What line of therapy 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.
  • Is the trial going to consist of a single arm, or will there be a control group?
  • 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 a priori 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".
  • What are the primary and secondary endpoints? I will venture to say, as I pointed above, VAS score will be the key measure here.
  • How many trial sites and in what geographies? 
  • How many patients would be enrolled? 
  • How long 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. 
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 not 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 fantastic final HEAT data, I think it is now time to turn our attention to these other innovative areas of use for ThermoDox.

As always, feel free to leave me any questions or comments.


Saturday, March 17, 2012

Interview with Celsion Investigator Dr. Steven Libutti

This 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 via a press release. 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.

Below are some of the salient highlights from this hour long interview, specifically as they pertain to ThermoDox:
  • Margins of ablation are "main Achilles heel" for RFA 
  • Temperature zone that activates ThermoDox extends "several centimeters" out from center of ablation
  • "Very reasonable safety profile"
  • "We saw interesting increases in the ablation zone, above and beyond what you would get with RF alone"
  • "PFS is an important endpoint for both HCC and metastatic liver disease"
  • "Plan is to get around 6 sites in the ABLATE trial...I believe Cleveland Clinic will be the next one"
  • "Ablative technologies like RF ablation and ThermoDox might be prime for the addition of an agent after 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.]"
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.