Monday, June 4, 2012

Dr. Ronnie Poon, HEAT Lead Investigator, Discusses HCC, Outlines Potential of ThermoDox

Released coincident to this year's ASCO conference, I was excited to see another investigator interview recording made available by Celsion today. 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), which I commented on as well.

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.

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).
  • 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. 
  • 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.
  • Transarterial treatments such as TACE and deb-TACE are used for patients with very large tumors, 5-6 lesions in number.
  • 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 (some data does challenge what he said though, but it's a moot point since few patients are eligible for surgery anyways).
  • 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. 
  • 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.
  • 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.
  • Regular doxorubicin suffers from very high toxicity, ThermoDox is "definitely a safe drug", with side effects that are "not clinically significant"
  • 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"
  • 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). 
  • High quality trial sites selected in the HEAT study should help to reduce site to site variation in data
  • 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. 
  • 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.
  • 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.
  • 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.
  • 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).
These were just the salient points brought up, again, I do recommend investors listen for themselves:

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.

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.

Best,
Siavoche

4 comments:

  1. Sia, given the Roth comments and now Dr. Poon, would you consider these "tells" in terms of thinking we should start upping the estimated pricing range?

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  2. Trond, great hearing from you! I think one could easily argue that, but there are lots of big assumptions that materially change estimates (like assuming 25,000 per dose versus 50,000 for pricing, for example, and pricing in China is still a mystery). I could easily envision a scenario with aggressive pricing and off-label inclusion where the stock could have a 15-20 target. I am happy with 10 at the moment!

    As you know, it will ultimately all depend on the data...

    Sia

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  3. Hah, Trond, I just realized you were talking about price ranges for the drug, not for the stock. I still think 50k per dose (per single administration that is) is far too expensive, especially for a repurposed version of generic drug, regardless. 15-30K max, that is the range I would be playing with.

    Where things get interesting with pricing is in the EU. Centralized filing for the EU is one thing in terms of the MAA, getting market access and reimbursement is a completely separate story, and one they will need to get on a country by country basis. Each country will require pharmacoeconomic modeling to support their pricing, and they will be looking at cost/QALY as one metric (beyond 30,000/QALY, things get hairy, at least according to UK's NICE).

    In the US, if they priced ThermoDox at 100,000 per dose, lets say as a wild example, nobody would stop them from doing so, but you can be sure payers would put all kinds of restrictions on the product, such as a prior authorization that might stipulate specific tumor sizes, evidence of technical failure first perhaps, evidence of documented recurrence perhaps, who knows. Or, they could say, try RFA + TACE first (called a Step Edit), then and only then, will we grant access to ThermoDox plus RFA.

    They have to be very careful with pricing, and I would argue that many analysts do not have a proper understanding of some of the aforementioned issues.

    Best,
    Sia

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  4. Sia:

    What is the latest on insider transactions? Any buys or sells? Yahoo finance doesn't seem to update it that well. Wondering if we will see any buys before q4 data. That will speak volumes imo. Thoughts?

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