The Celsion HEAT Study and Japan: Brief Overview

With respect to Celsion and the Phase III HEAT study, one of the questions potential investors/stakeholders might ask (and rightfully so) is the following:

"If things are going so well in the HEAT study, what is going on in Japan and why is the trial paused for enrollment there?"

Again, this is a great question and one that provoked me to coalesce all the facts from the various company conference calls and presentations into a cohesive article. Here is an overview of Celsion, the HEAT study, and Japan, broken into as many discrete facts as possible.

1. For starters, Japan is a indeed a very important and large HCC market, technically, the largest developed country market for HCC in the world. 
2. Celsion partnered with Yakult to develop Thermodox in Japan in mid 2008 (http://celsion.com/releasedetail.cfm?ReleaseID=328465), representing Celsion's first license agreement (later to be amended, see bullet 10 below). Yakult is funding the HEAT trial in Japan, and funds it solely.
3. A near consensus in the literature clearly shows Japan as having one of the slowest drug approval processes in the world, compounded by severe bureaucracy and stringent regulations. This is now a basic starting assumption most pharma companies have in approaching the Japanese market for product commercialization (As one example, Nexavar was approved for HCC in the US in November of 2007, and in Japan in May of 2009).
4. Japan will rarely allow manufacturers to skip to a phase 3 trial without prior clinical study in phase 1/2 studies specific to patients from its own population. Recall that Celsion's Phase 1 studies did not include any Japanese patients. Celsion's/Yakult's ability to jump straight to Phase 3 trial in Japan as part of the HEAT study is, in my opinion, somewhat of an 'innovative' approach, and not usually done. (Read item 3 on page 5 from this overview of conducting trials in Japan from the PMDA: http://www.pmda.go.jp/english/service/pdf/notifications/0928010-e.pdf)
5. In late 2010, the DMC decided to suspend further enrollment in Japan only following a review of safety data from 18 patients enrolled to date at that time (http://celsion.com/releasedetail.cfm?ReleaseID=512752). This was re-recommended in February, as the DMC was still 'pending certain guidance' from the Japanese FDA equivalent, the PMDA (http://celsion.com/releasedetail.cfm?ReleaseID=549437).
6. Dr. Borys mentioned in the Q1 2011 conference call that the hold was neither a 'clinical nor regulatory' hold, but rather, related to differences in standard of care. This was actually first reported by well-respected blogger, G. Chambers from Gekkowire.com (http://www.gekkowire.com/?p=7671). At the 2011 annual shareholders meeting, CEO Michael Tardugno mentioned in detail that the difference in SOC relates to the fact that Japanese patients undergoing RFA in general are often hospitalized for an extended period of time, in contrast to the rest of the world. Thus, Japan has collected an abundance of hospitalizaton-related safety data that appears to be incomparable to the rest of the world.
7. In the now outdated CEO letter from last December (http://celsion.com/letter.cfm), Michael Tardugno clearly states that the Japanese cohort, just like the rest of the world, have safety profiles consistent with the doxorubicin label. This is quite an important point as it pertains to safety.
8. Keep in mind outside of Japan, 582 patients were enrolled in the HEAT study. There have been four (unless I missed a PR) unanimous DMC recommendations to continue enrollment throughout the trial. To the extent that the pause in Japan is related to some kind of safety issue collected as part of routine hospitalization of patients undergoing RFA in Japan, the broader DMC recommendations for 582 patients likely eclipses those concerns (Not to mention, by the way, that recurrent chest wall (RCW) breast cancer patients treated with Thermodox receive 4-6 cycles of Thermodox, in contrast to just 1 in the HEAT study, and the MTD was recently set at 50mg/m2, exactly as in the HEAT study). 
• http://www.celsion.com/releasedetail.cfm?ReleaseID=469443 
• http://www.celsion.com/releasedetail.cfm?ReleaseID=512752 
• http://www.celsion.com/releasedetail.cfm?ReleaseID=549437 
• http://www.celsion.com/releasedetail.cfm?ReleaseID=590333
9. To round out potential safety concerns, in one of the very few instances where a key investigator of the HEAT trial was quoted publicly, Dr. Lencioni, one of the most influential KOLs in the HCC space and lead EU HEAT trial investigator, said there were no safety issues in the HEAT trial. In my opinion, his assessment was a reflection of the trial in its entirety, including Japan. (http://www.medscape.com/viewarticle/739078)
10. In January 2011, Yakult and Celsion agreed to a revised license agreement, whereby Yakult agreed to pay Celsion $2M upfront and $2M when and if enrollment resumes, in exchange for a 40% reduction of approval related milestone payments (http://celsion.com/releasedetail.cfm?ReleaseID=543572). I think one could reasonably conclude from this revised agreement that it represents a strong sign of confidence from Yakult. 
11. The data collected to date from the 18 patients enrolled in Japan will be used in all future trial analyses, including the interim and top-line read-outs. To hit the point home, these 18 patients forever will remain part of the HEAT study (I confirmed this with investor relations via a telephone call June, 2011).
12. Celsion needs 60 patients in Japan to support registration. Since enrollment has completed without Japan, Celsion will pursue patients from Japan above and beyond the 600 to support registration.
13. The current SPA agreed to with the FDA is completely unaffected by any of the above-mentioned issues in Japan, and the company will be able to get approval in the US, China, EU and any other country where they have recruited enough patients for local approval.
14. In the most recent 2011 Q2 conference call, Dr. Borys was quoted as saying: “Now that our HEAT study has met its goal of 600 patients, our partner in Japan, Yakult, is planning to continue an evaluation of Thermodox in Japan in a separate study.” What specific protocol is used, when this next study initiates, or any other details are not yet known, though I am sure we will be hearing from the company in the near future. But, we do know with certainty that Thermodox will be studied in Japan, with full support from their partner, Yakult.

In summary, it is unfortunate that potential approval of Thermodox in Japan (assuming the trial is successful, of course) is now all but guaranteed to be delayed relative to the rest of the world. However, given the unique characteristics of the Japanese regulatory system and the collective, historical experience of several other drug companies seeking to develop and commercialize their products in Japan, it also does not surprise me in the least bit. I'll be sure to provide any future updates on Japan as they materialize.

If you have any comments or if I missed something above, as always, feel free to let me know.

Best,
Siavoche