In all honesty, this is not good news. It means that FDA wants to seek ODAC input into some aspect of the approval decision. When the questions for ODAC are published we will get a clear look at what is motivating the FDA. My guess is that it is related to the toxicity vs efficacy profile. It does mean that we will get an in depth look at the data and the history of the trial.
Best case scenario is that the June 2011 survival data is not tilted against Cabo and the FDA simply wants reaffirmation of the PFS endpoint and perhaps has labeling issues. Worst case is that the survival data is tilted against Cabo and the approval is tabled until the final OS analysis in 2013 or 2014.
Since they are seeking MAA for the European Union by the end of 2012: It will mean income, if accepted. Maybe with the money they have and Scott Garland's marketing knowledge they will handle European sales by themselves. My question is, is getting MMA approval faster and/or easier than FDA approval? No one seems to be including the European MAA process in these discussions. I wonder how much more money Europe can generate? I would think a fair sum.
I'm pretty clearly not the right person to opine on this, but my thoughts are as follows:
1) The EXAM trial was quite positive and had prior FDA buy-in (SPA). An approval has to be a positive event for the company, hence PPS should rise in anticipation of approval.
2)The need for an ODAC raises some uncertainty and a result that is problematic (range from some labelling issues to need for more clinical follow up to the need for another trial) with significant dealy could be disasterous. Raising money now could be seen as a hedge against the latter scenario, but I personally doubt that was EXEL's thinking (note: my own speculation, NOT based on any info other than the public events discussed on this MB).
3)The only upside I could imagine is if there is more thyroid data and EXEL asked for approval in more than just MTC (I doubt it since in general, MM gives all the potential outcomes and doesn't leave much room for unexpected upside).
4)Assuming the ODAC is benign, the PDUFA date doesn't move, and Cabo gets approval as currently scheduled,I would imagine gradual increase in PPS (dilution has already happened) with no huge jump after approval. After that, I would imagine that analysts will want to see more about marketing plans and revenue, something that has not been detailed to date. If these plans and their execution aren't credible and revenue estimates aren't met, the stock could end up getting punished again (Now I'm talking April-June 2013).
Obviously in the middle of all this is the potential for a partnership which could add short term cash as well as expertise in world-wide marketing and would presumably result in an increase in PPS.
Sorry to be vague, but from my perspective, the next few years are going to be tough to call and not for the faint of heart. If you truly believe that not only is Cabo active in prostate cancer, but markedly better than the many other agents being used and on the horizon, then the current price is probably a bargain. Personally, my sense is that the drug is active against multiple tumors, however, how EXEL can differentiate it from the many other agents that are out there remains to be seen. Also, keep in mind that with all the dilution, a market cap of > $1B no longer requires a PPS of $10. That's the problem with almost 150M shares outstanding...
Note that the above is all personaly opinion and should not be the basis for anyone making financial/investment decision. Do your diligence and make your own decisions with your money and...
Thanks for the feedback Ernie and Oncodoc. I guess I am just searching for some good news to cling to since the dilution and announcement of the ODAC meeting.
Ernie and Onco- any thoughts yet on how you might trade EXEL leading up to the ODAC meeting and then the PDUFA???
<<Is there any chance FDA/ODAC will consider Matt Smith’s prostate data when they meet to discuss the EXAM/MTC data in November??? Is there any precedent for this type of thing?? I guess these are $64,000 questions.>>
The problem is that the diseases are so different. The Matt Smith study primarily used bone scan response (an invalidated endpoint even in prostate cancer) to find that inflection point in dosage that maximizes efficacy vs toxicity. While a substantial percentage of MTC patients develop bone mets, it is of a different genetic makeup than that caused by PC. Also, an indeterminate amount of the MTC efficacy is likely due to RET inhibition, so Cabo's MOA across disease types is different. Pooling safety data across trials has validity, but especially in this case, trying to determine an optimum dose which has an efficacy and safety component requires an apples to apples comparison.
FDA can consider any data EXEL submitted as part of the NDA. Matt Smith's prostate data could be submitted to address issues of dosing and safety, however FDA might (reasonably so) consider MTC and HRPC populations different. If you're asking, could FDA look at submitted prostate data and approve Cabo in prostate, the answer is no. Process-wise, EXEL would need to, as part of the NDA, submit data in support of a label including prostate. For example, "Cabo is approved for use in: patients with castrate-resistant prostate cancer with documented bone mets who have failed treatment with....." Of course, with that request there would need to be data from adequate and well controlled studies supporting that label. At present, none of the prostate studies have met the standard for deomnstrating a clinical benefit in a well controlled setting (i.e. clearly defined population with randomized trial and demonstration of survival benefit).
Hopefully there will be no unexpected issues with ODAC but given the SPA discussion with FDA, I can't believe there will be anything positive from FDA until there are data from the COMET studies.
<<My guess is that the 40mg dose likely represents a lowest effective dose that will be a good candidate for combination therapies and for use in earlier disease stages where lengthy treatment duration would be an important consideration.>>
Is there any chance FDA/ODAC will consider Matt Smith’s prostate data when they meet to discuss the EXAM/MTC data in November??? Is there any precedent for this type of thing?? I guess these are $64,000 questions.
<<I've doing some homework based on the published rationale for the Abby/ Cabo dose finding study...and am hopeful for a pronounced synergystic result when they publish.>>
That study is now posted on clinicaltrials
There is a certain amount of conjecture in the literature about abiraterone resistance being MET driven. With abiraterone's beneficial effect on soft tissue and PSA levels and Cabo's effectiveness on bone mets, there is reason to hope for a strong synergistic effect. The study is fairly small and is in a post chemo indication which should select for patients with bone mets.
Once again, thanks for the tutorial, Ernie.
I admire your ability to assimilate & diseminate.
As to the promise of future combination trials w Cabo, I've doing some homework based on the published rationale for the Abby/ Cabo dose finding study...and am hopeful for a pronounced synergystic result when they publish. I'm also a fan of ARQ-197, and suspect that a future combination w Abby is inevitable, as the same therapeutic rationale would seem to apply.
The RDT trial used a 100mg dose (equivalent to the GBM 125mg dose). This was the trial which revealed the the bone met resolution phenomenon. By this time also investigators were more aware of the toxicity issues and were quicker to reduce dose as problems arose. At the 100mg dose, the bone response rate was substantial, but the dose reduction rate was still high, 51%.
The GBM experience clearly showed that 100mg was a better dose than 140mg. Efficacy and safety were both improved. The data still did not identify where the inflection point was located at which further dose reduction would improve or worsen outcome. The optimum dose was less than 140, but sill open to question was whether 100 was still a higher dose than necessary. Treatment related grade 5 events were still occurring and toxicity was an issue with high SAE rates.
The Matt Smith dose reduction trial was initiated to help answer the dosing questions that remained. It primarily used bone scan response as a marker for efficacy. Circulating tumor cell data was also collected.
This trial clearly showed that 40mg was superior to 20mg. It also showed that 40mg from an efficacy perspective was probably comparable to 100mg and superior from a safety perspective. Confirmed bone response rate was 100mg=76% and 40mg=67%. Dose reduction rates were 100mg=51% and 40mg=0.
In addititon to the low dose study, the nonrandomized expansion cohort of the RDT is using a 40mg dose on 53 patients. Those results have not been reported yet.
EXEL looked at the 40mg data and felt that the optimum starting dose was likely between 40mg and 100mg. There was a very small drop in efficacy from 100 to 40 and a very large improvement in tolerability. Settling on the 60mg initial dose is an informed guess. Cabo is still a toxic drug. Even at 20mg, the low dose trial reported a venous thrombolytic event (serious blod clot). At 60mg in the various trials going forward, I think we will still see SAE's and the occasional treatment related death, but I suspect and hope that the fistula and colorectal perforation related deaths will diminish greatly.
My guess is that the 40mg dose likely represents a lowest effective dose that will be a good candidate for combination therapies and for use in earlier disease stages where lengthy treatment duration would be an important consideration.