I think yesterday's ODAC is hurting the stock a bit today. Here is the FDA briefing document:
and here are the formal questions to the committee:
And here is the Amgen Denosumab trial that is currently under consideration for a supplemental BLA. The application has a PDUFA date of Apr 26, 2012.
This meeting centered around a specific indication. Non Metastatic Castration Resisitant Prostate Cancer Patients. The FDA clearly resents the fact that this indication exists and that sponsors are developing drugs for use in this indication. First, who are these patients? They are men who initially presented with locally contained disease and underwent an attempt at a curative procedure, either prostatectomy, or radiation treatment. Such treatment should result in a PSA level of zero. Unfortunately many men go on to show detectable rising PSA levels indicating that the disease has spread, although on Non Metastatic patients, the disease is undetectable, except for serum PSA. There are currently no approved treatments for these men, but many oncologists do use physical or chemical castration on a subgroup of these men who appear to have more agressive disease. When these men relapse with PSA again detectable and rising, they then comprise the CRPC indication. Those with only PSA detectable disease are non metastatic CRPC.
Amgen did a study on these men with Denosumab and succeeded in delaying bone scan detected mets by 4 months (29.5 versus 25.2 months, respectively). So now the FDA is wondering what to do with that data. I suspect there was not an SPA.
In the meeting, there were two factions. The urological oncologists who were put on the defensive to explain the off label use of ADT in PSA only patients and the non-urologists who were critical of the current state of affairs. The urologists were also the most friendly toward the use of bone scan as a surrogate, but the non urologists were the most critical of this proposal. The off label use of ADT was compared to overuse of antibiotics for ear infections. A breast cancer specialist could not grasp why ADT was continued after progression, she could not get past a comparison to hormone sensitive breast cancer. Dr. Smith read a statement into the record and was castigated by more than one committee member and not being on the committee was unable to respond with counterargument.
It was an ugly day for Dmab, and by proxy any drug hoping to use a bone scan endpoint in a non metastatic CRPC indication.
The Cabo 306 trial will presumably be in a downstream indication, so what was said about bone scan relative to the upstream indication is not directly applicable. However, the tone of the meeting was such that the members are clearly anti-surrogate and pro survival and are relatively unsympathetic as to the difficulties posed by attempting to run a pivotal trial in the now crowded indications with long survival times.
Clearly, a bone scan resolution endpoint will be a tougher sell to the FDA today than it was last week. The briefing materials and committee bias assured a negative result. Had the board had more urologists, the outcome might have been more favorable.
Thanks Ernie for your insightful analysis,
Can you however explain -"The Cabo 306 trial will presumably be in a downstream indication, so what was said about bone scan relative to the upstream indication is not directly applicable"
<<Can you however explain -"The Cabo 306 trial will presumably be in a downstream indication, so what was said about bone scan relative to the upstream indication is not directly applicable">>
An indication is a specific description of the patient for whom a medication is recommended.
In general--a drug that is given in the adjuvant setting is given to a newly diagnosed patient in conjunction with surgery and/or radiation in a curative attempt. A drug given in first line metastatic disease is the first approved drug regimen for newly diagnosed metastatic inoperable disease. Second line treatment follows failure (progression) on first line. Salvage therapy is a vague term for an attempt at an improvement or remission after another therapy has failed. Finally, some drugs are considered palliative, they do not cure or impede disease progression, but relieve suffering and improve quality of life.
I used upstream and downstream to mean earlier or later in the disease cycle as defined by specific indication. Prostate cancer is becoming crowded and the lines of treatment progression are blurred. There are now 2 approved chemotherapies, besides physical castration there are at least two approved ADT agents, and now the immunotherapy, Provenge.
FDA has a sliding scale for allowable endpoints of a pivotal trial. Upstream (early) indications generally require endpoints that are of obvious direct benefit to the patient. Downstream (later and sicker) indications get more lenient treatment with the FDA allowing surrogate endpoints that are likely to correlate to something of benefit to the patient.
So as the discussion yesterday relates to EXEL. The meeting revolved around an indication that is early in the natural history of the disease and EXEL is contemplating a trial in this indication, but it is the 3rd trial on their current agenda. The first trial will be the 306 trial which presumably will be in an indication following progression on one or both approved chemotherapy regimens.
Statiscally speaking, the limited scope of this meeting makes it a clear miss. Don't a very large percentage of CRPC patients eventually display symptoms of bone metastasis...like close to 90%? if the FDA so clearly resents this limited non-metastatic indication, why mess around with it? Sounds a bit like a wasted afternoon, at least on behalf of the majority of CRPC patients...doesn't it?
<<Statiscally speaking, the limited scope of this meeting makes it a clear miss.>>
Yes and no. This is an indication that EXEL would like to do two trials in. The first would be a trial to prevent bone mets, similar to the one that Amgen just finished. The second would be a Cabo plus ADT vs ADT, (likely abiraterone) with a PFS or survival endpoint (very expensive). After what we heard, FDA would want that trial to be Cabo plus ADT vs ADT vs watchful waiting. That would pose enrolment problems. Nobody with agressive disease wants to be on placebo. That was pointed out several times yesterday, with limited impact.
For the near term you are right, except with the caveat that the committee members seemed pretty negative toward a bone scan endpoint, I think even in a post chemo indication, they would have objections. Scher tried to make the point that with more and more approved alternatives, teasing out the effect of a new drug with a survival endpoint would become more and more difficult. The FDA guy just blew him off saying that proper randomization could account for patient alternatives once off trial.
<<Don't a very large percentage of CRPC patients eventually display symptoms of bone metastasis...like close to 90%? if the FDA so clearly resents this limited non-metastatic indication, why mess around with it?>>
FDA can't stop off label use. Now that ADT is the de facto standard of care for aggressive non metastatic disease it is too late to put the genie back in the bottle and do a trial. They can't ignore the indication because drug companies are developing drugs to treat the population. They don't like an ADT control arm, because it has never been shown to be of benefit. They are a dog chasing its tail.
<<Sounds a bit like a wasted afternoon, at least on behalf of the majority of CRPC patients...doesn't it?>>
It does. I'll take it a step further. I see them erecting roadblocks to the development of effective drugs in the name of statistical sanctity.
Not to second-guess the expert clinicians at either Exelixis or FDA, enjoin me for a moment. Ernie, as one of the most informed on this MB - given the opportunity to design your considered optimum efficacy trial for CABO - and also one that might have the greatest chance of approval...while also providing the quickest pathway to access to the most numerically challenged unmet medical need... all the while optimizing shareholder value...
What might you design? How might you differently navigate the FDA minefield? Are you satisfied-at this juncture- that inasmuch as can be expected - CABO is being pushed in the best directions? What might you do differently?
<<What might you design? How might you differently navigate the FDA minefield? Are you satisfied-at this juncture- that inasmuch as can be expected - CABO is being pushed in the best directions? What might you do differently?>>
I have never worked in the industry, so anything I say is no more than rank speculation. It's really hard to second guess what is happening between EXEL and the FDA when we only get snippets of the exchanges. The only time those communications are ever revealed to any degree is if the drug goes before ODAC. In that case the back and forth on trial design and subsequent amendments are usually detailed.
There are two main aspects to designing a successful trial. Enriching the patient base with those most likely to benefit and then having an endpoint that has a high probability of success. The more the patient base is narrowed, the smaller the approvable indication becomes. If the sponsor wants to conduct the trial under an SPA, then the primary endpoint has to be negotiated with the FDA. Doing so can delay the trial start, but there is less danger of having what Amgen is going through now with Dmab, a successful outcome that is unlikely to gain approval.
In CRPC, Cabo has 2 likely treatment benefits that can translate into endpoints for which there is approval precedent established. It results in pain improvement and will likely result in fewer skeletal events. Of the two, pain improvement is the quicker and cheaper route to approval.
What EXEL should be doing (and probably is) is exploring what the FDA requires in the way of validation for a bone scan endpoint. The 307 trial is presently envisioned to be a survival trial. That would be an excellent opportunity to correlate bone scan improvement to improved survival. That could mean a quicker route to approval for other indications and could also lead to more off label use.
I cannot fault the current Cabo clinical program. Perhaps they have been slow to accept that lower doses may retain efficacy, but I'm pretty sure the MTC trial incorporates dose reductions into the protocol. They received a lot of criticism over the years for having a broad, diffused and expensive clinical development program, but I will point out that it was because of that ambitious program with a 12 indication RDT, that the bone scan resolution phenomenon was discovered. Gotta go.
<< In CRPC, Cabo has 2 likely treatment benefits that can translate into endpoints for which there is approval precedent established. It results in pain improvement and will likely result in fewer skeletal events. Of the two, pain improvement is the quicker and cheaper route to approval. >>
I guess till our antiquated regulatory science administrators can adequately & progressively evaluate these modern pharma technologies, we'll have to settle for what we can get, eh?
Thanks for the discussion, Ernie. Good luck to you, Sir...