Replies to post #129999 on Biotech Values

[p3analyze]

Well said. The SPA seems to have improved the pain response endpoint definition significantly. While the lack of resolved SPA is a disappointment, the number of pivotal studies that proceeded without fully resolving FDA comment is more prevalent than people may think. 306 may emerge as the only study in a while to attain the pain response endpoint as it seems clinical folks at EXEL fully understand the challenge of collecting such pain instruments in a large multinational trials and crafted this smaller study to focus on this endpoint, notwithstanding it remains to be seen whether the phase II pain response data were as robust as what have been claimed.

What's puzzling is how analysts underestimated the complexity of SPA and assigned such weight to it. So was the precipitous drop. The medullary thyroid cancer will get their foot in the door, and would lower technical risk for sNDA significantly imo. Without that, I suspect they will be less reluctant to invest in a 10- million dollar non-pivotal study.

That said, I agree the management's characterization of the event as a surprise is a bit disingenuous - they know all along an OS trial, aka 307, is needed for CRPC indication- and that bone scan endpoint is a novelty that FDA is not ready to embrace.

JMHO

[urche]

EXEL

To me, the lession is not to make big deal out of SPA, rather having FDA's input on trial design. Maybe I am biased because I really thought composite endpoint had no chance to succeed unless you have separate data to make that interpretation possible.

I agree with you and would argue , moreover, that the SPA attempt was misguided and far fetched using pain and/or bone scan resolution as endpoints.

Here are more of my thoughts cross-posted from a MF board which I post mostly because to my knowledge the 8-K filed yesterday was informative and I have not seen it discussed here.



The FDA's latest response, which the Company received on October 28, 2011 (the "October FDA Response"), raised the following concerns regarding the '306 trial design in the context of its consideration of a SPA for the trial, among other comments:

? A concern about the ability to maintain blinding of the trial due to differences in toxicity profiles between cabozantinib and mitoxantrone.

? A view that the assumed magnitude of pain improvement is modest and could represent a placebo effect or be attained with less toxicity by opioid therapy.

? A view that symptomatic improvement should be supported by evidence of anti-tumor activity, an acceptable safety profile and lack of survival decrement. The FDA also expressed the view that if the effect that the Company believes cabozantinib will have on pain is mediated by anti-tumor activity, that anti-tumor activity should translate into an improvement in overall survival.

? A recommendation that if the Company uses pain response as a primary efficacy endpoint, that it conduct two adequate and well-controlled trials to demonstrate effectiveness as, according to the FDA, a conclusion based on two persuasive studies will always be more secure. The FDA advised that for a single randomized trial to support a new drug application, the trial must be well designed, well conducted, internally consistent and provide statistically persuasive efficacy findings so that a second trial would be ethically or practically impossible to perform.

As I read this, CABO never had a chance for SPA with the trial envisioned by EXEL. In fact, with such strict criteria, IMO the bar is so high that it is hard to imagine any other new drug for prostate cancer being viewed more favorably. So, I think that being denied an SPA for a trial with pain or bone scan resolution as primary endpoint is not surprising.

For me the interesting question that I would like to see explained more to my satisfaction is, given the FDA response, why did EXEL choose to focus first on the 306 study instead of putting their energy and $ into the larger, more expensive survival study that they knew they would have to do anyway? Resources are now tight for EXEL, and to run even 307 to completion is likely to need more money which would be painful at the current share price.

Urche

[jq1234]

XL184 306 SPA

EXEL CEO gave more color on the 306 SPA during Piper Jaffray Health Care Conference Call on Nov 29, 2011. Transcript is terrible, but you get the idea: FDA thought the proposed delta of 17% for pain response rate between cabo and mito/prednisone as too small.

Mike Morrissey

Yeah. Well, I think an SPA would have been certainly to prefer really to go relative to having a loss in agreement on a trial which we believe is a very important part of the process relating to how we hope to again build this commercially differentiated profile for cabo.

That being said, we had a very good dialogue with the FDA. We’ve gone into great detail on the call we’ve had back in October and I think in all the different documentations. We have -- in that dialogue we had two-step process, if you will. We had a pre-end of Phase 2 meetings before ASCO. We’ve got some of the documentation after ASCO. The first set of feedback that we got in the August timeframe was actually very encouraging. We were -- a number of enhancements were suggested to put a protocol around inclusion criteria, response criteria, narcotic optimization, the nature of the bone scan response and primary what’s their endpoint.

All things that we, I think we’re very happy to deal with and include in the protocol relative to the fact that we had very high level of confidence in the bone scan response data that came from the RDT trial, as well as but we were seeing not from the normal randomized that was recently published now at EORTC.

I think the difference came into play on the second round of feedback, where I think the magnitude of the response was being to be small or too small relative to the potential for inability to under winding by the differential AE profile of cabo versus mitoxantrone.

We had a 17% delta in the confirmed team response rate between cabo and mito/prednisone. Cabo was the trial was designed at 25% confirmed response rate for pain, for cabo 8% was mitoxantrone/prednisone. And the feedback was that well that’s probably through small to be able to get around the idea of underlying with chemo.

And that was a judgment issue, I think at that point in time we had pretty clear picture of what the agency was looking for in terms of the overall protocol, importantly the magnitude of the effect of 25% versus 8% was reasonable. We think we could probably beat that certainly the -- if you look at the NRV data from EORTC that the number of patients that had about a 30% reduction was about half the patients that we studied, so using that as kind of a good metric for what we might see in 306, one could imagine we had a much higher confirm pain response.


We weren’t prepared to commit to a higher level, why raise the bar for a trial that obviously is important one too, I think the issue is the data will define the utility of that lead out relative to a label and we don’t really response for that, the data will speak for itself. We’re planning to run the trial very, very carefully and collected exhaustively and we’re confident in what we’ve seen so far from a data point of view relative to this impact on pain.

Again, this is a different profile and we’re seeing some other compounds to-date. Our goal ultimately is to have a survival trial i.e. 307 and the pain trial 306 lead out at approximately the same time where we’re modeling in the first half of 2014, if that is to be the case maybe a little bit sooner, we would be able to then again have a strong foundation to go forward with a label that would support both the survival we have, but also a reduction in pain, reduction in narcotics both in response.

So ultimately it’s that differentiated commercial opportunity that will drive value and we, again, based upon the data that we have from the last 275 patients its going pretty good as how that’s going to go.

http://seekingalpha.com/article/311125-exelixis-ceo-discusses-at-piper-jaffray-health-care-conference-call-transcript?source=yahoo