Replies to post #115059 on Biotech Values

[tinkershaw]

It’s touting a metric—“bone-scan resolution”—that isn’t precisely defined and hasn’t been cited in previous peer-reviewed studies.

I agree, there is ambiguity in bone scans. But I still hold, the reason for no peer reviewed data is that nothing has ever produced bone scan results approaching anything close to what is being seen with XL184.

I do think it is a fair question to ask, "so what?". As that is the real question to be answered. What do these bone scans really mean? But I am not so much holding the lack of peer-reviewed data against EXEL at this time, because it is my understanding (and this comes from the December conference call from EXEL in which the experts discussed the issue, my anecdotal knowledge, and my lay knowledge of the progression and prognosis of this disease once it hits the bone (as I understood that resolution once it hits the bone is rarely ever seen).

So the question is still open, "so what?" but the lack of peer review data on the subject is not so concerning to me given the unprecedented data that has been shown on the bone scans. There simply was never anything similar to produce a historical analog.

As for the drug being passed up, it would not be unprecedented for big pharma to pass up on something good. This is not big pharma, but the biggest incident in the history of business is Xerox giving windows technology to Apple. It happens. But as to why it was passed up is pure speculation, and is reason to be more skeptical but I don't think it necessarily clouds the clinical data seen to date. It is the "so what" information that needs to be further answered in regard to what these bone scans mean.

Tinker

[AlpineBV_Miller]

Dr. Scher talked about this tangentially and noted there need to be standards set. That said, there are two distinct issues.

The first issue is drug activity. With no standard for assessment of the bone scans, a company could take advantage and oversell the data.

With EXEL, it's a little hard to oversell these data. The scans are remarkable and every doc I've talked to with experience using XL184 says the benefits of the drug are obvious, happen quickly, and disappear quickly when the drug is withdrawn (RDT has a randomized component that deprives non- soft-tissue progressors of drug). Anecdotal information suggests crossover after placebo in the RDT results in obvious, quick drug effect.

Osteoclastic (CTx) and osteoblastic (ALP/ALK) bone markers are largely in the same direction as the bone scans. Lessening of anemia and pain are also clinically-relevant associates of bone disease.

Finally, there is no experience in PCa of spontaneous bone disease reduction. These patients don't get better without intervention. Furthermore, there is no intervention that has done this previously -- which is one reason why nobody has bothered to create a standard for bone scans.

So from a "is mgmt lying/overstating" view of the issue of no standardized definition of response, I think this isn't an issue.

The second issue is regulatory path. This is a problem. Bone scan progression has been the death of many PCa drugs. Reading the Clinical Trials Working Group recommendations on this is instructive. They recommend ignoring initial bone scan progressions when adjudicating response. It's not until two and sometimes three scans later under these guidelines that you confirm bone scan progression (and then backdate progression to the initial date, incidentally).

There are many reasons for this, but the simple explanation is scintographs target osteoblastic bone activity -- which can be tumors or natural bone remodeling. Newer scanning tech (PET) will help here, but are new enough that there are also no standards.

Coming into the FDA with endpoints that create standards is risky business. This is what EXEL will be doing with XL184. IMO, this is where the risk is -- i.e. regulatory, not efficacy. Regulatory risk is nothing to sneeze at when entering Pazdur's house.

So while I might not agree completely with how Dew got there, I agree caution is needed.