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Those lambda data make my head hurt.
Ipi pricing 3 vs 10 is among the many head-shaking things about today's news, I agree.
Man, I don't know but my guess is they are larger than chemo. About 13% of patients die from the drug or have to have surgical intervention. Some other percentage on that path are resuced by hospitalization and intensive steroid therapy. Patients can be sailing along fine then weeks to moths after last therapy have their GI tract go south unexpectedly, which means any decent doctor will schedule regular follow-ups for months after final dose -- not just to check disease but to check side effects.
To be honest, I can't believe.... well, I can't beleive the drug was approved on the 020 data so...
But past that, I can't believe it wasn't approved without a REMS program requiring education. The casual community oncologist trying this drug is going to kill patients. Provenge scored a 1,500 pt follow-up trial on a % point difference in stroke completely explainable by natural stroke hazard rates in their population. This drug kills or leaves people without GI tracts in 13% of patients and it gets only a black box.
While folks argue the side effects collectively are no worse than chemo, I think they miss the point. Even if I grant their argument, the side effects are very different from chemo and present in a completely different way. Except for some chemo cardio effects, most AEs for cehmo go away when you withdraw treatment. Ipi is different. Ipi's side effects don;t go away without counteracting treatment. Worse, a patient who has G1/2 AEs during treatment can lose their colon weeks to months after the last dose. Oncologists have no training or frame of reference in looking at such things.
I won't argue that ipi shouldn't have been approved. I will argue it needs a required REMS program -- at least for the first couple of years of use in each indication.
(EDIT: Looks like from Langreth's article there is a REMS. Thank goodness.)
Provenge will be the cheapest (or in the bottom couple) cancer biologics approved this decade.
(ok, for the AR folks out there, 2010 forward since technically the decade started 2011)
On days like today, absolutely...
FYI, I'm REALLY happy for melanoma patients. Pazdur has spent most of the last 7 years screwing them out of new treatments. I'm just pissed about his double standard.
Depends on reimbursement. If BMY sells the 10mg for the same price as the 3mg ($120,000 for typical course), then docs will use whatever dose gets them to the autoimmune side effects. But if a 3mg average course is $120K and a 10mg course is $360K, no way.
Not gonna buy it. With an incurable disease the goal is to get as many possible medications to patients as possible. If Pazdur had worked hard to limit the lesser-proof drugs to late-stage patients through aggressive use of the accelerated approval process, then yeah. He hasn't. If he allowed drugs like Iressa to stay on the market while docs worked out the right patient populations, then yeah.
What he's done is worshipped at the altar of p-value in ignorance of clinical results and patient comfort. He has drug his feet on biomarker trial guidance. He has a completely unreasonable affinity for objective response. His insistence on p<0.01 has increased costs dramatically for oncology companies, which is reflected in the soaring costs of oncology drugs.
He's arbitrary, carpicious, and clearly plays favorites.
He's a menace and should have been fired a long, long, long time ago.
Unbelievable. No way Pazdur gifts that label based upon those data to a small biotech company. No way.
Agreed. There is no doubt ipi will be approved now that the 024 data are here. The only question is label and timing.
BMY - ipi
As with nearly all writers, I don't choose nor am I often consulted on the headline. It's sometimes been a bone of contention. I don't disagree with your edit.
I doubt the FDA would have enough time with the 024 data between BMY's announcement and March 26 to let it factor into an approval. I doubt there will be an ODAC panel given the 024 data, unless it is to talk about whether ipi monotherapy is approvable in the second line setting.
The trick is whether the FDA just delays, which makes them look bad on year-end PDUFA tabulations or whether they issue a CRL, which counts as a timely response. If it is a CRL, then it will be important to determine whether it is a Class 1 or Class 2, the difference between 60 and 180 days.
I often tell a story about how you can always tell if a doc has the temperament to be a CEO. If they get incensed you don't call them "Doctor" run away from the company. That example comes from Quay.
Anatomic pathology.... Hmmm. I wonder what non-anatomic pathology would look like?
Now treating docetaxel's side effects will be an even bigger percentage of total cost of care.
The cash used also includes a couple hundred million of non-recurring manufacturing costs.
They'll sell a$175-200M in Q4 and a billion dollars in 2012. That's the allure.
I suspect we'll understand better after MSKCC presents their system for determining bone-based responses at ASCO.
I agree that's what Pazdur believes. There is a world of difference between COngressional requirement of doing the confirmatory and requiring it be substantially complete before accelerated approval is granted. Pazdur's way increases costs and slows development, which is the opposite of leg intent.
Indeed. I was honestly a little surprised at how little we understand about the mechanism of bone mets given this has been a known phenomenon for mostly ever and we've had drugs available for this for quite some time. Lots of theories, but also lots of opposite theories that make sense.
I have to say, and I'm as much a fan of diving into the scientific weeds as anyone I know, it was a little head-spinning going through all the research. The clearest research is on osteosarcoma. The issue is whether you can draw a bright line between osteosarcoma and bone involvement of disease that initiates in soft tissues.
CTI's Xyotax/Opaxio and Pixantrone, Genta's Genasense seem to fit that definition if memory serves me.
Absolutely. Most management teams I've spoken with who are candid about this say they believe it means more than half enrolled. The teams I would consider "excellent" try to have the trial almost completely enrolled or close to it.
It's worth repeating again that Pazdur has no statutory authority in this area. Legislative intent, in fact, argues directly against this desire. But people have learned not to cross him or he'll tie up your drug in limbo until he gets what he wants anyway.
I think simple scintography where pain site is related to bone lesion location is a suitable endpoint. This is the norm for patients on narcotic pain relievers anyway, so I think it shouldn't be too much of a burden to demonstrate for purposes of study entry.
Once you have corresponsing pain location and scintograph lesions established at baseline, it isn't too much of a leap to assume cessation of narcotics combined with bone scan resolution equates to clinical benefit.
EXEL is doing PET in the NRE, however, to try and understand the effect more.
As to your point of flare, it gets back to whether bone involvement for prostate cancer is primarily an osteoblastic or osteoclastic affair. I went into it thinking it was primarily an osteoblastic affair because the scintographs target osteoblastic activity. I'm not so certain now. If XL184 is working primarily on the osteoclastic pathway, you could theorize efficacy without flare.
If you look at the tALP and CTx data from the posters, which would theoretically communicate a flare, I'm not sure I see flare-like activity there.
Finally, even if there is a flare the FDA is clearly willing to allow for protocols that try and eliminate this for purposes of progression adjudication. All of the abiraterone and MDV3100 pivotal programs have protocols that require multiple bone scans for confirmation of new lesions instead of the traditional one-and-done approach used for all other drugs. That advance in progression measurement came courtesy of Scher and crew at MSKCC -- who are designing XL184s trials now.
I don't think the composite endpoint trial will have a survival endpoint. They seem to believe they can design a composite as a hard endpoint (i.e. not Subpart H) approval. They plan to do a survival trial, but it won't be the one that starts 2H-2011.
Pazdur already has gone beyond Congressional rules and requires a confirmatory trial be "substantially under way" before he will allow OOD/ODAC to consider accelerated approval.
For randomized trials, this usually now takes place in a very large single trial with a surrogate interim and OS as the final endpoint. Interestingly, this has resulted in two drug approvals where the 2-in-1 trials never generated prospective survival data (Nexavar and Sutent) because the trials were halted and drug was offered to placebo patients before the survival readout could be made.
For single-arm trials, the requirement is the confirmatory needs to be "substantially" under way. If a company decide to take him to court on this one, he'd lose. But I doubt any of them will.
This means in some way's ODAC was just blustering. More of his grandstanding.
2 fer 1 on EXEL
On the flare issue, the flare question was asked and the docs are not seeing it. They couldn't say for sure whether it happens between scans or doesn't happen at all, but they are not seeing it. Remember also reported data are best response, which is the only way they can report these data since some of these patients were randomized to placebo in the RDT since bone scan improvements don't count as responses under RECIST.
Sanofi argued hard for pain to go on the Tax label and the FDA didn't give it to them. As you know from reading our work I ahve always thought there was something fishy about the TAX-327 data. One of these days when I have a week to burn I might go through the FDA docs and see why the FDA rejected it.
The standard is 2-points on the scale, not 1 point. Satraplatin tried to use 1 point as part of their non-SPA composite endpoint. That was one of the things that got them into trouble.
As to rigorous measurement of the XL184 pain data, I would answer it was not. Not all patients had pain assessments. It happened at some centers but not all. BMY was sloppy in the setup of this trial, sloppy in the running of it. About the only thing that isn't sloppy are the bone scans since these are so run-of-the-mill for uro oncs to run.
Scher pointed out that no drug with a OS benefit in PCa has a pain benefit on its label. This includes cabazitaxel and docetaxel.
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.
I'm actually fond of a couple of their science guys and Channing Burke. Good people caught in a bad situation.
Nance is the Introgen guy I'm most familiar with.
GERN
Okarma "leaves" Geron (GERN)
http://finance.yahoo.com/news/Geron-Appoints-David-bw-2487246898.html?x=0&.v=1
Effective immediately, David L. Greenwood, Geron’s chief financial officer, becomes president, interim chief executive officer and a member of the board of directors. Hoyoung Huh, M.D., Ph.D., a director of the company, becomes executive chairman. Alexander E. Barkas, Ph.D., chairman of the board, moves to the role of lead independent director. In conjunction with the implementation of the new leadership structure, Thomas B. Okarma, Ph.D., M.D., has left as Geron’s president and chief executive officer and director of the company. Dr. Okarma will remain with the company as a consultant.
Anyone listen to the CC and can share any additional details? Thus exits one of the least trustworthy CEOs in biotech.
Zibotentan is now irrelevant for Provenge. The combination could be complicating for SNY's cabazitaxel, JNJ's abiraterone, and MDVN's MDV3100. As Dew notes, however, it seems more in the long shot camp that the combination will work.
I would be very interested to read a detailed analysis of how the randomized Phase II data fell off the rails from the early read, which was so promising, to the updated data -- which weren't.
Refunds for fees...
I don't know the federal case law on this, but in WA refunds would be required. I'm guessing PPACA-related fees would have to be returned, but I'm not certain I'd invest on that basis.
Anyone else read the Florida ruling yet?
EXEL -- Only took me 40 minutes with the CEO, too.
As a rule, dev stage biotech balance sheets should never take that long to understand.
lol... I wonder if this is the first court decision citing a Drew Carry owned web site?
Seriously, though, I read this opinion yesterday just after it came out. It makes for interesting reading and, I think, accurately sets up the central question the Supreme Court will need to answer:
Is not buying something "activity" and therefore subject to Congressional reach or is it "inactivity" and therefore not subject to Congressional reach?
This judge chose the latter, hence the decision.
His argument about throwing out the whole thing is, BTW, persuasive. The gov's lawyers need to come up with a better argument on this point.