Replies to post #144025 on Biotech Values

[pcrutch]

re ONXX

They do make a bigger deal of "cardiac disorders" in the briefing (30/526 patients, 6%), although I'm unsure how certain findings would relate given that the patient is on drug for a relatively brief period of time versus the typical trajectory of the disease (example: aortic valve stenosis). If I squinted hard to see a pattern, I would say exclude people with coronary artery disease from the drug. In the real world, the safety signals here should ideally be compared to Velcade, which also has cardiac effects. The disadvantage, in the case of these single arm trials, is that you don't have a comparator arm for safety. In one velcade trial, treatment-emergent cardiac disorders were 15% and 13% in the velcade and dexamethasone groups, respectively. Doesn't look as bad in that light, especially considering that patients in the carfilzomib trial did have the option of receiving low dose dexamethasone occasionally.

- This confounds any efficacy data that Onyx reports. They are also seeking approval as a single-agent, so this really complicates things. I think for this reason alone, you can not approve the drug without their Phase 3 trial. This also means their efficacy data isn't as good as reported.

All in all, you can tell by the way that the FDA is wording their document that they are not intending to approve. They say things such as the patients who were "unresponsive or intolerant" to all known drugs "was a very small fraction off the ITT population (69/266; 26%)" or that the ORR in the primary efficacy study was "only 22%" while making a very big deal about adverse events that were present at or less than 1%. In a sense this is their mandate to keep patients safe, but the tone seems to be one where they're stacking the deck against the drug a little bit.

It's too bad, because this appears to be a reasonable case of the sponsor following the accelerated approval guidelines. The phase 3 studies are under way, so the sponsor is acting in good faith.

From the BD's "Accelerated approval applies to certain new drug products that have been studied for their safety and effectiveness and treating serious or life-threatening illnesses and that provide
meaningful therapeutic benefit to patients over existing treatments [e.g., ability to treat
patients unresponsive to, or intolerant of, available therapy, or improved patient response
over available therapy (CFR 314.500)]. "

The FDA shouldn't have to baby sit sponsors. Onyx did a piss poor job running the trials(44% protocol violations in the study, 19% incorrectly enrolled!) and rushed the NDA. It's clear their trial and data does not meet the criteria. I agree with you that the FDA's tone is not one of an agency looking to approve CFZ at this point.

I think there are 4 major outstanding issues:

- I think Onyx's intolerance to Velcade argument appears to be a wash given that subQ Velcade is approved and much more tolerable.

- There is an appearance of a cardiac, respiratory and hepatic safety signal. Not sure the FDA can ignore this.

- Confounded efficacy data because of low-dose Dex. I suspect all the ORR's would be significantly lower without Dex.

- I think the fact that the FDA has Celgene's Pomalidomide NDA in front of them also makes them nervous approving Carfilzomib. Celgene has MUCH more comprehensive data than Onyx, so punting Carfilzomib seems like a no brainer at this point. Although I think the FDA wasnt happy about the design(Pom vs Pom + low Dex), it's at least randomized and controlled vs. Onyx poorly run single-arm Phase 2.