Puma Biotechnology will face some tough questions from regulators during Wednesday’s long-awaited panel review for its experimental cancer drug neratinib.
Not only did the FDA review, out this morning, raise pointed questions about the many changes that were made to Puma’s study for early-stage ERBB2-positive breast cancer, it also highlighted — as expected — the high rate of serious diarrhea experienced by patients in the study.
One critical issue: At one point, just four months before Puma filed for an approval, regulators also advised Puma execs against filing for an OK.
Pre-NDA meeting with Puma – FDA advised they did not encourage an NDA submission based on the efficacy and safety results of Study 3004. This was due to several study conduct issues which would make interpretation of the results problematic. The Applicant was advised that if an NDA was submitted, an Oncologic Drugs Advisory Committee discussion would be required.
At the same time, regulators did not condemn the drug, noting that even with the array of changes to the study, there is data supporting efficacy. And the bulls ran with the win combined with an overall neutral tone to the problems Puma may face. Its shares $PBYI rocketed up 80%, then quickly slid back down to a 50% gain on a second take of the review.
In its summary, the FDA noted that:
Despite the unplanned amendments and potential uncertainty introduced with respect to the magnitude of neratinib effect, based on the sensitivity analyses conducted, the results appear to be generally similar to the primary analysis results, supporting an effect of neratinib.
The FDA set up a relatively short panel review for Wednesday, which had triggered speculation from a host of short sellers who have dogged this biotech at every step that Puma was in line for a thumping. But as of now, that’s all it is.
Regulators noted, though, that they have concerns with the results from the study.
There remains some uncertainty regarding the true magnitude of the treatment effect since the primary analysis (truncated at 2-years follow-up) observed a hazard ratio of 0.66 (95% CI: 0.49, 0.90) which changed to 0.68 (95% CI: 0.51, 0.91) with the exploratory updated 2-year analysis and the exploratory 5-year analysis observed a hazard ratio of 0.73 (95% CI: 0.57, 0.92).
Puma has been pilloried routinely for the way it handled the severe instances of diarrhea in its studies. As the review notes, even with the addition of an antidiarrheal drug in Puma’s studies there was still a high rate of dropouts.
While there were fewer dose reductions and dose holds in the Loperamide Cohort of Study 6201 compared to patients in Study 3004, there remained a substantial rate of discontinuation due to diarrhea despite antidiarrheal prophylaxis with Loperamide (16.8% in Study 3004 and 20.4% in Study 6201). In addition, a higher incidence of constipation and nausea was reported in the Loperamide cohort.
The FDA review should raise some obvious questions on Wednesday. But the jury still remains out on Puma’s fate. Matthew Eckler at RBC looked over the docs and saw much to be happy with.
In our initial read, we didn’t come across anything that we view as overly surprising. As expected, the FDA documents read as harsh in some sections (many FDA briefing books can), but ultimately we see the points raised as having already been widely known including: 1) the clinical significance of iDFS benefit seen in ExteNET; 2) changes made to the design of ExteNET; 3) Neratinib-associated G3 diarrhea; and 4) benefit of neratinib in the HR+ subgroup. We also note that we don’t see any mention of Aphinity in the FDA briefing book. The bottom line is that the FDA documents read very balanced to us, and are frankly more positive than we anticipated, setting the stage ODAC to make an unambiguous recommendation.
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