Despite mixed opinions regarding the breadth of the proposed label for Puma Biotechnology Inc.'s lead candidate, Nerlynx (neratinib), members of the FDA's Oncologic Drugs Advisory Committee ultimately voted 12-4 in favor of recommending that the agency approve the candidate as an extended adjuvant treatment for HER2-positive early stage breast cancer. About 25 percent of breast cancer patients have HER2-positive disease.

Following a halt in trading during ODAC's morning meeting, shares in Los Angeles-based Puma (NASDAQ:PBYI) rose about 29.7 percent to close at $74.95.

Emmaus Medical Inc. also won committee support, with a 12-3 vote in favor of recommending approval of the company's pharmaceutical-grade L-glutamine, Endari, for adults and children with sickle cell disease (SCD).

The FDA is not obligated to follow the recommendations of its advisory panels, though it often does.

ODAC's morning session focused on Puma's phase III ExteNET study, also known as study 3004. It demonstrated that extended adjuvant therapy with one year of Nerlynx after completion of one year of adjuvant Herceptin (trastuzumab) resulted in a 2.3 percent improvement in invasive disease-free survival at two years. However, FDA reviewers expressed concern that adaptations to the study's design over the course of the drug's development program "created uncertainty around the magnitude of benefit," said Harpreet Singh, a medical officer in the FDA's Center for Drug Evaluation and Research.

Agency reviewers also spoke to safety concerns around gastrointestinal toxicities, especially diarrhea, which were common in the study and led to frequent dose modifications and discontinuations, but found that prophylactic antidiarrheal regimens may improve tolerability, something that Puma is currently investigating.

During time for clarifying questions, panelists expressed significant interest in how dropouts from ExteNET were accounted for, the broadness of the indication, what benefit might extend to estrogen receptor-negative patients, how prior lines of treatment might have impacted the perceived benefits of neratinib, and how patient demographics impacted incidence of diarrhea.

When it came time for committee members to vote, the 12 supporters cited being impressed with analyses by both Puma and the FDA supporting the benefit of the therapy and a general confidence that toxicities would be manageable. The study's large sample size, design, and work that Puma engaged in to obtain long-term follow-up data also drew praise from committee members.

The four "no" voters expressed concern about the broadness of the proposed indication, especially as it pertains to early stage breast cancer patients, and the magnitude of benefit vs. the side effects observed.

Despite the debate, following the vote, JP Morgan analyst Cory Kasimov wrote that "we believe being restricted to HR+ (which is how we've modeled it) is still more than sufficient to drive meaningful sales and strategic value." But he also pointed to upcoming events that could impact Nerlynx's reception, such as competitive data from Roche AG's APHINITY trial to be released at ASCO, the PDUFA in July, and metastatic phase III data in the coming months.

SUPPORT FOR NEW SICKLE CELL THERAPY

The committee's afternoon session supported a recommendation for approval of a 30 g maximum daily dose of Emmaus Medical's Endari as a treatment for adults and children with sickle cell disease, a deeply underserved condition.

Emmaus made a clear case for the need for new treatments in SCD – something no one disputes – but a chilly reception from FDA reviewers cast initial doubt on the company's odds of getting committee blessing. Che Smith, a CDER statistical reviewer who spoke to the agency's view, expressed concern about a high early dropout rate among SCD patients enrolled in the trial and differential dropout rates between treatment arms concern, non-optimal methods used to impute sickle cell crisis event counts, and the impact of those factors on interpretation of efficacy results based on data impacted by dropouts.

Later, an agency representative also expressed uncertainty about the clinical significance of one fewer median sickle cell crisis per year in patients with SCD.

Mary Brown, president and CEO of the Sickle Cell Disease Foundation of California spoke to that question directly, reporting back the views of some sickle cell families who said that one less crisis per year could mean fewer days out of work, equating to greater job security; fewer days out of school, improving chances of graduating on time; less anxiety about traveling; and, above all else, one less negative experience in the hospital dealing with health care providers who don't know much about SCD and often think patients are simply there to seek narcotics.

Following the final vote tally, of 12-3 in support of recommending approval of Emmaus' NDA for Endari, committee member Ralph D'Agostino, a professor of epidemiology and biostatistics at Boston University who voted in favor of the application, said "there were a lot of statistical questions. But if you look at the data," he noted, you see "there's a robustness to the sensitivity analysis, even if you push it."

Overall, committee members expressed thanks to Emmaus for conducting its development work and the studies backing its application, noting the difficulty of conducting studies in SCD populations, which are frequently stigmatized.

Brian Rini, acting chairman of the committee during Emmaus' ODAC session concluded it saying that "I think this one could have gone either way. Despite this desperate need, however, our job is to recommend approval of drugs not based on desperate need, but based on good data. And, I thought that there were a lot of data points that weren't known that could have been or should have been."