- Puma Biotechnology shares surged on Monday following the release of preliminary documents for an upcoming meeting with a Food and Drug Administration advisory committee about market authorization for its lead drug, yet that optimism may be premature.
- The Oncologic Drugs Advisory Committee (ODAC) plans to probe deeper into what risks and benefits the breast cancer therapy — tentatively branded as Nerlynx (neratinib) — offers patients, as well as the effects that big protocol changes had on the outcomes of a Phase 3 study dubbed ExteNET. Neratinib's approval filing is based on that study.
- Significantly more patients achieved invasive disease-free survival (iDFS) when taking neratinib versus placebo, according to data from ExteNet. But nearly all participants in the experimental arm experienced diarrhea, with 40% reporting serious episodes. Puma also changed a number of the trial's key elements, such as shortening the time at which investigators conducted follow-up assessments, which in turn affected the analysis of primary results.
In July 2016, Puma submitted a New Drug Application (NDA) for neratinib as an extended adjuvant agent for early-stage breast cancer patients who showed overexpression of a protein called HER2 and who previously took Roche's Herceptin (trastuzumab).
The filing hinged solely on the primary results from ExteNET, a study that spanned nearly eight years and switched sponsorships twice: from Wyeth to Pfizer and finally to Puma. Along the way, major amendments to the study took place — changes that now are spurring the FDA staff to question the level of certainty and significance in the trial results.
Shortly after Pfizer acquired Wyeth, for example, investigators stopped including breast cancer patients with the Phase 1 or node negative forms of the disease as a means of stocking the participant pool with those at higher-risk of having their cancer return. Trial conductors also excluded patients who had completed Herceptin treatment more than a year ago in an effort to "increase the likelihood of success of the trial based on data from adjuvant Herceptin trials, which showed a higher risk of recurrence closer to completion of Herceptin," according to documents prepared by FDA staff for the advisory committee.
Also in the ODAC documents is a timeline that shows the Food and Drug Administration told Puma in March 2016 not to submit the NDA for the drug because of "several study conduct issues which would make interpretation of the results problematic." That disclosure appears to contradict a stance from Puma leadership, which said during a call the same month that the FDA didn't object to the company's filing at the time.
Other potential obstacles to neratinib's path to market include the fact that it, unlike other adjuvant studies, wasn't compared to an active control, and, unlike other adjuvant therapies, doesn't have prior approval as a treatment for metastatic cancer. In fact, Puma's candidate missed the primary endpoints in two studies testing it in patients with metastatic or locally advanced breast cancer.
A primary analysis of the ExteNET investigation occurred two years after participants began receiving treatment. Patients on neratinib demonstrated significantly less disease progression than those on placebo, representing a 44% reduction in relative risk. A five-year follow-up comprised of almost 75% of the study's original 2,840 participants also showed Puma's drug besting placebo, though this time with a hazard ratio of 0.73.
Investors appeared to have expected a harsher view of neratinib from the FDA, pushing Puma shares up by northwards of 80% on Monday to $69.35 apiece before shares fell back down to $52.60 by close of market.
More details on neratinib and its possible path to market will come to the surface Wednesday during the ODAC meeting, which is scheduled to begin at 8 am. Stay tuned.