Puma Biotechnology grabbed its FDA approval for neratinib, the kinase inhibitor it’s been developing for HER2-positive breast cancer, but that doesn’t mean the newly dubbed Nerlynx will be roaring onto the market.
Nerlynx, which won a nod to prevent recurrence in women previously treated with Roche’s Herceptin, faces questions about efficacy—and worry about side effects—that could put a drag on its launch. Even the FDA advisory panel members who backed its approval weren’t thrilled with the study data supporting its application.
“It to me feels like it just needs to go back in the oven and cook a little longer. It is too broad, too much preliminary data,” one of the panelists said, as quoted by Forbes. “There’s no exclamation point after my ‘yes’,” said Andrew Seidman, an oncologist at Memorial Sloan Kettering after the FDA vote, as quoted by Endpoints News. “It’s just a yes.”
Still, it’s a yes, and the approval covers more patients than it might have. RBC Capital Markets analyst Matthew Eckler called the label “generally best-case scenario.”
Leerink agreed. “The product label looks broad, not restricting use to specific patient populations, e.g., hormone-receptor positive patients, and there is no black box warning,” Leerink analyst Michael Schmidt said in an investor note.
And analysts, including Schmidt, expect Nerlynx to break the blockbuster barrier. Schmidt pegs sales at $1.3 billion at their peak—a market he called “relatively conservative—while analysts at Evaluate Pharma expect sales of $1.25 billion in 2022. Puma hasn’t released pricing information or a launch date.
Will Puma launch the drug itself in the end, though? It hired more than 200 sales reps for the rollout, but only contingent on approval. With several major drugmakers in the market for oncology acquisitions, a buyout might put Nerlyx into Big Pharma's more experienced marketing hands. Those estimates, after all, are big numbers.
Real-world use could be more limited than the label suggests, however, Eckler wrote. “[D]espite this broad label, we continue to expect more narrow use of neratinib,” Eckler said in an investor note. “Given points raised at the AdCom, as well as our discussions with breast cancer oncologists, our current model assumes use of neratinib predominantly in higher-risk HR-positive and node-positive patients, with minimal penetration into HR-postive, node-negative patients.”
Indeed, during the advisory committee meeting, some panelists had suggested Nerlyx be limited to patients testing positive for HER2 and HR, given trial data showing the drug was more effective in patients with both. Limiting the approval to patients treated with Herceptin within the past two years also came up. The FDA chose not to do either, though some of that data will be included on the drug’s label.
Plus, Nerlyx delivered a marginal benefit overall. Among Nerlynx-treated patients in one study, 94.2% had not suffered a recurrence or death after two years, compared with 91.9% of placebo patients. The relative risk reduction of 30% translated into just two cases among 100 women in absolute numbers, Forbes pointed out.
Thing is, however, Nerlyx beat its control group better than Roche’s Herceptin-plus-Perjeta combo after surgery. For the Herceptin-Perjeta combo, given alongside chemo, 94.1% of patients were still alive and recurrence-free after three years, compared with 93.2% of those taking Herceptin and chemo.
The two studies are different, of course; one major departure is that the Roche study pitted its new combo against an actual treatment, rather than placebo. Exact comparisons therefore aren’t possible. Nerlynx did, however, best Herceptin in one phase 2 trial, and industry watchers were disappointed with the Aphinity results overall. The data were seen, in fact, as a potential benefit to Puma's product.
Safety had been an obvious concern. Almost all trial patients (90% to 95%) suffered diarrhea, and 40% of those cases were severe—grade 3 or 4. The FDA approval instructs doctors to stop therapy if patients suffer grade 4 diarrhea.
Puma, however, thinks it has the diarrhea problem sorted for most patients; its application included a separate study, that tested preventive use of Imodium (loperamide), which cut the rate and duration of diarrhea. The FDA label includes instructions for Imodium use alongside Nerlynx.
“When you use the Imodium, the rates come down dramatically and it completely changes the safety and tolerability profile of the drug,” CEO Alan Auerbach said in an interview last fall after side-effects analysts at Advera Health issued their report on the drug.