Puma's Likely Neratinib EU Knockback May Be Temporary
Executive Summary
A positive opinion on the marketing application for Puma's neratinib in the EU is unlikely next month after a recent discussion with regulators failed to satisfy risk-benefit concerns, but more data on controlling diarrhea are expected shortly.
Puma Biotechnology Inc.'s announcement on Jan. 23 that its new anticancer kinase inhibitor and lead product, neratinib, was unlikely to receive a positive opinion from the EU's top advisory panel, the Committee for Medicinal Products for Human Use (CHMP) came as a surprise to commentators and showed, once again, that regulatory approval in one major market may not automatically translate into approval in another.
Neratinib oral tablets (Nerlynx) were approved by the US FDA in July 2017, but Puma reported on Jan. 23, 2018 that the product had received a "negative trend vote" from the CHMP, after the company met with the committee to discuss neratinib's marketing authorization application (MAA) as an extended adjuvant treatment for early-stage HER2-positive breast cancer, a similar indication to that approved in the US (see sidebar).
The announcement was followed by a 27% decline in Puma's share price to $66.30 on the same day, as investors digested the news, and analysts expressed surprise about the CHMP's views after the "oral explanation" by the company.
If the trend vote is followed by a negative opinion at the CHMP's February meeting, the company has the option of requesting the CHMP to re-examine that decision, a path followed by PharmaMar SA when the CHMP rejected its anticancer, Aplidin (plitidepsin) last December. (Also see "CHMP Negative On PharmaMar's Aplidin In Multiple Myeloma" - Scrip, 15 Dec, 2017.)
And other companies have recently recovered from an adverse CHMP opinion, such as Takeda Pharmaceutical Co. Ltd. with its anticancer, Ninlaro (ixazomib), which gained an approval in a subgroup of patients with severe disease following an initial rejection, analysts have pointed out. (Also see "Takeda's Ninlaro Back In European Myeloma Race After CHMP Turnaround" - Scrip, 16 Sep, 2016.)
Additional Steps Needed
Puma said the negative trend vote "means it is unlikely that the CHMP will provide a positive opinion related to the company's MAA at the formal CHMP decision vote scheduled in February 2018. The company went on to say that "additional steps would need to be taken to gain marketing approval in Europe."
As to why the CHMP was unhappy, Puma indicated that, in the regulator's opinion, "the benefit risk assessment is negative as the study results are based on evidence from a single pivotal trial and the two- and five-year invasive disease free survival (iDFS) benefits observed to-date may lack sufficient clinical relevance."
The CHMP's opinion was based on results from the Phase III ExteNET trial in extended early-stage HER2-positive breast cancer and the Phase II CONTROL trial in extended adjuvant early-stage HER2-positive breast cancer. HER2-positive breast cancer is often more aggressive than other types of breast cancer, increasing the risk of disease progression and death, and although trastuzumab (Roche's Herceptin) can reduce the risk of early-stage HER2-positive breast cancer returning after surgery, up to 25% of patients treated with trastuzumab experience a recurrence.
Real World Applicability
Regulatory concerns about the efficacy and safety of neratinib are not new. "The benefit-risk profile of Nerlynx has been in question since US regulatory proceedings," noted Datamonitor Healthcare analyst Zachary McLellan.
"In the ExteNET trial, Nerlynx demonstrated a 27% relative iDFS improvement in the extended adjuvant setting after five years of follow up, versus placebo," he remarked. "But the absolute iDFS improvement with Nerlynx vs placebo was only 2.5% (90.2% vs. 87.7%), thus bringing the drug's real-world applicability into doubt, particularly when considering the severe diarrhea caused by Nerlynx treatment which requires intense prophylaxis."
In the US, Nerlynx is indicated for the extended treatment of adult patients with early-stage HER2 over-expressed/amplified breast cancer, to follow adjuvant trastuzumab-based therapy, a relatively broad label, even as some FDA advisory panel members expressed concerns about the drug's association with diarrhea. (Also see "Puma May Face Marketing Hurdles Even If Neratinib Wins Final Approval" - Scrip, 31 May, 2017.))
The US labeling for neratinib recommends that prophylactic therapies for diarrhea should be given, and any diarrhea that occurs despite prophylaxis should be aggressively managed with additional antidiarrheals, fluids and electrolytes. (Also see "Puma's Nerlynx Scores Broad Label Across Adjuvant Breast Cancer Subgroups" - Pink Sheet, 17 Jul, 2017.)
Analysts at Credit Suisse expect Puma to file for a re-examination of neratinib by the CHMP, with a new rapporteur and co-lead rapporteur. Further, full data from the Phase II CONTROL study, which is evaluating various strategies to lower diarrhea rates (loperamide alone, loperamide/budesonide, or loperamide/colestipol), are expected to be available in June 2018. There is still a chance that neratinib could be approved in Europe in 2018, they add.
At a US meeting in December 2017, interim data from the CONTROL study showed the incidence of grade 3 diarrhea during neratinib therapy was 30.7% during loperamide prophylaxis, 26.6% with loperamide/budesonide, and 10.8% with loperamide/colestipol.
And interim results from a second pivotal Phase III study of neratinib in the third-line metastatic HER2-positive breast cancer setting are also expected in the first half of 2018, noted Leerink analysts. The study is comparing neratinib/capecitabine with lapatinib/capecitabine, in 600 patients with PFS and overall survival as endpoints.
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