Cancer hopeful neratinib plagued by diarrhea, analysis shows, but Puma cites a solution

As California’s Puma Biotechnology ($PBYI) awaits FDA word on its breast cancer drug neratinib, an Advera Health analysis outlines the drug's risks--chiefly diarrhea--and paints a mixed picture for efficacy versus Roche’s ($RHHBY) Herceptin and Novartis’ ($NVS) Tykerb. Puma, for its part, says it has the GI problem handled.

The FDA last week accepted Puma's neratinib application as a treatment for HER2-positive breast cancer in certain patients, and analysts are looking for an approval in mid-2017. Advera says the drug “will likely be approved” for the indication

After analyzing 11 trials, Advera found that 90% of neratinib patients experienced diarrhea, and around 19% suffered serious cases. When patients took a low dose of the diarrhea remedy Imodium (loperamide), or didn't use it at all, serious diarrhea cases rang in at 30%. With a high Imodium dose, 14.71% of patients suffered serious diarrhea.

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Those numbers don't reflect proper use of Imodium with neratinib, however, Puma CEO Alan Auerbach told FiercePharma. He called the analysis "flawed" because it incorporated only two studies that used a high dose of loperamide up front to prevent diarrhea. Others treated the side effect after it occurred.

“They only analyzed the studies that didn’t include the prevention,” Auerbach said. “Because of that, yes, there’s a high rate of diarrhea. When you use the Imodium, the rates come down dramatically and it completely changes the safety and tolerability profile of the drug.”

In prevention studies, Puma was able to "dramatically" reduce the rate and duration of serious diarrhea, Auerbach said. In one, the duration of diarrhea went from 14 days to two. Auerbach cited a CONTROL study the company conducted, intended to prevent serious diarrhea, where the side effect ended in patients much sooner than in a large Phase III study, ExteNET.

That prophylactic loperamide, along with new 5-year survival data, have "been noted by both oncologists and investors and have served to improve sentiment around ... the drug," RBC Capital Markets analyst Simos Simeonidis wrote in a recent note. Simeonidis described an "improving perception" for neratinib in advance of FDA approval, as oncologists become aware of the preventive treatment with Imodium.

Seeking to analyze neratinib's efficacy against other breast cancer drugs, Advera also looked at studies pitting the drug against Roche’s Herceptin and Novartis’ Tykerb.

In HER2-positive stage 2 and 3 breast cancer patients, the Puma med combined with standard therapy “had a statistically significant higher rate of pathological complete response” than Roche’s Herceptin plus chemo, Advera said. The neratinib group saw a 39.4% response rate versus the control group’s 22.8%.

Versus Novartis’ Tykerb plus the chemo drug capecitabine in HER2-positive, locally advanced or metastatic cancer, Puma’s neratinib demonstrated a shorter median progression-free survival and shorter overall survival, Advera said, “making it unlikely that it will be replacing lapatinib in the treatment of patients with HER2-positive metastatic breast cancer if it ever gets approved in that setting."

In that comparison, neratinib’s progression-free survival was 4.53 months versus Tykerb’s 6.83 months, while overall survival lagged at 19.74 months versus 23.62 months for the Novartis med plus capecitabine combo.

Puma licensed neratinib from Pfizer ($PFE) in 2011. The company’s NDA contained the Phase III ExteNET results Auerbach mentioned, plus new 5-year survival data and Phase II numbers incorporating the Imodium prophylaxis trial, Simeonidis said.

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