Novartis punts a late-stage PI3K drug with a worrying safety profile to one of China’s upstart biotechs

Just months after a group of researchers warned against the further development of a worrying PI3K inhibitor project Novartis had been working on, the pharma giant licensed out the global rights to a newly active Chinese biotech. 

Novartis is the latest in a long string of Big Pharma players who have decided to bow out of a troublesome PI3K development program. But instead of dropping the drug the Swiss company handed worldwide commercial rights to the late-stage buparlisib to one of China’s new upstart biotechs — raising some thorny issues about how questionable drug assets may be passed to new players for a commercial rollout.

Angelo Di Leo

Late last year a group of scientists published a report in The Lancet — funded by Novartis — that concluded the drug’s safety profile “does not support its further development” in breast cancer. The group was led by Angelo Di Leo of Nuovo Ospedale di Prato Santo Stefano in Prato, Italy.

The Chinese company is Adlai Nortye, based in Hangzhou. There’s no word on the terms here, but there has been a considerable amount of marginal efficacy and worrying safety data on display. 

In a study called Belle-3 which combined buparlisib with fulvestrant, researchers found that there was a positive benefit in progression-free survival: 3.9 months compared to 1.8 months for a marginal but significant advantage for patients.

Grade 3/4 adverse events were reported in close to two out of three patients in the drug arm, compared to 34% in the control group. Serious adverse events, though, were reported in 22% of the drug arm, compared to 16% in the control group, with one treatment-related death to report in each arm. There were also three suicide attempts in the buparlisib group, raising concerns about suicidal ideation among patients exposed to the drug. Ruth O’Regan of the University of Wisconsin-Madison has raised concerns about the suicide attempts, noting that  “transaminase elevations and mood disorders in patients on this drug may represent a clinically relevant challenge.”

Ruth O’Regan

The researchers also noted in The Lancet that the work may have warned them off the drug for this setting, but concluded that “PI3K inhibitors plus endocrine therapy in patients with PIK3CA mutations” is a promising area of research.

The PI3K field has been plagued by safety concerns and weak efficacy. Roche dumped taselisib a few weeks ago at the end of a disappointing Phase III. Gilead’s pioneering Zydelig got slapped with a black box warning on serious and sometimes fatal toxicities, forcing an end to its quest to complete frontline trials. Bayer’s Aliqopa (copanlisib) was approved last fall for follicular lymphoma patients, crowding a field that Verastem hopes to join with duvelisib, a PI3K dropped by Infinity Pharmaceuticals after AbbVie walked away after getting a glimpse of unimpressive — but still approvable — results. And now noted cancer researcher Siddhartha Mukherjee is beginning a human study to determine if a ketogenic diet can close a feedback loop that defeats these drugs’ ability to fight cancer.

In its release, Adlai Nortye doesn’t mention the breast cancer study, or what kind of commercial prospects it has in an already well developed field. The company did, though, highlight “promising efficacy in combination with paclitaxel in head and neck squamous cell carcinoma” and the fact that the drug “has received a Fast-Track designation from the FDA.”

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Research Scientist - Immunology
Recursion Pharmaceuticals Salt Lake City, UT
Director of Operations
Atlas Venture Cambridge, MA

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