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Novartis just boasted of a big PhIII PI3K success, but here’s why we should hold our applause — for now

Just a few weeks after Novartis $NVS punted a potentially dangerous PI3K drug out of its pipeline to a drug developer in China, the pharma giant has come back with a positive set of Phase III progression-free survival data on another contender in this dicey cancer drug field. And now Novartis says it will start knocking on regulatory doors as it begins the approval process.

Samit Hirawat

All we have in this first cut is the headline material: The drug hit on the PFS primary endpoint, with a combination of BYL719 (alpelisib) and fulvestrant outperforming fulvestrant alone in a statistically significant fashion for “hormone-receptor positive, human epidermal growth factor receptor-2 negative (HR+/HER2-) PIK3CA-mutant advanced or metastatic breast cancer that progressed on or following aromatase inhibitor treatment with or without a CDK4/6 inhibitor.”

Adverse events were “consistent” with other studies of this drug.

“BYL719 is the only alpha-specific PI3K inhibitor and the first one to show potential increased benefit and acceptable tolerability for patients,” said Samit Hirawat, Novartis’ head of oncology global drug development.

We won’t see the data until a later conference, but some analysts are already assigning blockbuster sales forecasts for the drug. 

“We estimate alpelisib peak sales potential at $1.9 billion, and lift our probability of success to 80%,” said Bruno Bulic, an analyst at Baader Helvea, according to a Reuters report.

But let’s step back for a second. We’ve seen plenty of bullish forecasts for experimental PI3K drugs, and the harsh reality has never lived up to the hype.

As a field, PI3K research has been more of a disaster zone than blockbuster producer. 

Roche dumped taselisib at the end of a disappointing Phase III, after positive but weak PFS data failed to overcome a chancy risk profile. The Roche setback underscored the weak durability of the PI3K class that has tempered enthusiasm in recent years. 

Gilead’s pioneering Zydelig, meanwhile, 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 as AbbVie walked away after getting a glimpse of unimpressive — but still approvable — results. 

Then there’s buparlisib, another Novartis program. The pharma giant dispatched the drug to Adlai Nortye in an outlicensing deal in June, but only after researchers raised a red safety flag warning to the company that the safety profile is so troubling that it doesn’t “support its further development” in breast cancer.

Now noted cancer researcher Siddhartha Mukherjee is beginning a human study to determine if a ketogenic diet can close an insulin feedback loop that defeats these drugs’ ability to fight cancer.

So while the headline material looks good, the real story about this drug’s future will lie in the details, which we don’t have yet. Novartis is off to a good start, but the third act of this R&D epic is still in front of us.


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