Drug Development

IDO rout: Pivotal trials with Bristol-Myers, Merck and AstraZeneca dumped in wake of Incyte’s PhIII implosion

The IDO R&D pipeline is in danger of being exterminated.

In the wake of a pivotal failure of Incyte’s $INCY lead IDO drug epacadostat, Bristol-Myers Squibb $BMY became the third player forced to retrench in that immuno-oncology field, dropping three late-stage studies of a rival drug it bagged in a $1.25 billion buyout. But that was just the start of a rout.

Incyte reported this morning that its wide-ranging collaborations with Big Pharma players are coming undone. In their Q1 announcement, echoing the failure of ECHO-301, the company noted:

Enrollment will be discontinued in the four additional pivotal trials of epacadostat in combination with pembrolizumab (Merck’s Keytruda), and in the two pivotal trials of epacadostat in combination with nivolumab (Bristol-Myers’ Opdivo); each of these studies will be amended to enable patients and their physicians to consider alternative therapeutic options. The pivotal trial in combination with durvalumab (AstraZeneca’s Imfinzi) in Stage 3 lung cancer will not be initiated.

A spokesperson for AstraZeneca also tells me that there is “another Phase II (combination study) in solid tumors and we’re going to stop enrollment there too.” That will be all for the ECHO-203 study — epacadostat plus durvalumab again. “Incyte did present some data from ECHO-203 at AACR: 15 patients with pancreatic cancer were enrolled across multiple dose levels, no clinical activity was observed.”

In addition, Incyte said that it is “significantly downsizing the epacadostat development program,” signaling a painful retreat for a one-time star drug that commanded projections of blockbuster peak sales.

According to clinicaltrials.gov, investigators for the big biotech today terminated a Phase III study of BMS-986205 in combination with Bristol-Myers’ Opdivo for frontline head and neck cancer. Another Phase III study for frontline Stage IV or recurrent non-small cell lung cancer using BMS-986205 and Opdivo with or without chemo versus chemo alone was withdrawn. And there’s a third study for melanoma that’s now active but not recruiting after enlisting 72 patients.

A spokesperson for Bristol-Myers told us Monday night:

Based on emerging data on the IDO pathway, we closed registrational studies of our IDO inhibitor, BMS-986205, in melanoma, SCCHN and NSCLC. We remain committed to continued research of BMS-986205-based combinations in an informed and scientifically robust manner. We will continue to evaluate BMS-986205-based combinations in our Phase 1/2 study, CA017-003.

Separately, we are working quickly with Incyte to assess our program under the collaboration.

NewLink $NLNK was the first to overhaul its approach on IDO following the Incyte disaster.  The biotech scrapped a melanoma study that would have evaluated indoximod in combination with checkpoint inhibitors Keytruda or Opdivo in 600 patients. In a press release, NewLink explained the decision was made “in the context of the failure of a competitor’s trial of its enzymatic IDO inhibitor in a similar clinical setting.

Bristol-Myers’ decision — first reported by Xconomy — underscores a growing belief that Incyte’s failure was as much a failure of the class as an individual therapy, potentially torpedoing a wide swath of clinical trials now in the pipeline.

Incyte frankly conceded that its pivotal failure raised doubts about its entire effort, which includes a host of combination studies with checkpoint leaders like Merck and AstraZeneca. In this case, Bristol-Myers is cutting back on a drug that it acquired in a blockbuster deal to acquire Flexus 3 years ago. Investigators have repeatedly touted the drug as a potential lynchpin in immuno-oncology, focusing on an enzyme that suppresses the immune cells Opdivo and a whole new class of PD-1/L1 checkpoints are designed to unleash in an attack on cancer cells.

Ironically, Incyte has been pursuing litigation against one of its former scientists, claiming he defected to Flexus with IDO trade secrets in hand, well before the buyout. Bristol-Myers, though, has steadfastly asserted — with some support from analysts — that it had the better IDO that could leapfrog epacadostat. The leaping in IDO, though, has stopped. At least for now.


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