Combos, Results

Keytruda/epacadostat combo crashes in PhIII melanoma study, raising questions about the future of IDO for Incyte

A closely-watched Phase III study combining Merck’s PD-1 star Keytruda with Incyte’s IDO1 drug epacadostat for metastatic melanoma has failed, casting a pall over the future of this combination approach.

Absent a significant improvement in progression-free survival, as well as the likely failure of the drug combination to extend overall survival, the investigators are halting the study. Incyte stuck with the top-line results in their release, promising to roll out the full data set later. And they made it clear in a call with analysts this morning that the ECHO-301 study failure “has a negative impact on the probability of success of the other (combination) studies” — sending a shock wave through the I/O field.

Incyte’s shares plunged 23% on the news, wiping out more than $3.5 billion in market cap. The implications for other IDO1 drugs also damaged other companies in the field, including NewLink $NLNK, down 44%, as well as Bristol-Myers Squibb $BMY down 2.6%.

Steven Stein

Merck is one of a slate of biopharma companies to combine their checkpoints with Incyte’s IDO drug, looking to improve patients chances for living longer with cancer. The failure of this first late-stage test, after stoking hopes for some major advances, now leaves Incyte’s drug $INCY in a precarious position, creating a crisis for CEO Hervé Hoppenot.

Epacadostat was number 3 on Evaluate Pharma’s top 10 list of 2018 launches, with close to $2 billion in projected peak sales estimates. And UBS analysts gave this study a 100% chance of success, noting the high expectations — and hype — focused on this drug.

Investigators tracked a hazard ratio of 1.00, which “leaves no doubt that in this study… the compound didn’t perform,” said Steven Stein, the chief medical officer, in the call. And there was no positive glimmer of hope seen in any subgroup analysis. “Given those hazard ratios it is going to be difficult to discern a subgroup with sufficient effect.”

The failure of the study also raises the chances that other trials in the program may need to be adjusted, he added, with possible statistical and biomarker modifications.

Analysts had been encouraged last summer with the latest look at data from a single-arm melanoma study, making this one of the most anticipated studies of 2018. Incyte faces a difficult task now in rebuilding hopes for a blockbuster future as the field awaits a long string of read outs from combination trials.

Anticipating some big returns, a whole host of players has dived into IDO. A recent study from the Cancer Research Institute found that there were 18 IDOs in the pipeline. Epacadostat was the most advanced of them all, but there have been a number of setbacks, including a program pursued by Genentech, which the company abandoned after seeing weak results. And a growing lineup of failures will boost fears that this is the wrong target.

That woeful feeling didn’t help matters at Bristol-Myers, which has one of the most advanced IDOs in the clinic after Incyte’s program. Bristol-Myers paid $1.25 billion to obtain their drug in the Flexus buyout, which was implicated in a suit Incyte filed claiming that a former staffer had stolen trade secrets on their drug, handing them off to Flexus. Several analysts have outlined reasons why they think that Bristol-Myers has the better of the two drugs.

With the alarm bells ringing loudly all day Friday, NewLink responded by putting out a release asserting that its drug indoximod had a “differentiated mechanism of action.” The biotech also said that it would do a review of its programs in light of the setback at Incyte.

The failed study will help gain “understanding of the role of IDO1 inhibition in combination with PD-1 antagonists, and may inform our broader epacadostat clinical development program,” said Steven Stein, chief medical officer, Incyte. “We remain dedicated to transforming the treatment of cancer and will continue to explore how IDO1 inhibition and other novel mechanisms can potentially improve outcomes for patients in need.”

Image: Hervé Hoppenot, Incyte CEO at an Endpoints News event, January 2018. ENDPOINTS NEWS

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