SITC 2021 – Incyte unveils its oral checkpoint blocker

There are some remissions, but peripheral neuropathy casts a long shadow.

Incyte had not been considered a serious contender in the niche of oral checkpoint inhibition, but made its pitch at the SITC conference over the weekend. The small-molecule PD-L1 blocker INCB086550 showed promising pharmacodynamics, internalised PD-L1, and had efficacy in some patients to boot.

Unfortunately, though this looks like the first clinical activity from an oral checkpoint blocker, the toxicity price looks high, and raises questions over whether INCB086550 has a therapeutic window and can compete against established injectable MAbs. Incyte insists that the adverse events are manageable, and cites two other small-molecule shots on goal in its pipeline.

These are INCB099280, which is structurally similar to ‘550, and INCB099318, which is not. Both should yield clinical data next year, at which point Incyte says it will decide whether to take one or more of these three projects forward on a registrational path.

Eight remissions

For now, however, investors only have ‘550 data to go on, specifically from a phase 1 dose-escalation and expansion study that at SITC yielded results in 68 evaluable subjects at an April 9 cutoff. These yielded eight remissions, of which seven were in IO-naive patients, in squamous cell anal, ovarian, vaginal, and MSI-high/dMMR cancers; five remissions were ongoing at data cutoff.

However, the bad news came with reports of treatment-related AEs, which were described as typical for checkpoint blockade – except for peripheral neuropathy. This was seen in 10 of 79 safety-evaluable patients; four cases were grade 3, and were mostly managed with dose modification, discontinuation or steroids.

The finding raises questions over ‘550’s tolerability, according to Mizuho analysts.

On a call Incyte argued that an oral checkpoint blocker could present easier dosing than the IV infusion of current MAbs, along with possible cost savings and relatively easy combination with other orals.

However, with seven MAbs approved in the US, and Pfizer, Merck & Co, Roche and Bristol Myers Squibb all working swiftly on SC dosing, an oral drug with a less than stellar safety profile could find it hard to make an impression, and this is now the worry for Incyte’s ‘550. 

Undeterred, the company highlighted ‘280 and ‘318, whose clinical trials have so far enrolled “three dozen” and “about a dozen” patients respectively, and should yield data next year, along with a ‘550 update. ‘280 and ‘318 are showing signs of tumour shrinkage, Incyte teased, and apparently no peripheral neuropathy has been seen with either.

Source: Incyte presentation.

The company also said it was working to optimise ‘550’s dosing, including looking at intermittent 400mg administration, and played up the fact that its project was the first oral anti-PD-L1 to demonstrate clinical responses.

This in itself is quite a feat for a group that did not even feature in this space a few years ago. Instead it was Curis’s CA-170 that many had seen as leading the clinical charge, but this Vista/PD-L1 antagonist has yet to generate meaningful clinical data, even though it completed a phase 1 trial last year.

Still, the oral checkpoint space does not make up a significant chunk of Incyte’s valuation, so the stock was unmoved on Nasdaq.

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