Bristol’s Tyk2 ticks the boxes

Deucravacitinib could soon be coming for a chunk of these. However, safety is still the big unknown for the Bristol project. One of Otezla’s plus points is that it is seen as a safer alternative to injectables, as well as a more convenient one.

Meanwhile, the toxicity of Jak inhibitors is a major talking point, with the FDA recently postponing reviews of Abbvie’s Rinvoq, Pfizer’s abrocitinib and Lilly and Incyte’s Olumiant in atopic dermatitis.Tyk2 is part of the Jak family, so there is a risk that deucravacitinib gets dragged into this debate.

On the basis of the project’s safety profile in Poetyk PSO-1 and 2 this seems unlikely. Rates of serious adverse events were similar between the deucravacitinib, Otezla and placebo arms, and there was no signal with deucravacitinib on malignancies, major adverse cardiovascular events, thromboses and infections, all of which have been seen with Jaks.

Tyks and Jaks

Stifel analysts believe that deucravacitinib could avoid the black box warning with which Jaks have been saddled.

However, this might not be the case for all the Tyk2s. Notably, deucravacitinib hits the regulatory or allosteric domain of Tyk2; as this domain differs across the Jak family, this approach is thought to be selective for Tyk2. Others taking a similar tack include Nimbus Therapeutics and Ventyx Biosciences, whose VTX-958 recently went into phase 1.

Meanwhile, Pfizer’s PF-06826647 hits the active or catalytic domain of Tky2. As this domain shares similarities across the Jak family, using it to target Tyk2 selectively has been tricky. Indeed, PF-06826647 is thought to have Jak2 activity. Pfizer has discontinued this project in ulcerative colitis, but development continues in psoriasis and hidradenitis suppurativa.  

Galapagos also has a Tyk2 inhibitor, GLPG3667, in phase 1; according to Stifel, this also targets the active domain and could have Jak1 activity.

The risk/benefit profile of these agents might become clearer as data from more projects become available; Bristol itself has various trials of its Tyk2 ongoing in diseases including ulcerative colitis and Crohn’s.

In psoriasis deucravacitinib’s approval looks likely. The next job for Bristol is carving out a niche in a competitive sector.

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