Kymera’s pain could be Priovant’s gain

Pfizer’s Irak-4 inhibitor PF-06650833 definitely, definitely doesn’t work in hidradenitis suppurativa, but there’s at least partly better news for Priovant.

Since Pfizer had already discontinued its Irak-4 inhibitor PF-06650833 in May Kymera, tarred by having a similarly acting project, could not possibly have fallen any further, right? Wrong: investors sent Kymera down 9% yesterday when it became apparent how big a dud PF-06650833 actually was, courtesy of a late-breaking abstract at the upcoming EADV congress.

In fact, since May hopes had been building that PF-06650833 might show hints of activity to back up the Irak-4 inhibition approach, so yesterday expectations were dealt a second blow. However, the study included a separate Jak1/Tyk2 inhibitor that Pfizer had offloaded into Priovant, and this new venture’s private owners might today be celebrating.

At the time of PF-06650833’s discontinuation Pfizer had not shown any data to back its decision, so the EADV late-breaker reveals the first results from its phase 2 umbrella study in hidradenitis suppurativa. The trial tested PF-06650833, as well as the Tyk2 inhibitor ropsacitinib and a Jak1/Tyk2 agent, brepocitinib, against placebo.

Brepocitinib scores

Pfizer had canned the last two compounds last November, but two months ago revealed the formation of Priovant, part of the Roivant stable, to focus on developing brepocitinib. And it was brepocitinib that appeared to score on the study’s primary endpoint, hidradenitis suppurativa clinical response (HiSCR) at 16 weeks, according to the EADV late-breaker.

Priovant’s hope is that combining Tyk2 with Jak1 inhibition might “provide greater efficacy in multiple highly inflammatory autoimmune diseases, as compared to agents that inhibit either Tyk2 or Jak1 alone”. The EADV data suggest that it might be on to something, as the Tyk2 agent ropsacitinib was basically as inert as PF-06650833.

Priovant’s seeming success is not unequivocal. The group has also licensed ropsacitinib from Pfizer, but this was stated almost as a footnote in the launch announcement, and the Tyk2 asset no longer appears in Priovant's pipeline.

Cross-trial comparisons in hidradenitis suppurativa
Project Mechanism Placebo-adjusted HiSCR*
Pfizer's phase 2 umbrella study
PF-06650833 Irak-4 inhibitor 0.7%
Ropsacitinib (PF-06826647) Tyk2 inhibitor 3.7%
Brepocitinib (PF-06700841) Jak1/Tyk2 inhibitor 18.6%
Abbvie's Pioneer I study
Humira Anti-TNF-alpha MAb 16.0%
Abbvie's Pioneer II study
Humira Anti-TNF-alpha MAb 31.0%
Inflarx's Shine study
Vilobelimab (mid dose) Anti-C5a MAb 4.4%
Chemocentryx's Aurora study
Avacopan (high dose) C5a receptor inhibitor 4.3%
Note: *at 16wk for Pfizer & Inflarx's trials, 12wk for the others. Source: company statements.

It should be stressed that hidradenitis suppurativa is not the most important indication Priovant is investigating with brepocitinib; that claim goes to dermatomyositis, where the phase 3 Valor study began last month. Other uses include lupus and non-infectious uveitis.

In terms of cross-trial comparison, Abbvie’s Humira secured a hidradenitis suppurativa label based on placebo-adjusted week-12 HiSCR of 16-31% across two trials. Pfizer’s 33% placebo response is in line with the 26-28% seen by Abbvie and with the 31% in Chemocentryx’s failed trial of avacopan, and below the 47% seen in Inflarx’s failed trial of vilobelimab, so the optics for brepocitinib in general look good.

Out of luck

No such luck for Kymera, whose lead asset, KT-474, acts on Irak-4. Remarkably, the company’s stock had regained all the losses sustained when Pfizer pulled the plug in May, and investors were brought back down to earth yesterday.

Of course, the failure of one example of a mechanism does not damn them all, and analysts point out that KT-474 is a degrader rather than a straight inhibitor, something that could give it an efficacy edge. KT-474’s phase 1 study, expected to read out in the fourth quarter, is thus a key catalyst for Kymera.

Still, this might not yield much in terms of efficacy data. Sanofi licensed KT-474 in 2020, and is due to take over development at phase 2; whether it actually does so will provide a much better sign of KT-474’s potential.

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