Povorcitinib

Sanofi has initiated a first-in-human study of SAR447971 (also known as KT-485), an oral small-molecule IRAK4 targeted protein degrader discovered by Cambridge, Massachusetts-based Kymera Therapeutics (Nasdaq: KYMR), in patients with hidradenitis suppurativa — a chronic, painful inflammatory skin disease with limited oral treatment options. The trial is notable because SAR447971 is a second-generation compound, developed explicitly to improve on the potency and selectivity profile of its predecessor, KT-474 (SAR444656), which Sanofi had previously advanced into Phase II before discontinuing that program. Trial design and population The Phase I program (NCT07629336) comprises three sequential substudies enrolling approximately 114 participants in total at a single site in Leiden, Netherlands. The first two cohorts — a single ascending dose study (SAD20411, up to 46 healthy volunteers) and a multiple ascending dose study (MAD20412, up to 48 healthy volunteers) — are randomized, double-blind, and placebo-controlled, with the SAD arm also incorporating a food effect evaluation to characterize how fed versus fasted conditions affect oral absorption. A third open-label multiple ascending dose cohort (MAD24339) will enroll up to 20 patients with confirmed HS, defined by lesions in at least two distinct anatomic areas with at least one site at Hurley Stage II or III and a total abscess and nodule count of four or more. Primary completion is anticipated in Q1 2028. Primary endpoints across all three cohorts assess safety and tolerability through adverse event incidence, laboratory abnormalities, vital sign changes, and ECG parameters. The Sanofi clinical trial is registered under NCT07629336 according to the trial record. Mechanism and research context IRAK4 is a serine/threonine kinase that sits at a convergence point in innate immune signaling, mediating downstream inflammatory responses triggered by Toll-like receptors and interleukin-1 family cytokines. In HS, dysregulated innate immune activation drives the follicular inflammation, abscess formation, and sinus tract development that characterize the disease. SAR447971 is described by Kymera as a second-generation compound with increased potency and selectivity relative to KT-474, developed using Kymera’s proprietary Pegasus degrader discovery platform. The predecessor compound KT-474/SAR444656 had reached Phase II in both atopic dermatitis and HS before Sanofi discontinued that program and elected to advance the second-generation molecule instead. SAR447971’s improved selectivity profile is the stated rationale for the generational switch. Under the collaboration structure established in July 2020, Kymera discovered and characterized SAR447971 preclinically; Sanofi holds global inflammation and immunology development and commercialization rights. Kymera retains oncology rights and holds an option to co-develop and share US profits on a 50/50 basis. Kymera is eligible for up to USD 975 million in collaboration milestones, according to the company’s investor disclosures. Among active programs, Eli Lilly’s povorcitinib (LY3471851), a selective IRAK4 kinase inhibitor currently in Phase III for HS, represents the closest mechanistic comparator in the same indication, though it acts through inhibition rather than degradation and therefore preserves IRAK4 scaffolding function. SAR447971’s differentiation claim rests on whether complete protein elimination produces meaningfully greater or more durable pathway suppression. This article was generated with AI assistance and reviewed and edited by the AllSci editorial team Explore more at AllSci News: https://allsci.com/news/ Leave a Reply Cancel reply Your email address will not be published. Required fields are marked * Comment * Name * Email * Website Copyright © 2026. AllSci Corp. All rights reserved.

Avalo Therapeutics surged 35% on Wednesday after reporting mid-stage data for its experimental antibody abdakibart in hidradenitis suppurativa (HS). The results were released alongside the pricing of a $375-million public offering intended to bankroll the drug's progression into a pivotal Phase III programme and through to its topline readout.The LOTUS study tested two dosing regimens of abdakibart, a monoclonal antibody targeting IL-1β, in 253 patients with moderate-to-severe disease. The primary endpoint measured HiSCR75, defined as a ≥75% reduction in total abscess and inflammatory nodule count with no increase in abscess or draining tunnel count relative to baseline.'De-risking data'Both arms succeeded on that metric, with week-16 HiSCR75 response rates of 42.2% for the 150-mg regimen and 42.9% for the 300-mg regimen, versus 25.6% for placebo. The results were statistically significant (p=0.004) across both doses. Avalo noted that HiSCR75 response was similar in patients regardless of prior biologic exposure.Abdakibart also demonstrated statistically significant benefit across key secondary endpoints such as HiSCR50 response, reductions in the International HS Severity Score System (IHS4) and declines in draining tunnel counts.No safety signals were observed related to neutropenia, serious infections, or opportunistic infections during the 16-week treatment period. Side effects were typically mild or moderate, with headache and nausea being the most common. Full results from LOTUS will be shared at an upcoming medical congress."This de-risking data set gives us tremendous confidence to advance abdakibart into a pivotal Phase III registrational programme," said CEO Garry Neil. "With a differentiated and patient-friendly potential monthly dosing regimen, we aim to offer a truly innovative mechanism of action."Clinical hurdlesHowever, the HS space has been marked by several instances of candidates showing promising results, only to face challenges in later stages of testing.Insmed last month ended development of Brinsupri (brensocatib) in HS after the DPP1 inhibitor failed a mid-stage study. In 2023, Acelyrin's IL-17A inhibitor came up short in a Phase IIb/III study of HS patients after a "marked increase" in placebo response seen in the trial.Meanwhile, MoonLake Immunotherapeutics is evaluating a trispecific IL-17A/F nanobody called sonelokimab in a pair of Phase III trials involving more than 800 patients. VELA-1 met its primary endpoint at 16 weeks, with HiSCR75 achieved in 34.8% of sonelokimab-treated patients versus 17.5% on placebo, though VELA-2 fell short of statistical significance despite a 35.9% response rate because of a high placebo response. However, the company recently reported longer-term readouts hinting at deepening responses.Martina Porter, an assistant professor of dermatology at Harvard Medical School and an investigator on Incyte's STOP-HS programme testing the oral JAK1 inhibitor povorcitinib, recently told FirstWord that predicting treatment response remains a challenge."What we'll want to see over the next five years are clinical or demographic features or other biomarkers that will enable us to figure out what will help us predict response to therapy so we can make more informed decisions about treatment, so that patients don't need to cycle through so many drugs before they find one that works for them," she said (see – KOL Views Q&A: Better biomarkers are needed as the HS toolbox expands).