Background: Psoriatic arthritis (PsA) is a chronic, systemic, immune-mediated, inflammatory musculoskeletal disease in which dysregulated interleukin (IL)-17A activity plays a pivotal role in disease pathogenesis. Izokibep (IZO) is a small protein therapeutic (18.6 kDa) designed to selectively inhibit IL-17A with high potency through tight binding affinity [1]. IZO demonstrated efficacy across multiple PsA measures through week (wk) 46 in a phase 2 study.

Objectives: To evaluate the efficacy and safety of IZO through wk 16 in a phase 2b/3 study in patients (pts) with active PsA.

Methods: Study 22104 (NCT05623345) included a 16-wk, randomized, double-blind, placebo (PBO)-controlled treatment period. Eligible pts had adult-onset, active PsA (duration ≥6 months and ≥3 tender/swollen joints) and an inadequate response, intolerance, or contraindication to an NSAID, csDMARD, and/or TNFi. Pts reported here were equally randomized to IZO 160 mg every 2 wks (Q2W), IZO 160 mg every wk (QW), or PBO QW. The primary endpoint was ACR50 at wk 16.

Results: A total of 343 pts were included (IZO 160 mg Q2W, n=113; IZO 160 mg QW, n=112; PBO, n=118). The mean age was 51 years, BMI was 30 kg/m², time since diagnosis was 7 years, and 53% were male. Baseline (BL) disease characteristics were generally balanced across groups. The primary endpoint of ACR50 at wk 16 was met; a higher percentage of pts receiving IZO Q2W (43%, P<0.0001) and QW (40%, P<0.0001) achieved ACR50 vs PBO (15%), with improvement as early as wk 4 (Figure 1). Higher percentages of pts receiving either dose of IZO vs PBO achieved the high-hurdle endpoints of ACR70, PASI100, and MDA (Table 1). Higher percentages of pts receiving IZO also achieved HAQ-DI minimal clinically important difference (≥0.35) vs PBO (Table 1). Subgroup summaries showed clinically meaningful enthesitis resolution rates with IZO vs PBO in pts with high BL enthesitis burden (Table 1). Treatment-emergent adverse events (AEs) occurred in 66%, 72%, and 41% of pts receiving IZO Q2W, IZO QW, and PBO, respectively. The most common AEs were injection site-related events, the majority of which were mild to moderate in severity and infrequently led to discontinuation (1%, 4%, and 0% of pts receiving IZO Q2W, IZO QW, and PBO, respectively). Serious AEs were reported at low rates (2%, 3%, and 1%). Rates of ulcerative colitis (1%, 1%, and 0%) and candidiasis (0%, 1%, and 1%) were also low. No deaths, uveitis cases, or suicidal ideation were reported.

Conclusion: IL-17A selective inhibition by IZO in pts with active PsA resulted in rapid improvement in disease activity across multiple disease domains. In addition to meeting the primary endpoint of ACR50, a substantial portion of IZO-treated pts achieved responses for the high-hurdle endpoints of ACR70, PASI90, PASI100, and MDA. These findings are consistent with the hypothesis that the IZO molecular construct allows optimal efficacy by IL-17A inhibition, without requiring blockade of IL-17F. IZO treatment was well tolerated, with a safety profile generally consistent with that of other IL-17A inhibitors.

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Figure 1.

ACR50 Response Over 16 Weeks. Full analysis set; nonresponse imputation. Nominal significance: *P<0.05; ***P<0.0001.

REFERENCES: [1] Klint S, et al. MAbs. 2023;15(1):2209920.

Acknowledgements: NIL.

Disclosure of Interests: Philip J. Mease AbbVie, Amgen, Eli Lilly, Janssen, Novartis, Pfizer, and UCB, AbbVie, ACELYRIN, INC., Aclaris, Alumis, Amgen, Boehringer Ingelheim, Bristol Myers Squibb, Eli Lilly, Immagene, Janssen, Moonlake, Novartis, Pfizer, Takeda, UCB, and Ventyx, AbbVie, ACELYRIN, INC., Amgen, Bristol Myers Squibb, Eli Lilly, Janssen, Novartis, Pfizer, and UCB, Frank Behrens Abbvie, Affibody, Amgen, Boehringer Ingelheim, Galapagos, GSK, Janssen Cilag, Lilly, MoonLake, MSD, Novartis, Pfizer, Sandoz, Sanofi, and UCB, Abbvie, Affibody, Amgen, Boehringer Ingelheim, Galapagos, GSK, Janssen Cilag, Lilly, MoonLake, MSD, Novartis, Pfizer, Sandoz, Sanofi, and UCB, Bionorica, BMS, Chugai, Iron4u, Janssen-Cilag, LEO, Novartis, Pfizer, and Roche, Alan Kivitz AbbVie, Amgen, Flexion, GSK, Lilly, Pfizer, Sanofi - Regeneron, and UCB, Amgen, Gilead, GSK, Novartis, and Pfizer, AbbVie, Coval, Ecor1, Fresenius Kabi, Gilead, Grunenthal, GSK, Halia, Horizon, Janssen, Prime, Prometheus, Selecta, Synact, Takeda – Nimbus, UCB, and XBiotech, Edit Drescher: None declared, Piotr Adrian Klimiuk: None declared, Howard Sofen ACELYRIN, INC., Nehad Soloman AbbVie, Amgen, AstraZeneca, GSK, Scifer Medical, and UCB, Anne M. Stevens ACELYRIN, INC., ACELYRIN, INC., Myreen E. Tomas ACELYRIN, INC., ACELYRIN, INC., Brian Wiens ACELYRIN, INC. and Horizon, ACELYRIN, INC., Shephard Mpofu ACELYRIN, INC., ACELYRIN, INC., Peter C. Taylor AbbVie, ACELYRIN, INC., Aqtual, Inc., Biogen, Fresenius, Galapagos, Gilead, GlaxoSmithKline, Janssen, Lilly, Nordic Pharma, Pfizer, Sanofi, UCB, Galapagos.