OP0036 EFFICACY, SAFETY, AND PHARMACOKINETICS OF ANTI-CD40 ANTIBODY ABIPRUBART (KPL-404) IN PATIENTS WITH RHEUMATOID ARTHRITIS: A PHASE 2, RANDOMIZED, PLACEBO-CONTROLLED 12-WEEK-TREATMENT PROOF-OF-CONCEPT STUDY
Authors: E. Jenkins, I. Louw, A. Balog, E. Van Duuren, D. L. Horowitz, J. Jaworski, A. Kivitz, I. Ujfalussy, J. Pirello, E. Tessari, S. Wang, J. F. Paolini
Journal: Annals of the Rheumatic Diseases (2024)

<h3>Background:</h3> Patients (pts) with rheumatoid arthritis (RA) who have had inadequate response to or are intolerant of currently-available biologic or targeted synthetic disease-modifying anti-rheumatic drugs (b/tsDMARDs) have few treatment options and embody a crucial unmet need. Abiprubart (KPL-404) is a humanized monoclonal IgG4 antibody with a stabilized/functionally-silent Fc region that binds to CD40 and inhibits the CD40/CD154 costimulatory interaction without lymphocyte depletion. Abiprubart was well-tolerated in a Phase 1, single-ascending-dose healthy human volunteer study and showed full target engagement and sustained dose-dependent suppression of T-cell dependent antibody responses.[1] These data and abiprubart's high-concentration liquid formulation support investigation of chronic subcutaneous (SC) administration for the treatment of autoimmune diseases. <h3>Objectives:</h3> Pharmacokinetic (PK) lead-in: evaluate the safety and PK of multiple SC doses of abiprubart in RA pts vs placebo; Proof-of-concept (POC): evaluate the efficacy of abiprubart in RA pts vs placebo. <h3>Methods:</h3> This phase 2, randomized, double-blind, placebo-controlled study enrolled pts 18 - 80 years of age with moderate-to-severe active RA who had inadequate response to or intolerance of ≥1 bDMARD or Janus kinase inhibitor. Eligible pts were randomized in sequential cohorts to receive 12 weeks of treatment [Figure 1]. Primary outcomes in the PK lead-in (Cohorts 1 &amp; 2) were abiprubart safety and PK. The Cohort 3 (POC) primary efficacy endpoint was change from baseline in the Disease Activity Score of 28 Joints using C-Reactive Protein (DAS28-CRP) at Week 12. Efficacy comparisons in Cohort 3 were made using an analysis of covariance model to compare each abiprubart dose group vs placebo, with baseline value and randomization stratification as covariates. Other endpoints included change from baseline at Week 12 in Rheumatoid Factor (RF). <h3>Results:</h3> Overall, 16 pts were randomized in the PK lead-in and 78 in the POC portion. Demographics and baseline disease activity were balanced across groups. In the PK lead-in, Cohort 1 (2 mg/kg SC q2wk) and Cohort 2 (5 mg/kg SC q2wk), abiprubart was well-tolerated (DAS28-CRP in Figure 2) and enabled initiation of Cohort 3. In Cohort 3, the change in least-squares (LS) mean [95% confidence interval] from baseline in DAS28-CRP scores at Week 12 compared to placebo in the 5 mg/kg SC qwk group (-2.21 [-2.62, -1.80] points, n=27) vs placebo (-1.65 [-2.07, -1.23] points, n=26) was statistically significant (LS mean difference = -0.56, p=0.0487). In the 5 mg/kg SC q2wk group, here was a trend to improvement in the change from baseline in DAS28-CRP at Week 12 (-2.00 [-2.43, -1.58] points, n=25) vs placebo (-1.65 [-2.07, -1.23] points, n=26) which did not reach statistical significance (LS mean difference = -0.35, p=0.2140) [Figure 2]. Abiprubart significantly reduced RF (clinical marker of disease activity and autoantibody pharmacodynamic marker of CD40 target engagement) by over 40% in both the 5 mg/kg qwk and 5 mg/kg q2wk dose levels (Cohort 3). Incidences of non-serious TEAEs were similar across treatment groups, without dose relatedness, and all TEAEs were mild or moderate in severity. One serious adverse event of monoaural deafness was not drug-related and resolved with pulse-dose steroids. <h3>Conclusion:</h3> Treatment with abiprubart, an anti-CD40 monoclonal antibody, resulted in a statistically significant reduction in DAS28-CRP at Week 12 in the 5mg/kg SC weekly dosing group, compared to placebo, in refractory RA pts. Sustained treatment with abiprubart was well tolerated, with a PK profile that supports practical chronic SC dosing. A fourth cohort, administering a 600mg loading dose followed by fixed doses of 400 mg SC q4wk or placebo for 12 weeks is ongoing. These results support further clinical development of abiprubart in autoimmune diseases in which the CD40/CD154 costimulatory interaction has been implicated. <h3>REFERENCES:</h3> [1] Samant M et al. JPET, 2023. <h3>Acknowledgements:</h3> The authors present this study on behalf of KPL-404-C211 Investigators. <h3>Disclosure of Interests:</h3> Eric Jenkins Kiniksa Pharmaceuticals, Kiniksa Pharmaceuticals, Ingrid Louw Pfizer, Janssen, Lilly, Abbvie, Pfizer, Janssen, Lilly, Abbvie, Attila Balog: None declared, Elsa Van Duuren Pfizer, Aspen, Janssen, Lilly, Adcock-Ingram, Roche, Mundi-Pharma, Abbvie, Boehringer-Ingelheim, Abbvie, Aspen, Pfizer, Janssen, Diane Lewis Horowitz Pfizer, Set Point Medical, Kiniksa Pharmaceuticals, Janusz Jaworski: None declared, Alan Kivitz AbbVie, Amgen, Flexion, GSK, Lilly, Sanofi - Regeneron, Pfizer, GSK, Gilead, Novartis, Amgen, AbbVie, Chemocentryx, Coval, Ecor1, Fresenius Kabi, Gilead, Grunenthal, GSK, Horizon, Janssen, Prime, Prometheus, Selecta, Synact, Takeda – Nimbus, UCB, XBiotech, Ilona Ujfalussy Novartis, Joe Pirello Kiniksa Pharmaceuticals, Kiniksa Pharmaceuticals, Eben Tessari Kiniksa Pharmaceuticals, Kiniksa Pharmaceuticals, Sheldon Wang Kiniksa Pharmaceuticals, Kiniksa Pharmaceuticals, John F. Paolini Kiniksa Pharmaceuticals, Kiniksa Pharmaceuticals.