Safety and Biological Activity of Rozibafusp alfa, a Bispecific Inhibitor of Inducible Costimulator Ligand and B Cell Activating Factor, in Patients With Rheumatoid Arthritis: Results of a Phase 1b, Randomized, Double-Blind, Placebo-Controlled, Multiple Ascending Dose Study

Abstract

Objective: To assess the safety and biological activity of rozibafusp alfa, a first-in-class bispecific antibody-peptide conjugate targeting inducible costimulator ligand (ICOSL) and B cell activating factor (BAFF), in patients with rheumatoid arthritis (RA).

Methods: This phase 1b, double-blind, placebo-controlled, multiple ascending dose study included 34 patients (18-75 years; 82.4% female) with active RA (Disease Activity Score of 28 joints-C-reactive protein [DAS28-CRP] >2.6, on stable methotrexate) randomized 3:1 to receive rozibafusp alfa (n = 26, in four ascending dose cohorts of 70, 140, 210, and 420 mg) or a placebo (n = 8) subcutaneously once every 2 weeks for 10 weeks (six total doses), with 24 weeks of follow-up. The primary end point was the incidence of treatment-emergent adverse events (TEAEs). Additional assessments included serum pharmacokinetics (PK), pharmacodynamics (PD), immunogenicity, and RA disease activity measures (DAS28-CRP, Patient Global Assessment of Disease, and Physician Global Assessment of Disease).

Results: TEAEs occurred in 96.2% and 87.5% of patients receiving rozibafusp alfa and the placebo, respectively; most were mild or moderate in severity. Two (7.7%) patients treated with rozibafusp alfa reported serious TEAEs; none were considered treatment related. Multiple doses of rozibafusp alfa showed nonlinear PK (mean t_1/2 = 4.6-9.5 days) and dose-related, reversible PD (>90% ICOSL receptor occupancy in 210- and 420-mg cohorts; reduction in naïve B cells and increase in memory B cells in all cohorts). Five (20%) patients developed anti-rozibafusp alfa antibodies, with no apparent impact on safety. RA disease activity showed greater numerical improvement from baseline with rozibafusp alfa versus the placebo in the 210- and 420-mg cohorts.

Conclusion: Multiple ascending doses of rozibafusp alfa were well tolerated, with PK and PD reflecting dual ICOSL and BAFF blockade. Findings support further clinical evaluation of rozibafusp alfa in autoimmune disease.

Figure 1

Design of the phase 1b multiple ascending dose study. ^aCohorts 2, 3, and 4 were initiated only after six participants in cohorts 1, 2, and 3, respectively, had completed their day 29 visit, demonstrating that the preceding dose level was safe and well tolerated. ^bPatients were maintained on 5 to 25 mg of methotrexate weekly through the duration of screening and treatment. ^cIf patients had abnormal B cell counts at the EOS assessment on day 239, they were followed up every 3 months for up to 12 months after EOS. EOS, end of study; Q2W, once every 2 weeks; SC, subcutaneous.

Figure 2

Pharmacodynamic effects of rozibafusp alfa on B cells. Data show the mean and 95% confidence interval. ICOSL, inducible costimulator ligand; Q2W, once every 2 weeks; RO, receptor occupancy. A, change in percentage ICOSL RO on total B cells. B, change from baseline in naïve B cell percentage. C, change from baseline in memory B cell percentage.

Figure 3

Change from baseline in rheumatoid arthritis disease activity. Data show the mean and standard deviation. DAS28‐CRP, Disease Activity Score of 28 joints–C‐reactive protein; PhGA, Physician Global Assessment of Disease; PtGA, Patient Global Assessment of Disease; Q2W, once every 2 weeks. A, change from baseline in DAS28‐CRP. B, change from baseline in PtGA. C, change from baseline in PhGA.