Safety, tolerability, and efficacy of the PD-1 agonist antibody JNJ-67484703 in adults with active rheumatoid arthritis: results of a multicenter, double-blind, placebo-controlled, randomized, multiple-dose phase Ib study.

BACKGROUND

Programmed cell death protein 1 (PD-1) is associated with the immunopathology of rheumatoid arthritis (RA). JNJ-67484703 is a humanized IgG anti-PD-1 agonist antibody.

OBJECTIVES

To report results of a phase Ib study evaluating the safety, tolerability, and disease-related outcomes of JNJ-67484703 in adults with active rheumatoid arthritis.

DESIGN

A randomized, double-blind, placebo-controlled, multiple-dose, phase Ib study in adults with active RA who were inadequately controlled on conventional synthetic disease-modifying antirheumatic drugs.

METHODS

JNJ-67484703 at doses of 2 or 3 mg/kg or placebo was administered by subcutaneous injection for 10 weeks (on weeks 0, 1, 2, 4, 6, 8, and 10). Safety was assessed for the first 6 participants in the 2 mg/kg group to determine if enrollment would proceed to the 3 mg/kg dose. The primary endpoint was the proportion of participants with treatment-emergent adverse events (TEAEs). Secondary endpoints included change from baseline at week 12 in Disease Activity Score 28 using C-reactive protein (DAS28-CRP) and circulating PD-1+ T-cell counts at the 3 mg/kg dose level only. Least squares (LS) mean difference between JNJ-67484703 groups and placebo were based on mixed-effect model for repeated measures for DAS28-CRP.

RESULTS

A total of 44 participants were randomized to receive JNJ-67484703 2 mg/kg (n = 5), 3 mg/kg (n = 25), or placebo (n = 14); TEAEs were reported in 4 (80%), 17 (68%), and 10 (71%), respectively. None were severe in intensity, and no deaths were reported. TEAEs of infection were reported in 21% of placebo participants and 20% of those in the combined JNJ-67484703 groups. No injection-site or hypersensitivity reactions were reported. At week 12, reduction in DAS28-CRP from baseline was numerically greater in the JNJ-67484703 2 mg/kg and 3 mg/kg groups versus placebo, with a difference in LS means between the 3 mg/kg group and placebo of -0.69 (95% CI -1.55, 0.18; p = 0.117). JNJ-67484703 decreased circulating PD-1+ T cells, with the greatest effect on those with the highest baseline expression of PD-1.

CONCLUSION

JNJ-67484703 was well tolerated in participants with active RA and showed evidence for biologic and clinical activity in this small, proof-of-mechanism study.

TRIAL REGISTRATION: ClinicalTrials.gov, NCT04985812.