Background/Purpose: PD-1 pathway mutations increase human susceptibility to multiple autoimmune diseases, and insufficient PD-1 signaling can lead to dysregulated T cell responses. By targeting natural immune regulatory mechanisms to modulate immune cells driving disease, there is an opportunity to dampen the inflammatory cycle and restore immune balance. Rosnilimab is a PD-1 agonist antibody designed to inhibit activated T cells for the treatment of inflammatory diseases, including rheumatoid arthritis (RA).The primary objective of this first-in-human (FIH), healthy volunteer (HV) Phase 1 study was to assess the safety and tolerability of single ascending doses (SAD) and multiple ascending doses (MAD) of rosnilimab. Other objectives included the assessment of pharmacokinetic (PK) profile, immunogenicity, and translational pharmacodynamic (TPD) endpoints (e.g. PD-1 receptor occupancy (RO), reduction in various T cell populations and associated cytokine signaling).

Methods: This study was conducted at a single study center in the United States with 14 cohorts in SAD and 3 cohorts in MAD. Each cohort had 8 participants (6 active, 2 placebo (PBO)). Treatment cohorts were enrolled sequentially in each SAD/MAD phase. Intravenous (IV) and subcutaneous (SC) routes of administration were assessed in the SAD; SC route was assessed in the MAD.

Results: A total of 144 participants were enrolled; 90 randomized to the active SAD cohorts, 18 to the active MAD cohorts, and 30 and 6 randomized to the SAD and MAD PBO cohorts, respectively. All participants were assessed for safety and PD. Rosnilimab was well tolerated, with no dose-limiting toxicities or deaths. Two serious adverse events (SAEs) were reported in the SAD (obstructive pancreatitis in a PBO-dosed participant; COVID-19 infection in a rosnilimab-dosed participant leading to discontinuation; unrelated to treatment).No SAEs were reported in the MAD. TPD activity was rapid with sustained reduction in quantity and functional activity of PD-1+ T cells. Conventional T (Tcon) cells in the periphery expressing PD-1 were reduced, on average through Day 30 in the SAD where full RO was sustained following rosnilimab dosing, by ~50% in both CD4+ and CD8+ subsets, in a dose-dependent manner and in correlation with RO.This reduction was maximized on PD-1 high expressing T cells, ~90% reduction relative to baseline. There was no significant impact on the overall total T cell, Tcon or regulatory T (Treg) cell numbers, thereby resulting in an observed bias in favor of Treg:Tcon cell ratio post-dosing. An antigen-specific functional T cell assay measuring ex vivo interferon-gamma release in response to antigen challenge was inhibited up to ~90% relative to baseline within 30 days following a single dose. Rosnilimab has a favorable PK profile consistent with full RO, a two-week half-life, and exposure nearly dose-proportional in both IV and SC dosing.

Conclusion: Rosnilimab demonstrated favorable safety, PK, and TPD activity. These results demonstrate proof of mechanism in humans and support advancing rosnilimab into a phase 2b study in RA.

« Back to ACR Convergence 2023

ACR Meeting Abstracts - https://acrabstracts.org/abstract/rosnilimab-a-novel-pd-1-agonist-monoclonal-antibody-inhibits-peripheral-t-cell-proliferation-and-cytokine-secretion-and-reduces-circulating-pd-1-high-expressing-cd4-and-cd8-t-cells-results-from-a-p/