A depleter of pathogenic T cells, rosnilimab’s novel MOA generated a differentiated efficacy, tolerability and safety profile in recent Phase 2b study
Investigational rosnilimab, a selective depleter of pathogenic T cells, shows promise as a novel treatment for moderate-to-severe rheumatoid arthritis, a chronic autoimmune disease that primarily affects the joints, causing pain, swelling and inflammation.1
In a Phase 2b clinical trial, rosnilimab demonstrated rapid symptomatic improvement across diverse patient populations, driving patients into low disease activity (LDA) within three months, and continued to improve through six months. The data further indicated these responses were durable for at least three additional months off-drug. Rosnilimab also demonstrated favorable safety and tolerability, particularly when compared to the safety profiles of standard of care biologics or JAK inhibitors.
“Witnessing rosnilimab, with its novel mode of action, dramatically reduce RA disease activity through six months in most patients, whether having failed biologic or targeted synthetic disease-modifying anti-rheumatic drug (b/tsDMARD) therapies or b/tsDMARD-naïve, is truly exciting for patients living with this disease and the field of RA treatment,” said Jonathan Graf, M.D., professor of Medicine, Division of Rheumatology at the University of California, San Francisco, and an investigator for the trial.
The U.S. RA market is valued at more than $20 billion. Since 2012, no new classes of medicine have been approved, and many RA patients cycle through different therapies,2 with up to a quarter not finding symptom relief.3
Recognizing the Important Role of Pathogenic T Cells in Inflammatory Diseases
In people with RA, more than 80% of T cells found in the joint tissue or synovium, largely peripheral helper (Tph), follicular helper (Tfh) and effector (Teff) T cells, are pathogenic,4 and their peripheral blood contains twice as many pathogenic T cells, largely Tph cells, as found in non-RA patients.5 Selectively depleting only the pathogenic T cells while maintaining regulatory T cells (Tregs) normalizes remaining T cell composition to be more reflective of a healthy immune system, leading to durable responses and the potential to mitigate chronic inflammation associated with known comorbidities in RA.
Research shows that in the periphery, rosnilimab depletes more than 90% of the pathogenic T cells, which represent only a small portion of overall T cell composition. Rosnilimab also depletes ~90% of the pathogenic T cells in the synovium or joint tissue.
These data are different from Phase 2a RA data generated by other T cell-targeting therapies that only partially deplete. For example, Lilly’s PD-1 agonist peresolimab and JNJ’s JNJ-67484703 only deplete approximately 50-60% of the pathogenic T cells in the periphery6.7 and JNJ-67484703 only depletes ~40% pathogenic T cells in the synovium (no synovium data available from peresolimab to date).7 Additionally, Phase 2 clinical trial data suggest efficacy of peresolimab on various endpoints deteriorated significantly after three months.8
One of the challenges associated with only depleting approximately half of the pathogenic T cells is that the remaining half of these cells are still there and could also continue to propagate. This may lead to ongoing and rampant inflammation and cytokine secretion, leaving patients vulnerable to worsening of their disease and also potential comorbidities associated with uncontrolled, chronic inflammation.
Rosnilimab Phase 2b Trial Outcomes
Rosnilimab’s global Phase 2b trial enrolled 424 patients with moderate-to-severe RA on background conventional DMARDs (e.g., methotrexate) and evaluated three dosing regimens of rosnilimab—100 mg and 400 mg every four weeks and 600 mg every two weeks—against placebo (1:1:1:1).
Anaptys previously reported that patients on all three doses of rosnilimab achieved statistically significant reductions in mean change from baseline in the disease activity score in 28 joints (DAS-28) C-reactive protein (CRP), the study’s primary endpoint, as well as ACR20 response at Week 12 compared to placebo.
While cross-trial comparisons are for illustrative purposes only, during the three-month placebo-controlled period, in both b/tsDMARD-naïve and -experienced patients, rosnilimab demonstrated rapid onset of ACR20, a Phase 3 registrational endpoint. It also demonstrated substantial decreases from baseline in CRP, an objective inflammatory biomarker, sustained through six months, that appeared to be comparable to the Phase 2b trial results of the JAK inhibitor upadacitinib.9,10
At baseline, patients had high disease activity with a mean Clinical Disease Activity Index (CDAI) score of 38 and median CDAI score of 36. Of the 318 rosnilimab patients in the intent to treat (ITT) population, CDAI LDA, the level signifying disease control and requiring a CDAI score of less than 10, was achieved by 69% of patients (220 responders) across all three doses of rosnilimab at Week 14, the timepoint required to be eligible to remain in the all-active treatment period on rosnilimab through Week 28.
Importantly, maximal response rates for rosnilimab have not yet been observed as strict criteria at Week 14 prevented patients with meaningful improvement from continuing treatment in the trial.
At six months, rosnilimab demonstrated “JAK-like” efficacy with deepening responses on CDAI LDA, CDAI remission (CDAI ≤2.8) and ACR70. This was also observed in the subset of b/tsDMARD-experienced patients who received 600 mg every two weeks and 400 mg every four weeks, showing a dose response relative to the lower dose.
Patients who were in CDAI LDA at Week 28 further had durable responses off-drug for at least an additional three months, supporting the potential to test maintenance dosing with extended dosing intervals (e.g., every eight or 12 weeks) in future clinical trials.
“Impressive translational data provide further evidence that by targeting specific pathogenic T cells, rosnilimab has a substantial impact downstream on multiple known pathways that drive RA pathogenesis, with the potential to restore immune homeostasis necessary to achieve meaningful, long-lasting disease remission,” said Dr. Graf.
Consistent with prior rosnilimab studies, a favorable safety and tolerability profile across all rosnilimab doses was observed in this Phase 2b study with very few dropouts, and no treatment-related serious adverse events (SAEs), malignancies, anaphylaxis or systemic hypersensitivity. Relative to placebo, there was a low and balanced incidence of injection site reactions and serious infections. Most adverse events were mild or moderate.
Rosnilimab has been discovered and developed by San Diego-based AnaptysBio. Learn more here.
References
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2. Kavuncu V, Evcik D. Physiotherapy in rheumatoid arthritis. MedGenMed. 2004;6(2):3. Published 2004 May 17.
3. Zhao SS, Kearsley-Fleet L, Bosworth A, Watson K; BSRBR-RA Contributors Group, Hyrich KL. Effectiveness of sequential biologic and targeted disease modifying anti-rheumatic drugs for rheumatoid arthritis. Rheumatology (Oxford). 2022;61(12):4678-4686. doi:10.1093/rheumatology/keac190
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7. Ling I, Marciniak S, Clarke S, et al. POS0597 Safety, Tolerability, and Activity of JNJ-67484703 in Participants with Active Rheumatoid Arthritis: Results of a Multicenter, Double-blind, Placebo-controlled, randomized, Multiple-dose Phase 1b Study. Ann. Rheum. Dis. 2025;84;794-795.
8. Tuttle J, Drescher E, Simón-Campos JA, et al. A Phase 2 Trial of Peresolimab for Adults with Rheumatoid Arthritis. N Engl J Med. 2023;388(20):1853-1862. doi:10.1056/NEJMoa2209856
9. Genovese MC, Smolen JS, Weinblatt ME, et al. Efficacy and Safety of ABT-494, a Selective JAK-1 Inhibitor, in a Phase IIb Study in Patients With Rheumatoid Arthritis and an Inadequate Response to Methotrexate. Arthritis Rheumatol. 2016;68(12):2857-2866. doi:10.1002/art.39808
10. Kremer JM, Emery P, Camp HS, et al. A Phase IIb Study of ABT-494, a Selective JAK-1 Inhibitor, in Patients With Rheumatoid Arthritis and an Inadequate Response to Anti-Tumor Necrosis Factor Therapy. Arthritis Rheumatol. 2016;68(12):2867-2877. doi:10.1002/art.39801