peresolimab (LY3462817) / Eli Lilly - LARVOL DELTA

RESOLUTION-1: A Study of Peresolimab (LY3462817) in Participants With Moderately-to-Severely Active Rheumatoid Arthritis (clinicaltrials.gov) - P2 | N=491 | Completed | Sponsor: Eli Lilly and Company | Active, not recruiting ➔ Completed

Trial completion • Immunology • Inflammatory Arthritis • Musculoskeletal Diseases • Rheumatoid Arthritis • Rheumatology

PD-1 antibody interactions with Fc gamma receptors enable PD-1 agonism to inhibit T cell activation - therapeutic implications for autoimmunity. (PubMed, J Autoimmun) - "We recently showed in a phase 2a trial that PD-1 could be stimulated with the PD-1 agonist antibody peresolimab to treat rheumatoid arthritis...Three PD-1 agonist antibodies with different antigen binding domains, including the clinically validated PD-1 blocking antibody pembrolizumab, suppressed T cell activation to a similar degree; this finding suggests that a specific PD-1-binding epitope is not required for PD-1 agonism...Using a series of human Fc mutants with altered affinities to various FcγRs, we dissected the contributions of FcγRs and found that multiple FcγRs rather than a single receptor contribute to agonist activity. Our work reveals an important role for FcγR binding in the activity of PD-1 antibodies, which has implications for optimizing both PD-1 agonist and antagonist antibodies."

IO biomarker • Journal • Immunology • Inflammatory Arthritis • Rheumatoid Arthritis • Rheumatology

Exhausted T-cells Are Increased in Autoimmune Diseases and Predict Response to Anti-TNF in RA and SPA Patients (ACR Convergence 2024) - "Exhausted T-cells are differentially enriched between IMIDs. Sjögren patients showed the most consistent increased in T4ex and T8ex,T4ex being associated with IgG levels, IFNg and IP-10. High baseline levels of T4ex are associated with better response to anti-TNF."

Clinical • IO biomarker • Ankylosing Spondylitis • Immunology • Inflammatory Arthritis • Oncology • Rheumatoid Arthritis • Rheumatology • Seronegative Spondyloarthropathies • Sjogren's Syndrome • Spondylarthritis • CD4 • CD8 • IFNA1 • IFNB1 • IFNG • PD-1 • TIGIT

A Lilly spokesperson explained the removal of a phase 2 trial of peresolimab from the pipeline. (FierceBiotech) - “Lilly decided to terminate its phase 2b study (KDAF) of peresolimab in rheumatoid arthritis following Lilly’s analysis of the overall benefit/risk profile of peresolimab. This decision by Lilly was made specific to the phase 2b KDAF study of peresolimab for rheumatoid arthritis,'..."

Trial termination • Rheumatoid Arthritis

CELLULAR AND PROTEOMIC CHANGES FOLLOWING ADMINISTRATION OF PERESOLIMAB, IN A PHASE 2A TRIAL IN RHEUMATOID ARTHRITIS (EULAR 2024) - P2 | "We report here changes in several exploratory biomarkers from patients enrolled in the Phase 2a study of peresolimab in RA patients. A rapid reduction was observed in circulating PD-1 high CD4+ T cells lasting through week 12, but no changes in any of the major lymphocyte subsets were detected with peresolimab treatment. Several molecular pathways that are altered in RA patients, trended towards patterns in healthy subjects with peresolimab treatment as early as week 8, which corresponds to the timing of DAS28-CRP improvements."

IO biomarker • P2a data • Immunology • Inflammatory Arthritis • Rheumatoid Arthritis • Rheumatology • CD4 • CD8 • IL6 • PD-1

Immune Checkpoint Inhibitor-induced Polymyalgia Rheumatica. (PubMed, Rheum Dis Clin North Am) - "Comparisons between ICI-PMR and classical PMR may provide further bidirectional insights, especially given that important questions remain unanswered about both diseases. The cause of classical PMR remains poorly understood, and ICI-PMR may represent a model of induced PMR, with important therapeutic implications."

Checkpoint inhibition • Journal • Review • Giant Cell Arteritis • Immunology • Musculoskeletal Pain • Oncology • Pain • Rheumatology

A Relative Bioavailability Study of Peresolimab (LY3462817) Formulations in Healthy Participants (clinicaltrials.gov) - P1 | N=57 | Completed | Sponsor: Eli Lilly and Company | Recruiting ➔ Completed

Trial completion

RESOLUTION-1: A Study of Peresolimab (LY3462817) in Participants With Moderately-to-Severely Active Rheumatoid Arthritis (clinicaltrials.gov) - P2 | N=491 | Active, not recruiting | Sponsor: Eli Lilly and Company | Phase classification: P2b ➔ P2

Phase classification • Immunology • Inflammatory Arthritis • Musculoskeletal Diseases • Rheumatoid Arthritis • Rheumatology

‘A great step forward’: The next wave of rheum therapies offers ‘tantalizing’ approaches (Healio) - "'The peresolimab trial is very exciting,' Strand said. 'The safety profile is very good, not like what we worry about with more extreme approaches like CAR T cells.' Calabrese acknowledged that although such 'extreme approaches” have the alure of potentially being curative, many of the other strategies in the rheumatology pipeline are geared toward minimizing disease activity, reducing steroid use and helping patients reach remission."

Media quote

Cellular and Proteomic Changes Following Administration of Peresolimab, in a Phase 2a Trial in Rheumatoid Arthritis (ACR Convergence 2023) - P2 | "We report here changes in several exploratory biomarkers from patients enrolled in the Phase 2a study of peresolimab in RA patients. A rapid reduction was observed in circulating PD-1 high CD4+ T cells lasting through week 12, but no changes in any of the major lymphocyte subsets were detected with peresolimab treatment. Several molecular pathways that are altered in RA patients, trended towards patterns in healthy subjects with peresolimab treatment as early as week 8, which corresponds to the timing of DAS28-CRP improvements."

IO biomarker • P2a data • Immunology • Inflammatory Arthritis • Rheumatoid Arthritis • Rheumatology • CD4 • CD8 • IL6

A Relative Bioavailability Study of Peresolimab (LY3462817) Formulations in Healthy Participants (clinicaltrials.gov) - P1 | N=56 | Recruiting | Sponsor: Eli Lilly and Company | Not yet recruiting ➔ Recruiting

Enrollment open

RESOLUTION-1: A Study of Peresolimab (LY3462817) in Participants With Moderately-to-Severely Active Rheumatoid Arthritis (clinicaltrials.gov) - P2b | N=491 | Active, not recruiting | Sponsor: Eli Lilly and Company | Recruiting ➔ Active, not recruiting

Enrollment closed • Immunology • Inflammatory Arthritis • Musculoskeletal Diseases • Rheumatoid Arthritis • Rheumatology • CRP

Phase 2 Trial of Peresolimab for Adults with Rheumatoid Arthritis. Reply. (PubMed, N Engl J Med) - No abstract available

Journal • P2 data • Immunology • Inflammatory Arthritis • Rheumatoid Arthritis • Rheumatology

Phase 2 Trial of Peresolimab for Adults with Rheumatoid Arthritis. (PubMed, N Engl J Med) - No abstract available

Journal • P2 data • Immunology • Inflammatory Arthritis • Rheumatoid Arthritis • Rheumatology

"It does! Hoping peresolimab goes the same" (@EBRheum)

A Relative Bioavailability Study of Peresolimab (LY3462817) Formulations in Healthy Participants (clinicaltrials.gov) - P1 | N=56 | Not yet recruiting | Sponsor: Eli Lilly and Company

New P1 trial

A Phase 2 Trial of Peresolimab for Adults with Rheumatoid Arthritis (EULAR 2023) - P2 | "**p value < 0.01. ***p value < 0.001."

Clinical • P2 data • Immunology • Inflammatory Arthritis • Oncology • Rheumatoid Arthritis • Rheumatology • CRP

"New treatment -Peresolimab, Liposomal antagomiR-115-5p, NNanocatalytic treatment with Ru@TiO2 #EULAR2023" (@drtune3640538)

Peresolimab’s Potential in Rheumatoid Arthritis (RheumNow) - "Peresolimab is a humanized IgG1 monoclonal antibody that acts as a programmed cell death protein 1 (PD-1) agonist (stimulator). The NEJM reports that PER met its efficacy primary endpont in treating patients with active rheumatoid arthritis (RA)....The ACR responses at week 12 were only significant for PER 700 mg (compared to placebo), but not significant for ACR 50, ACR70."

Online posting

A Phase 2 Trial of Peresolimab for Adults with Rheumatoid Arthritis. (PubMed, N Engl J Med) - P2 | "Peresolimab showed efficacy in a phase 2a trial in patients with rheumatoid arthritis. These results provide evidence that stimulation of the PD-1 receptor has potential efficacy in the treatment of rheumatoid arthritis. (Funded by Eli Lilly; ClinicalTrials.gov number, NCT04634253.)."

Journal • P2 data • Immunology • Inflammation • Inflammatory Arthritis • Rheumatoid Arthritis • Rheumatology • CRP

A Safety Study of LY3462817 in Healthy Japanese and Non-Japanese Participants (clinicaltrials.gov) - P1 | N=33 | Completed | Sponsor: Eli Lilly and Company | Active, not recruiting ➔ Completed

Trial completion

A Safety Study of LY3462817 in Healthy Japanese and Non-Japanese Participants (clinicaltrials.gov) - P1 | N=32 | Active, not recruiting | Sponsor: Eli Lilly and Company | Recruiting ➔ Active, not recruiting

Enrollment closed

A Phase 2 Trial of Peresolimab for Adults with Rheumatoid Arthritis (ACR Convergence 2022) - P2 | "These clinical data represent the first meaningful evidence that stimulating the PD-1 receptor has the potential to treat RA. Peresolimab was superior to placebo at Week 12 for several key endpoints. Safety events were similar between treatment groups."

Clinical • Late-breaking abstract • P2 data • Immunology • Inflammation • Inflammatory Arthritis • Oncology • Rheumatoid Arthritis • Rheumatology

"New mechanism of action in #RA treatment @LillyPad @LillyPadCA PD-1 agonist Peresolimab for treatment of RA Being presented at #ACR22 by Professor Paul Emery" (@MayKazem)

PD-1

A Study of Peresolimab (LY3462817) in Participants With Moderately-to-Severely Active Rheumatoid Arthritis (clinicaltrials.gov) - P2b | N=420 | Recruiting | Sponsor: Eli Lilly and Company | Not yet recruiting ➔ Recruiting

Enrollment open • Immunology • Inflammatory Arthritis • Musculoskeletal Diseases • Rheumatoid Arthritis • Rheumatology • CRP