According to a phase 2a study published in New England Journal of Medicine, peresolimab has shown effectiveness in rheumatoid arthritis (RA) patients. Peresolimab is a humanized IgG1 monoclonal antibody that accelerates the endogenous programmed cell death protein 1 (PD-1) inhibitory pathway. PD-1 acts as a negative regulator and immunological checkpoint inhibitor, inhibiting T-cell responses. The PD-1 axis plays a critical role in restoring tolerance and preventing the accumulation of self-reactive T cells.
PD-1, discovered by Honjo and his team in 1992, serves as an inhibitory factor for the immune system. Previous animal studies demonstrated that PD-1 knockout mice exhibited a predisposition to autoimmune disorders, including lupus-like glomerulonephritis, late-onset inflammatory arthritis, and dilated cardiomyopathy. In a study conducted by Greisen et al., it was reported that individuals with early or chronic RA displayed higher levels of soluble PD-1 compared to healthy volunteers. Furthermore, the researchers found that PD-1 levels in synovial fluid were higher than in plasma. Additionally, they observed a significant direct correlation between PD-1 values at these two anatomical locations within individual RA patients.
The current double-blind, randomized, placebo-controlled phase 2a trial conducted by Tuttle and co-researchers included adults with moderate-to-severe RA who had insufficient or lack of response, or intolerable side effects with conventional synthetic DMARDs or biologic or targeted synthetic DMARDs. The selected participants were randomized in a 2:1:1 ratio to receive either 700 mg of peresolimab, 300 mg of peresolimab, or a placebo intravenously once every four weeks.
The researchers revealed that the change from baseline in the disease activity score for 28 joints based on c-reactive protein level was considerably superior in the 700-mg peresolimab group compared to the placebo group after 12 weeks (least-squares mean change, −2.09 ± 0.18 vs −0.99 ± 0.26). Furthermore, the findings indicated that the 700-mg dosage outperformed the placebo regarding the percentage of patients achieving an American College of Rheumatology 20 response.
Immunotherapies utilizing anti-PD-1 monoclonal blocking antibodies have revolutionized human cancer therapy. However, innovative therapeutic options are warranted in managing RA to enhance overall patient care, particularly for individuals who are refractory to treatment or have previous experience with biologic therapies. Peresolimab holds promise as a potential therapy for RA and other autoimmune diseases. Nevertheless, further studies are necessary to evaluate and establish the evidence supporting peresolimab as a viable treatment option for RA.
References
- Tuttle J, Drescher E, Simón-Campos JA, Emery P, Greenwald M, Kivitz A, Rha H, Yachi P, Kiley C, Nirula A. A Phase 2 Trial of Peresolimab for Adults with Rheumatoid Arthritis. N Engl J Med. 2023 May 18;388(20):1853-1862.
- Keir ME, Butte MJ, Freeman GJ, Sharpe AH. PD-1 and its ligands in tolerance and immunity. Annu Rev Immunol. 2008;26:677-704.
- Ishida Y, Agata Y, Shibahara K, Honjo T. Induced expression of PD-1, a novel member of the immunoglobulin gene superfamily, upon programmed cell death. EMBO J. 1992 Nov;11(11):3887-95.
- Nishimura H, Nose M, Hiai H, Minato N, Honjo T. Development of lupus-like autoimmune diseases by disruption of the PD-1 gene encoding an ITIM motif-carrying immunoreceptor. Immunity. 1999 Aug;11(2):141-51.
- Nishimura H, Okazaki T, Tanaka Y, Nakatani K, Hara M, Matsumori A, Sasayama S, Mizoguchi A, Hiai H, Minato N, Honjo T. Autoimmune dilated cardiomyopathy in PD-1 receptor-deficient mice. Science. 2001 Jan 12;291(5502):319-22.
- Greisen SR, Rasmussen TK, Stengaard-Pedersen K, Hetland ML, Hørslev-Petersen K, Hvid M, Deleuran B. Increased soluble programmed death-1 (sPD-1) is associated with disease activity and radiographic progression in early rheumatoid arthritis. Scand J Rheumatol. 2014;43(2):101-8.