New Strategies, Biomarkers Needed for DMARD Pipeline

For patients with spondyloarthritis (SpA), including psoriatic arthritis (PsA), and axial SpA (axSpA), 26 disease-modifying anti-rheumatic drugs (DMARDs) are currently in clinical development, including 15 molecules for PsA and 18 for axSpA. This is according to a systematic review published in RMD Open, which found that the target diversity of these molecules was low.¹

Renaud Felten, MD

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“The identification and development of specific molecular targets and intracellular pathways lead to new therapeutic strategies and will probably improve our therapeutic armamentarium for personalized patient treatment,” wrote Renaud Felten, MD, associate professor at Strasbourg University Hospital in France, and colleagues.

Treatment for SpA has advanced with the introduction of tumor necrosis factor (TNF), interleukin 17 (IL-17), IL-12/IL-23, IL-23, and Janus kinase (JAK) inhibitors. However, a proportion of patients remain non-responders and some DMARDs are ineffective for certain disease manifestations. To find the most suitable treatment for each patient, new molecules and therapeutic strategies are needed.

This systematic review included 17 international clinical trial databases that were searched in February 2023, using 3 keywords “spondyloarthritis,” “ankylosing spondylitis,” and “psoriatic arthritis.” The researchers aimed to provide an overview of potential therapeutic options for the SpA spectrum in the coming years by identifying all DMARDs currently marketed, in clinical development or withdrawn for PsA and axSpA.

Overall, the search identified 3574 trials, with 63 DMARDs evaluated for PsA and axSpA, including 9 conventional synthetic DMARDs (csDMARDs), 37 biological DMARDs (bDMARDs), and 17 targeted synthetic DMARDs (tsDMARDs). Of the 63 DMARDs, 17 were already marketed and 26 were in clinical development.

For PsA, a total of 44 DMARDs were identified, including 5 csDMARDs, 27 bDMARDs, and 12 tsDMARDs. Among the 15 molecules in development, 8 reached phase 2 trials and 7 reached phase 3 trials, while 6 were JAK inhibitors, 6 were IL-17 inhibitors, and 1 was an IL-23 inhibitor.

For axSpA, a total of 44 DMARDs were identified, including 6 csDMARDs, 27 bDMARDs and 11 tsDMARDs. Among the 18 treatments in development, 1 reached phase 1 trials, 10 reached phase 2 trials and 7 reached phase 3 trials. Ten molecules were IL-17 inhibitors, 2 were JAK inhibitors and 2 were granulocyte-macrophage colony-stimulating factor inhibitors.

Of the IL-17 inhibitors in development, netakimab and brodalumab have shown promising phase 3 study results, while bimekizumab is under review by the European Medicines Agency for approval in Europe. Meanwhile, izokibep, a bispecific fusion protein, and sonelokimab, a trivalent nanobody specific to IL-17A, IL-17F and serum albumin, may offer new ways to target IL-17. Among the most advanced JAK inhibitors in clinical development are ivarmacitinib, filgotinib, and deucravacitinib. Four of the 6 JAK inhibitors evaluated for PsA inhibit TYK2, which mediates signaling by cytokines, such as IL-12 and IL-23, that are involved in the pathogenesis of PsA. Meanwhile, new targets are also in development. Zunsemetinib and CC-99677 are oral selective covalent MK2 inhibitors being evaluated in phase 2 trials for PsA and axSpA, respectively.

Limitations to the study included its reliance on a time-dependent update of the DMARD development pipeline and the use of keywords from the description of clinical trials.

“IL-17 inhibitors represent 56% of the DMARDs in development for axSpA and 40% for PsA, whereas JAK inhibitors represent 40% of the DMARDs in development for PsA,” the investigators noted. “With so many new DMARDs in development for SpA, but low target diversity, we will need to develop new strategies or biomarkers to help clinicians make informed treatment decisions.”

Reference:

1. ^{Denis A, Sztejkowski C, Arnaud L, Becker G, Felten R. The 2023 pipeline of disease-modifying antirheumatic drugs (DMARDs) in clinical development for spondyloarthritis (including psoriatic arthritis): a systematic review of trials. RMD Open. 2023;9(3):e003279. doi:10.1136/rmdopen-2023-003279}