THE OFFICIAL NEWS SOURCE OF ACR CONVERGENCE 2022 • NOVEMBER 10-14



New molecular targets could advance OA treatment

Philip Conaghan, MBBS, PhD
Philip Conaghan, MBBS, PhD

Only in the past 15 years or so have people accepted the idea that molecular targeting could lead to disease modification in osteoarthritis. 

The ACR Convergence 2020 educational session New Targets in Osteoarthritis will cover the latest targets in preclinical models and early phase trials involving both mice and humans. The session will have its first showing on Sunday, Nov. 8, from 3 – 4 p.m. and will feature a live question-and-answer session. Registered attendees can watch a replay of the session on demand through March 11, 2021

Tonia Vincent, PhD, professor of musculoskeletal biology, director, Centre for Osteoarthritis Pathogenesis Versus Arthritis, and consultant rheumatologist, Kennedy Institute of Rheumatology, University of Oxford, will discuss the role murine OA models provide for novel target discovery in OA. Philip Conaghan, MBBS, PhD, professor of musculoskeletal medicine and director of the Leeds Institute of Rheumatic and Musculoskeletal Medicine at the University of Leeds, will cover new testing targets in early phase studies in humans.

“Osteoarthritis remains a massive problem, and, if anything, we have fewer therapies than we had 10 years ago as we realize the limited analgesic benefits of acetaminophen and opioids,” Dr. Conaghan said. “We desperately need new therapies and understanding the success or failure of certain targets and pathways in humans will be insightful for where the field may move.”

During his presentation, Dr. Conaghan will focus on pharmacological therapies that have reached at least phase 2 trials that attempt to provide pain relief, structure modification, or both. The featured agents target cartilage, bone, and inflammation.

So far, Dr. Conaghan said, trials into the efficacy of structure modification have not demonstrated symptom benefit, but trial design issues may confound pain signal interpretation. Trials involving anti-interleukin-1 therapies haven’t seen success, but data from the canakinumab cardiovascular trial (CANTOS), which enrolled a population with cardiovascular disease and elevated inflammation markers, demonstrated an impressive reduction in joint replacement.

The most promising new therapies for OA appear to be ones targeting peripheral nerve nociceptive pathways, Dr. Conaghan said, especially monoclonal antibodies to NGF.

“Don’t dismiss the mouse as being a valuable route to novel target discovery in OA,” Dr. Vincent said. “Murine models provide a valuable route to novel target discovery, but murine and human OA researchers and industry must trust one another more in order to realize the translational benefits.”

As part of her presentation, Dr. Vincent will share examples of how target discovery in the mouse has translated to patient benefit, e.g., with anti-NGF treatment, and will share information from recent mouse studies that could point to the next promising disease targets.

“Never has there been a greater need to have models that help identify those molecular targets,” Dr. Vincent said. “Trying to extrapolate targets from other inflammatory conditions really hasn’t worked; a hardly surprising phenomenon when one considers the disease’s distinct biology. Mouse models do recapitulate the human disease at the level of joint pathology and pain. Despite limitations intrinsic to mouse studies, as well as those associated with clinical trial design, I would argue that target validation generally shows good agreement in mouse and human OA.”