Intra-articular, localized DMOADs include UBX0101, a senolytic agent targeting the age-related senescence response in cartilage. It selectively inhibits the MDM2/p53 protein reaction, which triggers the elimination of senescent cells. UBX0101 slowed OA progression in aging mice.8
Another intra-articular DMOAD, SM04690, is a Wnt-β catenin inhibitor in Phase 3 clinical trials. “The Wnt signaling pathway has been shown to be essential in the homeostasis of cartilage and bone,” said Dr. Malfait. “On a molecular level, there’s a fine-tuned balance of Wnt signaling that maintains the homeostasis of osteoblasts and chondrocytes.” SM04690 interferes with this signaling pathway, and showed statistically significant improvements from baseline in both pain and function in a Phase 2b study of patients with knee OA, and is well tolerated and safe.9
OA Pain Relief
In OA, “modifying disease is not enough. Our patients complain of pain. They don’t complain of their X-rays,” said David Walsh, MD, director, Arthritis Research UK Pain Centre at the University of Nottingham. “There is a clinical conundrum with pain relief in arthritis. Do we want to treat the pain? Will we cause problems if we just mask pain?” Normal activity, or even running, does not worsen OA or pain.10
Potential therapeutic targets in OA include structural abnormalities: bone marrow lesions (BMLs), synovitis and cartilage damage, said Dr. Walsh. Zoledronic acid reduced knee pain and BMLs in OA patients in six months in one study, but at two years, patients showed no significant improvement.11
“It’s not to say that BMLs aren’t a realistic target for treating pain, but the link may not be structural,” he said. Subchondral bone may reveal clues. “There is increased bone turnover, increased osteoclast activity and a reduction in PH, which we know sensitizes peripheral nerves.”
Osteoclasts play a strong role in OA pain. “If you take matched cases of people with the same severity of chondropathy, and take a group with severe pain who have had joint replacements and group who haven’t had surgery, the number and density of osteoclasts in subchondral bone is higher in the group with pain.” Treatment with osteoprotegrin, which targets osteoclasts, quickly reduced OA pain in one rat study.12 “I’d argue this analgesic effect is because it is suppressing the metabolic activity of osteoclasts, which are drivers of sensitization in subchondral bone,” he said. Bisphosphonates are in OA clinical trials because of their effects on remodeling subchondral bone.13
OA pain is due to sensitization of peripheral nerves, said Dr. Walsh. “We don’t want to abolish pain. We don’t want to lose the reflex that, when you put your hand to a hot plate, it hurts. We need that normal nociceptive response. But what we don’t need is constant sensitization.” Nerve growth factor (NGF), a neurotrophin that plays a role in both nociception and inflammation, is the most exciting target in OA, he said. Two monoclonal antibodies to NGF are in development: tanezumab and fasinumab.
