NGF is involved in several key pain mechanisms: It phosphorylates TRPV-1, alters gene expression in the sensory nerves and facilitates transmission of the central synapse. NGF is associated with synovitis pain in knee OA and in the subchondral bone.14
Tanezumab relieved pain in both knee OA and chronic low back pain, “and this is most impressive, because nothing works in low back pain,” said Dr. Walsh.15,16 The Food and Drug Administration (FDA) stopped these trials because some patients’ joint damage accelerated. “I think you should put this into context: It matters if people on these treatments are more likely to have total joint replacements.” Trials were restarted with patients on tanezumab monotherapy, not combined therapy with NSAIDs. Combination therapy did not show any additional analgesic benefit in new comparative trials.17
FGF & Gene Therapy
Two other emerging therapies in Phase III include fibroblast growth factor (FGF-18)/sprifermin (AS902330), an intra-articular injection, and tissuegene-C (TG-C), a gene therapy for cartilage regeneration, said David Hunter, MBBS, PhD, professor of medicine, University of Sydney, Australia.
Sprifermin induces chondrocyte proliferation, improves phenotypic changes in chondrocytes, and increases production in the extracellular matrix, and is well tolerated.18 In a five-year trial, total femorotibial joint thickness scores for patients in treatment arms were better than placebo at three years, but “there are no clear indications of a symptomatic effect,” he said. At five years, “it’s hoped there will be symptomatic improvement following that structural effect.”19
In TG-C, chondrocyte cells are harvested from a single donor, genetically modified to produce TGFβ-1, and administered to OA patients via intra-articular injection. In Phase 2 trials, TG-C improved pain scores compared to placebo at 18 months, and “most of the adverse events are mild, and related to local site reaction and self-limited,” he said.20 Another trial suggested TG-C improved structural progression, but not meaningfully.21
Why have so many OA clinical trials failed? “One of the great challenges has been translating preclinical animal models to the human models,” said Dr. Hunter. Structural progression may not tell us how well therapies work in humans, and the placebo effect in OA also makes gauging agents’ therapeutic effects very challenging.22 Pre-trial screening to exclude patients likely to have a high placebo response may help improve future studies, he said.
“Another challenge is that the mean time of this disease is about 20 years. We tend to focus on the past two years,” or end-stage OA, said Dr. Hunter. “Our ability to meaningfully intervene would probably be a lot better if we intervened much earlier, before marked structural changes and mechanical destruction occur.” Emerging therapies should focus on multiple molecular pathways in OA, including those associated with inflammation, such as synovitis and BMLs, he concluded.
