TrkA inhibitor disappoints in knee osteoarthritis trial
medwireNews: The tropomyosin receptor kinase A (TrkA) inhibitor ASP7962 has failed to improve pain or physical function among patients with painful knee osteoarthritis in a phase II trial.
Fiona Watt (University of Oxford, UK) and co-investigators found that WOMAC pain scores improved to a similar degree from baseline to week 4 among the 85 participants randomly assigned to receive oral ASP7962 at a dose of 100 mg twice daily and the 85 patients given placebo, with mean decreases of 1.98 versus 1.66 points.
Average WOMAC physical function, stiffness, walking pain, and total scores also improved in both the ASP7962 and placebo groups over 4 weeks, with no significant differences between the arms.
On the other hand, the 42 participants randomly assigned to receive the active control naproxen at a dose of 500 mg twice daily experienced a significantly greater improvement in average WOMAC pain scores than those given placebo (2.45 vs 1.66 points), which confirms “that the study design was appropriate to detect treatment efficacy,” write Watt and colleagues in Osteoarthritis & Cartilage.
They report that the TrkA inhibitor was “well tolerated,” with 30.6%, 22.4%, and 28.6% of patients in the ASP7962, placebo, and naproxen groups, respectively, experiencing treatment-emergent adverse events (TEAEs) over the 4-week treatment period, most frequently vertigo and nasopharyngitis.
Watt and colleagues’ findings are in contrast to those of a recent phase II trial demonstrating that GZ389988A, another TrkA inhibitor, may provide pain relief for individuals with knee OA.
Discussing the possible reasons behind these conflicting findings in an accompanying editorial, David Walsh (University of Nottingham, UK) and Tuhina Neogi (Boston University, Massachusetts, USA) suggest that “[s]tudy population differences between the trials might have contributed to better signal detection over placebo in the trial of GZ389988A.” They explain that the GZ389988A trial excluded patients with high neuropathic-like pain scores, and included “only participants with minimal pain in the contralateral knee.”
They also hypothesize that “pharmacological differences between GZ389988A and ASP7962,” including the lipophilic nature of the former and the lower affinity for TrkA of the latter, “might lead to different trial outcomes.”
Walsh and Neogi note that development of antibodies blocking nerve growth factor (NGF), the ligand for TrkA, “has been hampered by the detection in Phase 3 studies of rare but important treatment emergent adverse events characterized as rapidly progressive OA,” adding that it is currently “unclear” whether blocking the binding of NGF to TrkA contributes to this elevated risk.
They conclude that “[t]he NGF-TrkA system is a promising therapeutic target that merits further development,” but additional research into the mechanisms behind the development of adverse joint events is needed “to further optimize […] risk mitigation strategies for these agents.”
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