Tropomyosin receptor kinase A inhibition shows potential for knee osteoarthritis
medwireNews: Findings from a phase II proof-of-concept trial suggest that the tropomyosin receptor kinase A (TrkA) inhibitor GZ389988A may provide pain relief for patients with knee osteoarthritis (OA).
Emmanuel Krupka (Sanofi R&D, Montpellier, France) and co-researchers explain that TrkA is the receptor for nerve growth factor (NGF), which “mediates pain sensitization to noxious stimuli,” and that mutations in the gene for the receptor have been linked to congenital pain insensitivity, suggesting that “TrkA receptors may play a major role in mediating NGF-induced pain signaling.”
The trial included 104 individuals aged an average of 63.1 years with moderate-to-severe knee OA pain who were randomly assigned to receive a single intra-articular injection of GZ389988A or placebo. Average WOMAC A1 walking pain scores at baseline were 68.09 points in the GZ389988A group and 63.97 points in the placebo arm.
As reported in Osteoarthritis and Cartilage, patients in both groups experienced significant improvements in the primary endpoint of WOMAC A1 score from baseline to week 4. The 52 participants given GZ389988A experienced a significantly greater improvement than the 52 patients given placebo, with an average between-group difference of 7.49 points.
Krupka et al say that this difference between the groups was statistically significant at each weekly assessment from week 2 to week 5, but lost significance by week 12, which they suggest could be “due to the diminishing drug amount within the joint space over time.”
In all, 94.2% of participants treated with GZ389988A and 75.0% of those given placebo experienced treatment-emergent adverse events (AEs). Injection site joint inflammation was the most common event associated with TrkA inhibitor use, affecting 67.3% of patients versus none in the placebo group.
The investigators say that injection site joint inflammation “was likely an innate immune response to foreign particles as it is accompanied with [high-sensitivity C-reactive protein] elevation and mild neutrophils and monocytes increases in some study participants,” and note that the AE “could be mitigated with rest, cold pack and/or acetaminophen treatment.”
Rescue treatment, primarily with acetaminophen, was more common in the active treatment group, with 61.5% of patients using rescue treatment in the GZ389988A group, compared with just 36.5% of those given placebo.
Taken together, the trial results “proved the clinical concept that locally [intra-articular]-delivered TrkA inhibitor GZ389988A suspension provided persistent clinical benefits over placebo in knee OA subjects,” write Krupka and colleagues.
Noting that no treatment-related structural knee damage was observed on magnetic resonance imaging, they say that “GZ389988A may be worth testing for chronic and repeat use.”
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