MIV-711 warrants further investigation as a disease-modifying osteoarthritis drug
medwireNews: Phase 2a trial results suggest that the cathepsin K inhibitor MIV-711 does not improve pain outcomes for patients with osteoarthritis (OA), but may reduce bone remodeling and cartilage volume loss.
“These are exciting findings, reflecting a pivotal step forward in the quest for agents capable of slowing or arresting the pathologic processes leading to joint destruction,” writes Jeffrey Katz (Brigham and Women's Hospital, Boston, Massachusetts, USA) in an editorial accompanying the research published in the Annals of Internal Medicine.
For the trial, 244 patients with primary knee OA, a Kellgren–Lawrence score of 2 or 3 points, and a pain score of 4 points or higher on a 10-point numeric rating scale (NRS) were randomly assigned to receive 26 weeks of oral MIV-711 at a daily dose of 100 or 200 mg, or to receive placebo.
Philip Conaghan (University of Leeds, UK) and co-investigators found that the primary outcome of pain severity in the target knee improved to a similar degree in all groups.
The estimated least-squares mean reduction in pain NRS score from baseline to week 26 was 1.7, 1.5, and 1.4 points for patients given MIV-711 100 mg, MIV-711 200 mg, and placebo, respectively, with no significant differences between the active treatment and placebo arms.
However, the cathepsin K inhibitor significantly reduced bone remodeling as measured by magnetic resonance imaging (MRI); the estimated mean increase in medial femoral bone area was 7.9 mm2 for MIV-711 100 mg and 8.6 mm2 for the 200 mg dose, compared with 23.3 mm2 for placebo.
Cartilage volume loss in the femoral region was also significantly attenuated among patients given the 100 mg dose of MIV-711 compared with those receiving placebo, with an average improvement of 0.011 mm versus an average loss of 0.066 mm.
The average reduction in cartilage volume was numerically lower in the 200 mg than the placebo group (0.022 vs 0.066 mm), but the difference did not reach statistical significance.
In addition, MIV-711 treatment significantly reduced biomarkers of bone resorption (serum type I and urine type II collagen C-telopeptide levels) relative to placebo, which Conaghan and team say provides “convincing evidence for target engagement.”
The team reports that MIV-711 had “a reassuring safety profile.” Rates of treatment-emergent adverse events were comparable in the 100 mg, 200 mg, and placebo groups (54.9%, 52.4%, and 55.0%, respectively), and there were no serious adverse events considered to be treatment-related.
Taken together, the investigators say their results indicate that MIV-711 “may merit further evaluation as a disease-modifying osteoarthritis drug.”
Discussing the reasons why the cathepsin K inhibitor reduced bone progression and cartilage volume loss but had no impact on pain, they point out that the duration of their study was limited, and “may have been too short for the improvements in joint structure to lead to statistically significant reductions in symptoms.”
They add: “Further evaluation of MIV-711 in longer and larger trials to confirm the structural benefits observed here and whether these translate to more tangible benefits on symptoms is warranted.”
And Katz says that based on the results of this “expertly executed trial,” the cathepsin K inhibitor “now joins sprifermin, a fibroblast growth factor that promotes proliferation of chondrocytes, as an agent capable of modifying structure, as defined by MRI, in randomized trials of patients with OA.”
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