Mixed Results for Novel Drug for Osteoarthritis
NEW YORK (Reuters Health) – MIV-711, a potent, selective cathepsin K inhibitor, was no better than placebo in relieving pain related to knee osteoarthritis in a randomized, placebo-controlled, phase 2a study. However, the drug led to a significant reduction in bone and cartilage progression.
The potential disease-modifying effect of MIV-711 is “exciting” and reflects a “pivotal step forward in the quest for agents capable of slowing or arresting the pathologic processes leading to joint destruction,” Dr. Jeffrey Katz from Brigham and Women’s Hospital, Harvard Medical School, Boston, writes in an editorial published with the study in Annals of Internal Medicine.
MIV-711 is being developed by Medivir, which funded the multicenter study led by Dr. Philip Conaghan from University of Leeds, UK, and colleagues.
Participants included 244 patients with primary knee osteoarthritis, Kellgren-Lawrence grade 2 or 3, and pain score of 4 to 10 on a numerical rating scale (NRS).
They were randomly allocated to MIV-711 100 mg daily (82 patients) or 200 mg daily (81 patients) or matching placebo (77 patients) for 26 weeks. Forty-six patients in the 200 mg MIV-711 group and four in the placebo received 200 mg of MIV-711 daily during a 26-week open-label, safety extension substudy.
There was no statistically significant change in NRS pain score (the primary outcome) between MIV-711 and placebo, the researchers report. Patients in both active treatment groups and the placebo group reported substantial improvement in pain and functional status, with the active groups reporting slightly more improvement than the placebo group.
However, the between-group differences in pain relief did not reach statistical significance; did not show a dose response (the 100-mg group had more pain relief than the 200-mg group); and did not appear to be clinically meaningful, with differences in pain relief between the active groups and placebo group of 0.1 to 0.3 point on the 10-point NRS.
However, changes in disease progression assessed using quantitative MRI clearly favored MIV-711. Compared with placebo, MIV-711 significantly reduced medial femoral bone area progression (P=0.002 for 100 mg/d and P=0.004 for 200 mg/d) and medial femoral cartilage thinning (P=0.023 with 100 mg/d and P=0.125 for 200 mg/d).
Treatment with MIV-711 was also associated with sustained reductions in biomarkers of bone resorption (CTX-I) and cartilage loss (CTX-II), which correlate with progression of osteoarthritis.
MIV-711 had an “acceptable” and “reassuring” safety profile through the 26-week extension substudy. There were nine serious adverse events in six participants (three in the 100-mg group, two in the 200-mg group, and one in the placebo group. None were considered treatment-related.
“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,” Dr. Conaghan and colleagues conclude.
“Sadly,” Dr. Conaghan told Reuters Health, “we still don’t quite understand where the pain comes from in an osteoarthritic knee. There are likely a number of tissues important in producing pain, including the damaged bone adjacent to the joint, inflamed joint lining tissue (called synovitis, caused by shedding of bone and cartilage molecules), and where the tendons attach around the knee. If we can slow the bone and cartilage damage within the joint we may be able to help some of the causes of pain (damaged bone and synovitis), but any effects on pain would likely only follow months after reducing the damage progression,” he explained by email.
“The next step is a larger trial where we have to follow people for a longer period of time. Also, need to focus on only including patients with moderate to severe pain to optimize chances of showing a difference,” said Dr. Conaghan.
Dr. Katz agrees that more research is needed to determine the longer-term benefits of MIV-711. And he points out in his editorial that the study findings do not contradict the “foundational link between modification of structure and improvement in osteoarthritis pain, but rather clarify that changes in structure do not beget immediate changes in symptoms.”
Structural changes occur “well ahead” of symptoms, he adds, and “these data suggest that longer follow-up will be required to test whether the structural benefits of MIV-711 are indeed accompanied by clinically important improvements in pain and function.”
The study was funded by Medivir. Several investigators have financial relationships with the company and other pharmaceutical companies.
SOURCE: http://bit.ly/2QejVg9 and http://bit.ly/2MHldhf Annals Internal Medicine, online December 30, 2019.