LONDON – Early clinical data show that a novel injectable drug holds promise for becoming the first disease-modifying osteoarthritis drug.
The results of a randomized, placebo-controlled, double-blind phase I trial involving 61 patients showed that a single intra-articular injection of SM04690 was associated with improved Western Ontario and McMaster Universities Arthritis Index (WOMAC) function and pain scores. The investigational drug also seemed to slow joint-space narrowing, compared with baseline values, with the suggestion that it may even increase joint space width.
However, those were exploratory efficacy analyses because the primary objective of the trial was to examine the safety of SM04690, a small molecule that inhibits the Wnt signaling pathway.
Dr. Yusuf Yazici
“The Wnt pathway has been implicated in the development of osteoarthritis [OA],” said Dr. Yusuf Yazici during a poster presentation at the European Congress of Rheumatology.
“Overactivity of Wnt signaling leads to stem cells constantly differentiating into osteoblasts, leading to osteophyte formation,” he explained, noting that Wnt signaling also stimulates the secretion of cartilage-destroying metalloproteases (Osteoarthritis Cartilage. 2012;20:162-71). “It has been very well established in the literature that if you could somehow turn that off you, could maybe improve some of the things that are happening in osteoarthritis.”
SM04690 works by “pushing the lineage fate of progenitor stem cells in the knee towards chondrocyte formation and away from osteoblast formation,” said Dr. Yazici of New York University Langone Medical Center, New York, and the chief medical officer of Samumed, the San Diego–based company developing the novel Wnt inhibitor.
He noted preclinical data had been presented orally at the EULAR congress showing that there was cartilage growth, suppressed protease production, and reduced proinflammatory cytokine (interleukin-6 and tumor necrosis factor–alpha) production.
The phase I data represent the first in-human results, with three doses of SM04690 evaluated (0.03 mg, 0.07 mg, and 0.23 mg) versus placebo in patients with moderate to severe symptomatic OA. For inclusion, patients had to have a WOMAC total score of between 36 and 72 and Kellgren-Lawrence (KL) grade 2 or 3 knee OA, and be willing to forgo pain medication for 24 hours prior to pain assessments being performed.
At baseline, the mean age of patients ranged from 60 to 64 years, their body mass index ranged from 28.7 kg/m2 to 31.4 kg/m2, and 41%-69% had KL grade 3 knee OA.
In terms of safety, the primary objective of the trial, there were no reports of serious adverse events related to the study drug. One patient who had reported increased knee pain and paroxysmal tachycardia 2 months after the injection was found to have a history of the condition, and after unblinding, none of the patients had detectable drug levels outside of the knee.
Overall, the number of adverse events was low and no different from placebo, Dr. Yazici said. The percentage of patients reporting an adverse event with the three rising doses of SM04690 were 53%, 35%, and 44%, respectively, compared with 55% of those given placebo.
WOMAC function scores for the 0.03-mg dose declined by a mean of –18.4 at week 12 and by –20.1 at week 24 from a baseline of 39.1; for 0.07 mg, by –19.5 at week 12 and by –18.9 at 24 weeks from 37.5; for 0.23 mg, by –17.8 at week 12 and by –12.4 at week 24 from 40.4; and for placebo, by –14.9 at week 12 and by –16.0 at week 24 from 34.4.
WOMAC pain scores at baseline were a respective 10.8, 10.8, 11.4, and 9.9, and the mean changes at week 12 were –4.4, –5.8, –5.7, and –4.2. At week 24, the mean declines were –5.6, –5.3, –4.3, and –4.8.
Medial joint space width was a mean of 4.5, 3.72, 3.62, and 3.74 mm at baseline in the four treatment groups, with mean changes from baseline to 24 weeks of 0.00, 0.49, –0.15, and –0.33 for the 0.03-mg, 0.07-mg, and 0.23-mg SM04690 and placebo groups, respectively.
Although the trial was not powered to detect any statistically significant differences between the active treatment dose and placebo, there was an indication that more patients treated with SM04690 than with placebo were likely to achieve an OMERACT-OARSI strict response.
These data support the ongoing phase II trial that is being conducted in 455 patients, Dr. Yazici said. The results of that trial are expected around October 2016, which should be in time for their presentation at the annual meeting of the American College of Rheumatology.