Further development of novel OA drugs supported
medwireNews: Phase II trial results presented at the Annual European Congress of Rheumatology (EULAR) 2017 support the efficacy of two new compounds for the treatment of osteoarthritis (OA).
Yusuf Yazici (Samumed, LLC, San Diego, California, USA) presented the radiographic outcomes of the interim analysis of a placebo-controlled trial of SM04690, a Wnt pathway inhibitor, for the treatment of knee OA.
“The Wnt signaling pathway is overly activated in osteoarthritis,” Yazici told delegates in Madrid, Spain.
“If [this] pathway could be safely inhibited, it could protect cartilage and regenerate cartilage.”
The researchers found that 111 patients receiving the 0.03 mg dose of SM04690 experienced a mean decrease in medial joint space width (mJSW) of 0.07 mm at 26 weeks, while 117 patients in the 0.07 mg group and 109 patients in the 0.23 mg group experienced a decrease of 0.16 and 0.03 mm, respectively.
By comparison, 116 participants in the placebo group had a mean decrease in mJSW of 0.22, a significantly larger decrease than that experienced by patients receiving SM04690 at a dose of either 0.03 or 0.23 mg.
Yazici cautioned that the study was “not formally powered to look at radiographic outcomes,” but concluded that “SM04690 maintained or increased joint space width compared to placebo, and the radiographic and clinical outcomes considered together suggest that SM04690 has potential as a disease-modifying drug for the treatment of knee OA.”
The efficacy of a novel compound for the treatment of moderate-to-severe knee OA pain – the synthetic capsaicin CNTX-4975 – was discussed by Randall Stevens, from Centrexion Therapeutics in Boston, Massachusetts, USA, who outlined the results of a dose-ranging study.
After 12 weeks of treatment, Stevens and colleagues observed a dose-dependent improvement in daily Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) A1 pain scores between 70 patients receiving CNTX-4975 1.0 mg, 33 patients receiving CNTX-4975 0.5 mg, and 69 patients receiving placebo. Over 60% of the study participants had a body mass index over 30 kg/m2.
Baseline WOMAC A1 scores were 7.2, 7.2, and 7.4 in the 1.0 mg, 0.5 mg, and placebo groups, respectively, and the least squares mean differences in scores at 12 weeks for CNTX-4975 versus placebo were −1.6 points for participants in the 1.0 mg group and −0.8 points for those in the 0.5 mg group.
There were also significant improvements in WOMAC A1 scores between patients receiving either dose of CNTX-4975 versus placebo at week 24.
“Current therapies [for OA] have significant toxicities, which are of concern in our aging populations,” said Stevens, noting that CNTX-4975 has a half-life of 4 hours and is no longer present in the body after 24 hours, and therefore has a favorable adverse event profile.
Treatment-emergent adverse events occurred in 30% of participants in the CNTX-4975 1.0 mg and placebo arms, and in 47% of those receiving CNTX-4975 0.5 mg. The most common adverse event associated with the 1.0 mg dose was arthralgia, experienced by 7.0% of patients compared with 5.7% in the placebo group.
“These findings support the continued development of CNTX-4975 1.0 mg for the treatment of subjects with moderate-to-severe pain associated with knee osteoarthritis,” concluded Stevens.
“We are moving into phase III [trials] with the 1.0 mg dose,” he added.
Whereas both SM04690 and CNTX-4975 were suggested as promising treatment options for knee OA disease modification and analgesia, respectively, Margaret Kloppenburg (Leiden University Medical Center in the Netherlands) presented the results of a trial suggesting that inhibition of interleukin (IL)-1α and -1β with ABT-981 is unlikely to improve outcomes for patients with erosive hand OA.
The reduction in Australian Canadian Osteoarthritis Hand Index hand pain scores from baseline to week 12 was similar among the 64 participants receiving ABT-981 and the 67 patients in the placebo group, with least squares mean reductions of 9.2 and 10.7 points from a baseline of 38.0 and 39.0, respectively.
However, the team observed a significant reduction in high-sensitivity C-reactive protein, neutrophils, IL-1α, and IL-1β among patients treated with ABT-981 compared with those in the placebo group. A stable concentration of ABT-981 was reached after 8 weeks of treatment.
The overall incidence of adverse events was comparable between the groups, but injection site reactions and neutropenia occurred more frequently among patients receiving ABT-981 than placebo.
Kloppenburg concluded: “Despite adequate pharmacodynamic results, these data suggest that targeting interleukin-1 may not be effective in erosive hand osteoarthritis, given that ABT-981 did not improve outcomes.”
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