Sprifermin may confer greater benefit to patients at risk for rapid knee OA progression
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Sprifermin improved cartilage thickness and pain symptoms in a subgroup of patients with knee osteoarthritis who demonstrated low minimum joint-space width and moderate-to-high pain at baseline, according to data.
“The phase 2 FORWARD trial demonstrated differences in longitudinal cartilage thickness change with sprifermin versus placebo in people with symptomatic radiographic knee OA; at Year 2 and 3, significant dose-dependent effects on total femorotibial joint (TFTJ) cartilage thickness (primary endpoint) were demonstrated,” Hans Guehring, MD, medical director at Merck KGaA, in Darmstadt, Germany, and colleagues wrote in Seminars in Arthritis and Rheumatism. “Two- and 3-year improvements in Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) scores and sub-scale scores were seen in all treatment groups.”
“Recent literature supports selection of patients with moderate-high WOMAC scores and low joint space width to improve detection of a pain response while enriching for structural progression,” they added. “Such patients display greater cartilage loss than those without joint space narrowing and low pain frequency. Insights from FORWARD suggest a floor effect due to the relatively high proportion of patients with low pain (32% with WOMAC pain sub-scale score <40/100) and relatively high minimum joint space width (mJSW; 50% >3.7 mm) at baseline.”
To examine pain outcomes and changes in cartilage thickness in patients with OA who are at risk for further disease progression and treated with sprifermin, Guehring and colleagues conducted a post-hoc analysis of the FORWARD trial. According to the researchers, FORWARD was a multicenter, randomized, double-blind, placebo-controlled, dose-finding, phase 2, 5-year trial of patients aged 40 to 85 years with symptomatic, radiographic knee OA, a Kellgren-Lawrence (KL) grade of 2 or 3, and a medial minimum joint-space width of at least 2.5 mm in the target knee.
In that trial, the investigators randomly assigned 549 participants 1:1:1:1:1 to receive three once-weekly inter-articular injections of either sprifermin 100 µg every 6 months, 100 µg every 12 months, 30 µg every 6 months, 30 µg every 12 months or placebo for 18 months. For their own study, Guehring and colleagues defined their at-risk subgroup as those who at baseline had medial or lateral minimum joint-space widths of 1.5 to 3.5 mm and a WOMAC pain score of 40 to 90 units. This analysis included 161 participants. Guehring and colleagues examined 3 years of follow-up data in their analysis, with treatment benefit explored by repeated measures and linear dose-effect trends by timepoint.
Among participants in the at-risk subgroup, the mean difference in WOMAC pain at year 3 in those who received 100 µg every 6 months, compared with placebo, was –8.75 (95% CI, –22.42 to 4.92), vs. 0.97 (95% CI, –6.22 to 8.16) for the intent-to-treat population, according to the researchers.
Participants in the at-risk subgroup who received placebo lost more cartilage over 2 years than those in the placebo group in the modified intent-to-treat population, with a mean change from baseline of –0.05 mm (standard deviation = 0.1) compared with –0.02 (0.07). In addition, net total femorotibial joint thickness gains in participants who received sprifermin 100 µg every 6 months were similar in the at-risk subgroup and the modified intent-to-treat population, at 0.06 (95% CI, 0.01-0.11) compared with 0.05 (95% CI, 0.03-0.07).
“Our findings indicate that, in addition to increasing cartilage thickness, treatment with sprifermin may confer symptomatic benefits, such as decreased pain,” Guehring and colleagues wrote. “This is the first analysis to provide a proof of concept that structure (cartilage thickness) modification in knee OA by an [intra-articular] drug may translate into symptomatic clinical benefit, provided an adequate patient cohort with established disease is selected and followed for a duration long enough to determine potential symptom benefits.”
“Furthermore, this analysis is the first to suggest that enriching a trial population with low [minimum joint-space width] and high WOMAC pain at baseline results in greater differentiation between a [disease-modifying OA drug (DMOAD)] and placebo in WOMAC pain,” they added. “Selecting a more homogenous patient population that is likely to progress within an OA clinical trial timeframe may improve the ability to reach a symptomatic endpoint and ultimately lead to the approval of potential DMOADs. The patient subgroup identified in this analysis may represent a target population for future clinical trials of sprifermin or other potential DMOADs.”
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