Sprifermin provides long-term benefits for knee OA

The structural and symptomatic benefits observed with intra-articular sprifermin at 2 and 3 years were sustained by year 5 in individuals with knee osteoarthritis (OA), updates from the FORWARD* study have shown.

“In the longest DMOAD** trial reported to date, [the structural improvement with sprifermin was] maintained over a 3.5–4-year post-treatment period, [with potential] clinical benefit,” said the researchers. “Clinically relevant improvement in pain was also sustained up to [5 years] in the subgroup at risk (SAR***).” [JAMA 2019;322:1360-1370; Semin Arthritis Rheum 2021;51:450-456]

Of the 549 participants in the overall cohort, 378 completed the 5-year follow-up, while 161 met the SAR criteria. Participants were randomized 1:1:1:1:1 to receive intra-articular injections of sprifermin 100 or 30 μg Q6M or Q12M, or placebo. [Ann Rheum Dis 2021;80:1062-1069]

Structural improvement

The significant dose-response in cartilage thickness with any sprifermin dose (p_trend<0.001) and adjusted mean difference (adjMD, 0.05 mm) with sprifermin 100 μg Q6M vs placebo were sustained at 5 years.

In the SAR, a similar cartilage thickness improvement was seen with sprifermin 100 μg Q6M (adjMD, 0.06 mm); however, cartilage loss was more rapid. “This is an important finding, as DMOADs [are presumed to be] ineffective in patients with more severe disease at baseline and in those with faster structural progression … [In the current study,] structural modification by sprifermin is at least as strong in more severe OA as in milder OA.”

In the lateral femorotibial compartment (LFTC), the dose-effect of sprifermin on cartilage thickness change was sustained from year 2 to 5 (p_trend<0.05). “Since most [participants] had medial disease, the less weight load in the lateral compartment … may have allowed for a more pronounced effect by sprifermin in the LFTC,” they said.

Symptomatic benefit

In terms of WOMAC^# pain score, there was no difference between any sprifermin dose vs placebo at year 5 in the ITT cohort (adjMD, −1.06; p=0.99). In the SAR, the clinically meaningful numerical difference in WOMAC pain score between sprifermin 100 μg Q6M and placebo seen at year 3 (adjMD, −8.58) persisted until year 5 (adjMD, −10.08).

“The pain benefit of sprifermin in [the SAR] required 2–3 years to become clinically relevant, [aligning] with the hypothesis that this occurs subsequent to structural modification of cartilage thickness,” the researchers explained. “These results are plausible, as patients with less mJSW^##, lower cartilage thickness, and more pain at baseline are more likely to symptomatically benefit from cartilage structural modification than those with only mild disease.”

Safety profile

There were similar fractions of sprifermin and placebo recipients reporting adverse events (AEs) over 5 years (96–98 percent vs 98 percent), local AEs in the target knee (49–51 percent vs 49 percent), and serious AEs (29–38 percent vs 36 percent). Withdrawal rate due to AEs across all arms was only <10 percent. Fifteen patients underwent partial or total replacement of the treated knee, but none were from the sprifermin 100 μg Q6M arm.

Safety findings for the SAR mirrored those observed in the ITT, but serious AE rates were higher with placebo than sprifermin (53 percent vs 31–37 percent).

Filling an unmet need

“DMOADs that not only alleviate symptoms but also modify structure are an important and unmet clinical need for knee OA,” said the researchers. While the findings imply that it might take a while before structural benefits manifest symptomatically, the results underscore the potential of intra-articular sprifermin to provide structural benefit that will, in turn, lead to clinical benefit and disease modification for knee OA, they said.