FORWARD: Sprifermin yields durable structural improvements in knee OA

In patients in knee osteoarthritis (OA), the disease-modifying OA drug (DMOAD) sprifermin produces a favourable change in articular cartilage, which is sustained for more than 3 years after treatment, according to 5-year data from the FORWARD* trial.

“Sprifermin … was shown to increase articular cartilage thickness compared with placebo … at the primary endpoint (year 2) of the FORWARD trial and was well tolerated. Structural benefits with sprifermin were observed in a subgroup at risk (SAR) of progression, who also demonstrated improvements in pain over placebo at year 3 follow-up,” the investigators pointed out.

“Here we show that long-term structural modification of articular cartilage was maintained with sprifermin versus placebo over a 3.5-year to 4-year post-treatment period. Similar maintenance of structural improvements over this time was seen in the SAR, and clinically relevant improvement in pain over placebo in this subgroup was also sustained up to year 5 follow-up,” they added.

Of the 549 patients (age 40–84 years, 69 percent female) randomized initially, 378 (69 percent) completed the 5-year follow-up. ‘Withdrawal of consent’ (n=63) was the most common reason for discontinuation, followed by ‘other’ (n=52) and ‘adverse event’ (AE; n=24).

The patients had received intra-articular sprifermin 100 µg or 30 µg (n=74) every 6 months (q6mo; n=77 and n=74, respectively) or 12 months (n=82 and n=80, respectively), or placebo (n=65), for 18 months.

In the sprifermin group, the dose-dependent increase in total femorotibial joint (TFTJ) cartilage thickness seen at year 2 relative to the placebo group was preserved through year 5 (p<0.001). The difference was particularly significant between placebo and the 100 µg q6mo dose (mean, 0.049 mm; p=0.015). [Ann Rheum Dis 2021;10.1136/annrheumdis-2020-219181]

Pain also subsided across all treatment groups, with scores on Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) decreasing by about 50 percent. In addition to this, none of the patients who received the 100 µg q6mo regimen underwent replacement of the treated knee.

AEs occurred in 96–98 percent of patients in the active treatment groups and 98 percent of those on placebo. Most AEs were mild or moderate and considered unrelated to treatment. AE-related study withdrawals were <10 percent.

In the SAR subgroup (baseline minimum radiographic joint space width [JSW] 1.5–3.5 mm and WOMAC pain 40–90; n=161), the difference in WOMAC pain between sprifermin 100 µg q6mo and placebo detected at year 3 likewise persisted at year 5 (−10.08, 95 percent confidence interval, −25.68 to 5.53).

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

It indicates that relatively long observation intervals may be needed to establish the translation of structural modification into symptomatic benefit, they added.

Despite being exploratory and the SAR subgroup comprising a modest number of patients, the 5-year FORWARD data are said to confirm the long-term structural benefit with sprifermin, with potential durable clinical benefit and disease modification for knee OA and no safety concerns.

“The FORWARD trial had the longest follow-up time for DMOAD efficacy using quantitative imaging and provides an exemplar for the feasibility of long-term OA trials. Enrichment of patient populations with higher likelihood of structural and symptomatic progression may increase the chance of successful DMOAD development,” the investigators said.

*FGF-18 Osteoarthritis Randomized Trial with Administration of Repeated Doses