Background/Purpose: The 5-year Phase II FORWARD study assessed the efficacy and safety of the potential disease-modifying osteoarthritis drug (DMOAD) sprifermin (recombinant human fibroblast growth factor 18) in patients with symptomatic, radiographic knee osteoarthritis (OA). Here, we report the long-term 5-year efficacy and safety results of FORWARD.

Methods: Patients were randomized 1:1:1:1:1 to intra-articular sprifermin 100 or 30 µg q6mo, 100 or 30 µg q12mo, or placebo (PBO), for 18 months. The treatment period-related analysis for the primary endpoint was at Year 2, with an extended 3-year observation period. The intent-to-treat (ITT) population included all randomized patients; the modified (m)ITT population all patients with a baseline and ≥1 qMRI reading up to Year 2. Post-hoc exploratory analysis was conducted in a ‘subgroup at risk’ (SAR, n=161), with minimum medial or lateral joint space width of 1.5–3.5 mm and WOMAC pain 40–90 at baseline. Treatment differences vs PBO were estimated using a repeated measures model controlling for baseline, treatment, time, pooled country and treatment by time interaction. Confidence intervals (CIs) were adjusted for multiplicity of treatments using Dunnett adjustment. Linear dose-effect trend tests were performed exploratively at each timepoint.

Results: 474 (86.3%) patients completed the primary 2-year observation period; 442 (80.5%) and 378 (69%) patients completed the 3- and 5-year extended follow-up periods, respectively. The significant dose-response effect of sprifermin on longitudinal change in total femorotibial joint (TFTJ) cartilage thickness (trend test, p< 0.001), and the 0.05 mm mean increase in TFTJ cartilage thickness with sprifermin 100 µg q6mo (highest dose) vs PBO (95% CI 0.004, 0.095; p=0.015; Table 1) observed at Year 2 were sustained to Year 5. WOMAC pain scores improved by ~50% from baseline to Year 5 in all cohorts, including PBO (Figure 1). Post-hoc analysis of the SAR identified a differentiation in WOMAC pain scores between the sprifermin 100 µg q6mo and PBO groups at Year 2 (–5.82; 95% CI –18.87, 7.23), Year 3 (–8.75; 95% CI –22.42, 4.92) and Year 5 (–10.08; 95% CI –25.68, 5.53; Figure 2). AEs were mostly moderate in severity. 181 patients (33%) reported serious AEs, none of which were deemed related to treatment. AE-related study withdrawals were < 10%, the majority of which were musculoskeletal and soft tissue disorders. At Year 5, there was no notable difference in the incidence of adverse events (AEs), serious AEs or study discontinuation due to AEs in any sprifermin group vs PBO.

Conclusion: In FORWARD, the longest DMOAD study ever reported, sprifermin maintained long-term structural modification of articular cartilage vs PBO despite a 3.5-year treatment-free period, with no new safety signals. Pain improvement vs PBO was sustained in a subgroup at risk of structural and symptomatic progression. This suggests potential disease modification with sprifermin, with delayed knee OA structural progression and translation of structural modification to clinical benefit. It also identifies a potential target dose and patient population for future Phase III trials.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/long-term-efficacy-and-safety-of-intra-articular-sprifermin-in-patients-with-knee-osteoarthritis-results-from-the-5-year-forward-study/