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Summary Objective Sprifermin (recombinant human fibroblast growth factor-18), a potential disease-modifying osteoarthritis (OA) drug, demonstrated dose-dependent effects on femorotibial cartilage thickness (by quantitative magnetic resonance imaging [MRI]) in the phase II FORWARD study. This post-hoc analysis evaluated the potential effects of sprifermin on several articular structures in the whole joint over 24 months using semi-quantitative MRI assessment. Design Patients aged 40–85 years with symptomatic radiographic knee OA, Kellgren–Lawrence grade 2 or 3, and medial minimum joint space width ≥2.5 mm in the target knee were randomized (1:1:1:1:1) to receive three double-blinded, once-weekly, intra-articular injections of sprifermin 30 μg or 100 μg or placebo every 6 (q6mo) or 12 months. 1.5- or 3 T MRIs were read using the Whole-Organ Magnetic Resonance Imaging Score (WORMS) system at baseline and 24 months. Change from baseline at 24 months on compartment and/or whole knee level was assessed for cartilage morphology, bone marrow lesions (BMLs), and osteophytes by delta-subregional and delta-sum (DSM) approaches. Menisci, Hoffa-synovitis, and effusion-synovitis were also evaluated for worsening. Results 549 patients were included. Dose-dependent treatment effects from baseline to 24 months were observed on cartilage morphology (sprifermin 100 μg q6mo vs placebo; mean DSM (95% confidence interval [CI]) −0.6 (−1.5, 0.2); less cartilage worsening) in the entire knee and BMLs sprifermin 100 μg q6mo vs placebo; mean DSM (95% CI) −0.2 (−0.5, 0.1) in the patellofemoral compartment. No effects over 24 months were observed on osteophytes, menisci, Hoffa-synovitis or effusion-synovitis. Conclusions Positive effects associated with sprifermin were observed for cartilage morphology changes, and BML improvement. There were no meaningful negative or positive effects associated with sprifermin in the other joint tissues examined.

Background Results from the 5-year Phase II FORWARD study showed significant dose-dependent modification of total femorotibial joint (TFTJ) cartilage thickness change with sprifermin at 2 and 3 years, by quantitative MRI. Total Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) scores improved by ∼50% in all treatment groups, including placebo (PBO). Selection of a patient (pt) subgroup with higher pain scores and lower joint space width (JSW) at baseline (BL), to identify pts who are at risk of further structural and symptomatic progression, may facilitate better WOMAC discrimination. Objectives Post-hoc analysis to evaluate cartilage thickness changes and symptomatic outcomes in an “at risk” subgroup of pts (BL medial or lateral minimum [m]JSW 1.5–3.5 mm and BL WOMAC pain score of 40–90). Methods Pts in FORWARD were randomized 1:1:1:1:1 to: sprifermin 100 µg every 6 months (q6mo); 100 µg q12mo; 30 µg q6mo; 30 µg q12mo; and PBO. The treatment period was 2 years, with an extended follow up at 3 years. Post-hoc analysis was conducted in the “at risk” subgroup. Treatment effects were estimated using a repeated measures model, controlling for BL, treatment, time, country and treatment by time interaction. Linear dose-effect trend tests were performed exploratively at each timepoint. Confidence intervals (CIs) were adjusted for multiplicity of treatments using Dunnett adjustment. Results 161/549 (29%) pts met criteria for the “at risk” subgroup. In this subgroup, BL characteristics were balanced between treatment arms. Pts in the PBO arm had more cartilage loss at 2 and 3 years vs the modified intent-to-treat (mITT) PBO arm (mean change from BL in mm [SD]: Year 2 -0.05 [0.10] vs -0.02 [0.07]; Year 3 -0.07 [0.09] vs -0.05 [0.07]), but TFTJ net cartilage modification with sprifermin 100 µg q6mo vs PBO was similar (adjusted mean difference from PBO [95% CI] in the at risk subgroup vs the mITT group: Year 2 0.06 [0.01, 0.11] vs 0.05 [0.02, 0.08]; Year 3 0.05 [-0.01, 0.12] vs 0.05 [0.02, 0.09]). Having both medial or lateral mJSW 1.5–3.5 mm AND pain score ≥40 at BL led to greater differentiation in WOMAC total and pain scores for sprifermin 100 µg q6mo vs PBO than having either BL characteristic alone. At Year 3 (18 mos after last injection), the exploratory dose-effect trend test had a nominal p-value of Conclusion Despite substantial structural and symptomatic progression in the “at risk” subgroup, structural improvement with sprifermin was maintained, and WOMAC score improvements vs PBO increased over time and were significant at Year 3. This supports further investigation of sprifermin as a potential disease-modifying osteoarthritis drug in a targeted population where structural improvement may translate into symptomatic benefit vs PBO within a reasonable timeframe. Disclosure of Interests Hans Guhring Employee of: Employee of Merck KGaA, Darmstadt, Germany, Jeffrey Kraines Employee of: Employee of EMD Serono (a business of Merck KGaA, Darmstadt, Germany), Flavie Moreau Employee of: Employee of EMD Serono (a business of Merck KGaA, Darmstadt, Germany), Benjamin Daelken Employee of: Employee of Merck KGaA, Darmstadt, Germany, Christoph Ladel Employee of: Employee of Merck KGaA, Darmstadt, Germany, Wolfgang Wirth Shareholder of: Shareholder of Chondrometrics GmbH, Ainring, Germany, Employee of: Employee of Chondrometrics GmbH, Ainring, Germany, Philip G Conaghan Consultant for: Flexion Therapeutics, AbbVie, Medivir, Merck Serono, Novartis, GlaxoSmithKline, Felix Eckstein Shareholder of: Shareholder of Chondrometrics GmbH, Consultant for: Consulting fees from Merck KGaA, Samumed LLC, Abbvie, Bioclinica, TissueGene, Servier, and Roche, Employee of: Employee of Chondrometrics GmbH, Marc Hochberg Shareholder of: BriOri Biotech, Theralogix LLC., Consultant for: Bristol Myers Squibb, Eli Lilly, EMD Serono, Novartis Pharma AG, Pfizer Inc., Samumed LLC, Symic Bio Inc., Theralogix LLC, TissueGene Inc., TLC Biopharmaceuticals, Inc., Zynerba, Galapagos, IQVIA, Hoffman LaRoche.

Background Sprifermin is under investigation as a potential disease-modifying osteoarthritis drug (DMOAD). 2-yr results from the FORWARD study showed significant dose-dependent modification of cartilage thickness in the total femorotibial joint (TFTJ), medial and lateral femorotibial joints (MFTC, LFTC), and central medial and lateral TFTJ subregions, by quantitative (q)MRI.1 Objectives To determine whether qMRI findings from FORWARD (manual segmentation) could be reproduced in the same cartilage regions using an independent method (automated segmentation), on the same dataset/time period. Methods Pts were randomized 1:1:1:1:1 to: sprifermin 100 μg q6mo; 100 μg q12mo; 30 μg q6mo; 30 μg q12mo; and placebo (n=110/110/111/110/108).1 Cartilage thickness was assessed at baseline and 6, 12, 18, and 24 months using 1.5- or 3-Tesla MRI images, analyzed manually.1 The same images were analyzed by automated cartilage segmentation using active appearance models, a supervised machine learning method, to produce maps of cartilage thickness for weight-bearing femoral and tibial cartilage surfaces, subdivided into anatomical masks. Results were blinded for treatment and timepoint for both methods. No statistical comparisons between methods were conducted. Endpoints were change from baseline in: 1) cartilage thickness in the TFTJ, MFTC and LFTC, using regions duplicated based on published data;1 2) cartilage thickness in the central subregion of the medial and lateral tibia and femur (cMT, cMF, cLT, cLF [conventions used by the automated analysis investigators]). As in previous analyses, treatment effect was assessed by observed changes and adjusted using repeated ANCOVA on change from baseline, including treatment group, timepoint, and country as fixed factors, baseline value as covariate and treatment by timepoint as interaction. Results Based on automated segmentation, statistically significant, dose-dependent structural modification of cartilage thickness was observed over 2 yrs with sprifermin vs placebo for the TFTJ (overall treatment effect and dose response across all doses, both P Conclusion Cartilage thickness assessed by automated segmentation provided a consistent pattern of structural modification in FORWARD compared with manual segmentation. This is the first time that two independent methods of image analysis have reached the same conclusions in an interventional DMOAD trial. The findings strengthen the conclusions that sprifermin modifies cartilage loss/structural progression in knee OA. References [1] Hochberg, et al. ACR 2017 Disclosure of Interests Alan Brett Employee of: Employee of Imorphics, Manchester, UK, Michael A Bowes Employee of: Employee of Imorphics, Manchester, UK, Philip G Conaghan Consultant for: Flexion Therapeutics, AbbVie, Medivir, Merck Serono, Novartis, GlaxoSmithKline, Christoph Ladel Employee of: Employee of Merck KGaA, Darmstadt, Germany, Jeffrey Kraines Employee of: Employee of EMD Serono (a business of Merck KGaA, Darmstadt, Germany), Hans Guhring Employee of: Employee of Merck KGaA, Darmstadt, Germany, Flavie Moreau Employee of: Employee of EMD Serono (a business of Merck KGaA, Darmstadt, Germany), Felix Eckstein Shareholder of: Shareholder of Chondrometrics GmbH, Consultant for: Consulting fees from Merck KGaA, Samumed LLC, Abbvie, Bioclinica, TissueGene, Servier, and Roche, Employee of: Employee of Chondrometrics GmbH