OP0010 CARTILAGE THICKNESS MODIFICATION WITH SPRIFERMIN IN KNEE OSTEOARTHRITIS PATIENTS TRANSLATES INTO SYMPTOMATIC IMPROVEMENT OVER PLACEBO IN PATIENTS AT RISK OF FURTHER STRUCTURAL AND SYMPTOMATIC PROGRESSION: POST-HOC ANALYSIS OF THE PHASE II FORWARD TRIAL
Authors: Hans Gühring, Jeffrey Kraines, Flavie Moreau, Benjamin Daelken, Christoph Ladel, Wolfgang Wirth, Philip G. Conaghan, Felix Eckstein, Marc Hochberg
Journal: Annals of the Rheumatic Diseases (2019)

<h3>Background</h3> 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. <h3>Objectives</h3> 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). <h3>Methods</h3> 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. <h3>Results</h3> 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 &lt;0.05 (<b>Fig 1; Table 1</b>). <h3>Conclusion</h3> 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. <h3>Disclosure of Interests</h3> Hans Gühring 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.