Pos1348 effects of sprifermin on a novel outcome of osteoarthritis symptom progression: post-hoc analysis of the forward randomized trial

Background People with knee osteoarthritis (OA) (KOA) desire therapies which delay disease progression [1] supporting the need for disease-modifying OA drugs (DMOADs). Sprifermin, truncated recombinant human fibroblast growth factor-18, promotes chondrocyte proliferation and extracellular matrix production [2] , improves cartilage biomechanical properties [3] , and in the Phase 2 FORWARD study [4] , dose-dependently increased knee cartilage thickness. In FORWARD, improvement from baseline in the Western Ontario and McMaster Universities OA Index (WOMAC) symptom subscales occurred in all study arms, but lack of differentiation from placebo (PBO) was thought to be due to inclusion of participants not at risk of KOA progression. A subsequent post-hoc analysis identified a subgroup at risk (SAR) enriched for disease progression [5] . Clinically meaningful change in WOMAC Pain and Function has been defined as ≥10 points (0-100 scale) [6,7] , with this degree of worsening pain predictive of structural progression and knee replacement in KOA cohorts [8-10] ; this endpoint has not been applied to evaluate symptomatic progression in DMOAD studies to date. Objectives Evaluate the effect of sprifermin on symptomatic progression of KOA. Methods In FORWARD, participants were randomized 1:1:1:1:1 to intra-articular PBO or sprifermin 30 µg or 100 µg every 6 or 12 months (Q6M or Q12M) for 18 months. WOMAC was collected Q3M and MRI performed Q6M. In the current Kaplan-Meier analysis, time to symptomatic progression (i.e., first occurrence of worsening [increase] of WOMAC Pain of ≥10 points with no improvement [≤9 point decrease] in WOMAC Function) was evaluated over 3 years. The individual treatment arms of the intent-to-treat population (ITT) and the SAR (i.e., baseline WOMAC Pain 40-90, mJSW of 1.5-3.5 mm) were analyzed, as well as the sprifermin 100 µg groups combined for additional power. Time to symptomatic progression was also analyzed by changes in cartilage thickness (decrease or no change/increase) for the populations with an evaluable MRI, i.e., the modified (m) ITT and SAR. Results The FORWARD ITT and SAR sprifermin individual treatment arms (Table 1) showed dose-dependent benefits in the time to symptomatic progression compared to PBO, with clinically meaningful and statistically significant separation from PBO for the sprifermin 100 µg groups combined (logrank p-value ITT=0.0282, SAR=0.0099) (Figure 1); separation from PBO was more pronounced in the SAR compared to the ITT. The sprifermin 100 µg groups combined also demonstrated less symptomatic progression than PBO regardless of an increase or no change/decrease in cartilage thickness in the mSAR and mITT. Table 1: FORWARD Study Populations Population (n) Placebo Sprifermin Total (N) 30 µg x 2 30 µg x 4 100 µg x 2 100 µg x 4 100 µg groups combined ITT 108 110 111 110 110 220 549 Modified ITT 96 99 99 99 101 200 494 SAR 34 36 27 31 33 64 161 Modified SAR 32 32 26 29 32 61 151 x 2=Q12M; x 4 = Q6M; ITT=intent-to-treat; SAR=subgroup at risk. Conclusion These post hoc results support the hypothesis that sprifermin may prevent symptomatic progression of KOA, with benefits seen in both ITT and SAR populations for the sprifermin 100 µg groups combined. As differences between the sprifermin- and PBO-treated groups were detectable in a 3-year time frame, time to symptomatic progression of KOA could be a meaningful endpoint for an investigational DMOAD trial. Symptomatic and structural benefits of sprifermin need to be confirmed in the planned Phase 2b SPRING study. References [1]Arthritis Foundation 2017. ‘The Voice of the Patient’ [2]Gigout et al. Osteoarthritis Cartilage 2017;25:1858 [3]Dahlberg et al. Clin Exp Rheumatol 2016;34:445 [4]Hochberg et al. JAMA 2019;322:1360 [5]Guehring et al. Semin Arthritis Rheum 2021;51:450 [6]Angst et al. Arthritis Rheum 2001;45:384 [7]Conaghan et al. J Rheumatol 2022;49:615 [8]Wirth et al. Osteoarthritis Cartilage 2017;25:2063 [9]Deveza et al. Osteoarthritis Cartilage 2019;27:257 [10]Gademan et al. Acta Orthop 2018; 89:528 Acknowledgements I have no acknowledgements to declare. Disclosure of Interests Philip G Conaghan Speakers bureau: AbbVie, Novartis, Consultant of: AbbVie, AstraZeneca, Biosplice, BMS, Eli Lilly, Galapagos, Genascence, GSK, Merck, Novartis, Pfizer, Regeneron, Stryker, and UCB, Nathaniel Katz Consultant of: TrialSpark, David Hunter Consultant of: Lilly, Novartis, Pfizer, TissueGene, TLCBio, Ali Guermazi Consultant of: AstraZeneca, Grunenthal, Levicept, Novartis, Organogenesis, Pfizer, Regeneron, TissueGene, TrialSpark, Employee of: Owner, Boston Imaging Core Lab (BICL), Marc Hochberg Paid instructor for: TrialSpark, Kenneth Somberg Shareholder of: TrialSpark, Consultant of: TrialSpark, Employee of: Former employee of TrialSpark, Julia Clive Consultant of: TrialSpark, Mary Johnson Consultant of: TrialSpark, Niti Goel Shareholder of: UCB, Employee of: TrialSpark.