FRI0404 SEPERATION OF HIGH AND LOW RESPONSE GROUPS IN OSTEOARTHRITIS USING SERUM CARTILAGE DEGRADATION AND FORMATION MARKERS – A 3 YEAR FOLLOW-UP ON THE FORWARD STUDY TESTING THE EFFICACY OF SPRIFERMIN
Authors: H. Gühring, A. C. Bay-Jensen, F. Moreau, J. R. Andersen, A. R. Bihlet, M. Karsdal
Journal: Annals of the Rheumatic Diseases (2020)

Background: In osteoarthritis (OA), response to different interventions could be more pronounced in different endotypes of cartilage turnover. Data from UK biobank suggest that an endotype of low cartilage repair is associated with structural progression in osteoarthritis (OA)[1]. Sprifermin a truncated and recombinant FGF18 have been shown to induce chondrocyte proliferation and cartilage formation in in vitro settings[2–4]. Efficacy on cartilage thickness in OA was recently demonstrated in the FORWARD study[5]. Objectives: We investigated markers of cartilage formation (serum PRO-C2) and degradation (urine CTX-II), to assess profiles indicative of chondrocyte metabolic activity would be associated with both structural and symptomatic responses to sprifermin. Methods: Serum and urine from participants of the FORWARD study, a phase II clinical trial testing the efficacy of intra-articular (IA) sprifermin, were collected throughout the study. Clinical data recorded at baseline, year 2 and year 3 follow-up were used, including cartilage thickness and WOMAC. All available baseline samples of the placebo and treatment arms were assessed for serum PRO-C2 and urinary CTX-II. Patients were separated into dichotomized groups based on 33, 50 or 66 percentiles cut-points and two-year treatment responses were compared in a prospective-retrospective statistical design manner. Results: Patients with low baseline PRO-C2 (&lt;66%), in the 100ug/4x treatment arm, had greater difference to placebo in cartilage thickness as compared to the high PRO-C2 and all-comers groups (0.06 vs 0.03 and 0.05 mm, respectively) at two and three years (Fig.). Similar effect was seen for low CTX-II (&lt;50%) (0.07 vs -0.03 and 0.05 mm, respectively). In addition, the WOMAC placebo effect was reduced in the low PRO-C2 and the low CTX-II groups, resulting in a difference compared to placebo of -0.81vs. 1.35 (low vs high proC2 and -2.35 vs 1.47 (low vs high CTX-II). Conclusion: We noticed that low baseline PRO-C2 and CTX-II indicative for low metabolic activity of chondrocytes were associated with improved symptomatic outcome and slightly increased cartilage thickness compared to high metabolic activity. The parallelism between PRO-C2 and CTX-II point towards the existence of a low cartilage repair endotype and might reflect a subgroup of patients with higher sensitivity towards interventions - an effect that was maintained over three years. References: [1]Tachmazidou I, et al. ”Identification of new therapeutic targets for osteoarthritis through genome-wide analyses of UK Biobank data.” Nat Genet 2019;51:230–6. [2]Gigout A, et al. ”Sprifermin (rhFGF18) enables proliferation of chondrocytes producing a hyaline cartilage matrix”. Osteoarthr Cartil. 2017;25. [3]Reker D et al. “Sprifermin (rhFGF18) modulates extracellular matrix turnover in cartilage explants ex vivo”. J Transl Med. 2017;15. [4]Luo Y et al. ”A Novel High Sensitivity Type II Collagen Blood-Based Biomarker, PRO-C2, for Assessment of Cartilage Formation”. Int J Mol Sci 2018;19:3485. [5]Hochberg MC et al. “Effect of Intra-Articular Sprifermin vs Placebo on Femorotibial Joint Cartilage Thickness in Patients With Osteoarthritis”. JAMA. 2019; Oct 8;322(14). Disclosure of Interests: Hans Gühring Employee of: Merck KGaA, Anne-Christine Bay-Jensen Shareholder of: Nordic Bioscience A/S, Employee of: Full time employee at Nordic Bioscience A/S., Flavie Moreau Employee of: Merck KGaA, Jeppe Ragnar Andersen Shareholder of: Nordic Bioscience A/S., Employee of: Full time employee of Nordic Bioscience., Asger Reinstrup Bihlet Shareholder of: Nordic Bioscience A/S., Morten Karsdal Shareholder of: Nordic Bioscience A/S., Employee of: Full time employee at Nordic Bioscience A/S.