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Osteoarthritis (OA) is characterized by the gradual loss of cartilage. Sprifermin, a recombinant FGF18, is being developed as a cartilage anabolic drug. PRO-C2 is a serum marker of type II collagen formation and low levels have been shown to be prognostic of radiographic progression. The aim of the study was to investigate whether the patient groups with either high or low PRO-C2 levels responded differently to sprifermin.PRO-C2 was measured in synovial fluid (SF) (n = 59) and serum samples (n = 225) from participants of the FORWARD study, a 2-year phase IIb clinical trial testing the efficacy of intra-articular (IA) sprifermin over placebo. The difference between sprifermin and placebo in respect to in change cartilage thickness (measured by quantitative (q) MRI) was analyzed in groups with either high or low (3SF levels of PRO-C2 increased over time in response to sprifermin, but not to placebo. In the placebo arm, significantly (p = 0.005) more cartilage was lost in the low vs high PRO-C2 group over the 2-year period. The contrast between sprifermin and placebo was significant (p 0.001), ranging from 0.104 mm at week 26 to 0.229 mm at week 104 in the low PRO-C2 group. This result was not significant in the high PRO-C2 group ranging from -0.034 to 0.142.Patients with low serum PRO-C2 levels lost more cartilage thickness over time and grew more cartilage in response to sprifermin vs a placebo when compared to patients with high PRO-C2 levels.

Post-traumatic osteoarthritis is a disabling condition impacting the mostly young and active population. In the present study, we investigated the impact of intra-articular sprifermin, a recombinant truncated fibroblast growth factor 18, on the outcome of microfracture treatment, a widely used surgical technique to enhance cartilage healing at the site of injury. For this study, we created a cartilage defect and performed microfracture treatment in fetlock joints of 18 horses, treated joints with one of three doses of sprifermin (10, 30, or 100 μg) or with saline, hyaluronan (HA), and evaluated animals functional and structural outcomes over 24 weeks. For primary outcome measures, we performed histological evaluations and gene expression analysis of aggrecan, collagen types I and II, and cartilage oligomeric matrix protein (COMP) in three regions of interest. As secondary outcome measures, we examined animals' lameness, performed arthroscopic, radiographic, and CT scan imaging and gross morphology assessment. We detected the highest treatment benefit following 100 μg sprifermin treatment. The overall histological assessment showed an improvement in the kissing region, and the expression of constitutive genes showed a concentration-dependent enhancement, especially in the peri-lesion area. We detected a significant improvement in lameness scores, arthroscopic evaluations, radiography, and CT scans following sprifermin treatment when results from three dose-treatment groups were combined. Our results demonstrated, for the first time, an enhancement on microfracture outcomes following sprifermin treatment suggesting a cartilage regenerative role and a potential benefit of sprifermin treatment in early cartilage injuries. This article is protected by copyright. All rights reserved.

Objective To assess pain outcomes and cartilage thickness change in a subgroup at risk (SAR) of further progression in the FORWARD trial of knee osteoarthritis patients treated with sprifermin. Methods Patients were randomised 1:1:1:1:1 to: sprifermin 100 µg every 6 months (q6mo), 100 µg q12mo, 30 µg q6mo, 30 µg q12mo, or placebo for 18 months. SAR was defined as baseline medial or lateral minimum joint-space width (mJSW) 1.5–3.5 mm and Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) pain score 40–90 units. Follow-up to 3 years was included in the analysis. Treatment benefit was explored by repeated measures, linear dose-effect trends by timepoint. Results The SAR comprised 161 (29%) of 549 patients. Mean difference (95% CI) in WOMAC pain at year 3 for sprifermin 100 µg q6mo vs placebo SAR was -8.75 (-22.42, 4.92) for SAR vs 0.97 (-6.22, 8.16) for the intent-to-treat population. SAR placebo patients lost more cartilage over 2 years than the modified ITT (mITT) placebo arm (mean change from baseline, mm [SD]: -0.05 [0.10] vs -0.02 [0.07]). Net total femorotibial joint thickness gain with sprifermin 100 µg q6mo (adjusted mean difference from placebo [95% CI] was similar in the SAR and in the mITT group: 0.06 [0.01, 0.11] vs 0.05 [0.03, 0.07]). Conclusions Selection for low mJSW and moderate-to-high pain at baseline resulted in more rapid disease progression and demonstrated translation of structure modification (with maintained net benefit on total cartilage thickness) into symptomatic benefit. This subgroup may represent a target population for future trials. Clinical trial registration : NCT01919164.

Sprifermin is under investigation as a potential disease-modifying osteoarthritis drug. Previously, 2-year results from the FORWARD study showed significant dose-dependent modification of cartilage thickness in the total femorotibial joint (TFTJ), medial and lateral femorotibial compartments (MFTC, LFTC), and central medial and lateral TFTJ subregions, by quantitative magnetic resonance imaging (qMRI) using manual segmentation.To determine whether qMRI findings from FORWARD could be reproduced by an independent method of automated segmentation using an identical dataset and similar anatomical regions in a post-hoc analysis.Cartilage thickness was assessed at baseline and 6, 12, 18 and 24 months, using automated cartilage segmentation with active appearance models, a supervised machine learning method. Images were blinded for treatment and timepoint. Treatment effect was assessed by observed and adjusted changes using a linear mixed model for repeated measures.Based on automated segmentation, statistically significant, dose-dependent structural modification of cartilage thickness was observed over 2 years with sprifermin vs placebo for TFTJ (overall treatment effect and dose response, both P 0.001), MFTC (P = 0.004 and P = 0.044), and LFTC (both P 0.001) regions. For highest dose, in the central medial tibial (P = 0.008), central lateral tibial (P 0.001) and central lateral femoral (P 0.001) regions.Cartilage thickness assessed by automated segmentation provided a consistent dose response in structural modification compared with manual segmentation. This is the first time that two independent quantification methods of image analysis have reached the same conclusions in an interventional trial, strengthening the conclusions that sprifermin modifies structural progression in knee osteoarthritis.

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.

PURPOSE OF REVIEW: The decreased contact area, edge loading, and increased stress in the adjacent area cartilage resulting from chondral defects are believed to predispose this tissue to degenerative changes that have significant economic implications, especially when considering its progression to osteoarthritis of the knee. Growth factors are considered therapeutic possibilities to enhance healing of chondral injuries and modify the progression to degenerative arthritis. Thus, the purposes of this review are to first to summarize important points for defect preparation and recent advances in techniques for marrow stimulation and second, and to identify specific growth factors and cytokines that have the capacity to advance cartilage regeneration and the treatment of osteoarthritis in light of recent laboratory and clinical studies. RECENT FINDINGS: TGF-β, BMP-2, BMP-7, IGF-1, as IL-1 receptor antagonist, and recombinant human FGF-18 are some of the promising growth factor/cytokine treatments with pioneering and evolving clinical developments. The bulk of the review describes and discusses these developments in light of fundamental basic science. It is crucial to also understand the other underlying advances made in the surgical management of cartilage defects prior to onset of OA. These advances are in techniques for defect preparation and marrow stimulation, a common cartilage repair procedure used in combination with growth factor/cytokine augmentation. SUMMARY: Multiple growth factor/cytokine modulation therapies are currently undergoing clinical trial investigation including Invossa (currently in phase III study), Kineret (currently in phase I study), and Sprifermin (currently in phase II study) for the treatment of symptomatic osteoarthritis.

Osteoarthritis (OA) is a serious and incurable disease leading the disability. Surgical treatment is the last but not necessarily the best approach for patients with high risks and costs. However, there are no disease-modifying OA drugs (DMOADs) developed for the disease so far, leaving a huge unmet need for drug treatments. Sprifermin is a recombinant human fibroblast growth factor 18 (rhFGF18) and has been confirmed to have anabolic effects on articular cartilage, which makes it a promising DMOAD.The content of this review includes overview of the market, discovery and development, molecular mechanism, preclinical studies, clinical efficacy, safety, and tolerability of sprifermin. It examines the potential of sprifermin as a disease modifying drug for the treatment of knee OA.Sprifermin could be one of the most promising DMOADs, especially for cartilage phenotype. Current studies show good tolerability and no safety concerns. Well-designed phase 3 clinical trials are required to examine its effects on symptoms and cartilage loss in knee OA.

Cartilage is a specialized tissue that has a relatively homogenous endogenous cell population but a diverse extracellular matrix (ECM) with depth-dependent mechanical properties. Cartilage repair remains an elusive clinical goal, with biological interventions preferred to arthroplasty in younger patients. Osteochondral transplantation (OCT) has emerged for the treatment of cartilage defects and osteoarthritis. Fresh allografts stored at 4 °C for periods of time have been utilized, though matrix and cell viability loss remained an issue. To address this, several studies have developed media formulations to maintain cartilage explants in vitro. One promising factor for these applications is sprifermin, a human-recombinant fibroblast growth factor-18 which stimulates chondrocyte proliferation and matrix synthesis and is in clinical trials for osteoarthritis treatment. We hypothesized that addition of sprifermin during storage would maintain the unique depth-dependent mechanical profile of cartilage explants, a feature of cartilage not often evaluated. In this study, cartilage explants were maintained for up to 6 weeks with or without a weekly 24-hour exposure to sprifermin (100 ng/ml) and the compressive modulus was assessed. Results showed that sprifermin treated samples maintained their depth-dependent mechanical profile through 3 weeks, whereas untreated samples lost their mechanical integrity over 1 week of culture. Sprifermin also affected ECM balance by maintaining levels of extracellular collagen and suppression of matrix metalloproteinase production. These findings support the use of sprifermin as a medium additive for OCT allografts during in vitro storage, and present a potential mechanism where sprifermin may impact a functional characteristic of cartilage in repair strategies.

ObjectiveThe FORWARD (FGF-18 Osteoarthritis Randomized Trial with Administration of Repeated Doses) trial assessed efficacy and safety of the potential disease-modifying osteoarthritis drug (DMOAD) sprifermin in patients with knee osteoarthritis. Here, we report 5-year efficacy and safety results.MethodsPatients were randomised to intra-articular sprifermin 100 µg or 30 µg every 6 months (q6mo) or 12 months, or placebo, for 18 months. The primary analysis was at year 2, with follow-up at years 3, 4 and 5. Additional post hoc exploratory analyses were conducted in patients with baseline minimum radiographic joint space width 1.5–3.5 mm and Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) pain 40–90, a subgroup at risk (SAR) of progression.Results378 (69%) patients completed the 5-year follow-up. A significant dose-response in total femorotibial joint cartilage thickness with sprifermin (trend test, pConclusionIn the longest DMOAD trial reported to date, sprifermin maintained long-term structural modification of articular cartilage over 3.5 years post-treatment. Potential translation to clinical benefit was observed in the SAR.Trial registration numberNCT01919164

Objective To perform a meta-analysis comparing the structural progression and clinical symptom outcomes as well as adverse events experienced from intra-articular injections of sprifermin compared to a placebo treatment for patients with knee osteoarthritis (KOA). Method We systematically searched the literature for studies that compared long-term outcomes between sprifermin and placebo injections for KOA treatment. Meta-analysis was performed with RevMan5.3 using an inverse variance approach with fixed or random effects models. Odds ratios (ORs) and 95% confidence intervals (CIs) were estimated. Results Eight studies were included. Overall, there was significantly less improvement of WOMAC total scores in patients receiving sprifermin, compared with the placebo (mean difference (MD) = 3.23, 95% CI 0.76–5.69; I2 = 0%; P = 0.01). Further, sprifermin injection patients gained more, and lost less, cartilage thickness and volume in total femorotibial joint (cartilage thickness: standardized mean differences (SMD) = 0.55, 95% CI 0.26–0.84; I2 = 78%; P = 0.0002; cartilage volume: SMD = 0.39, 95% CI 0.20–0.58; I2 = 49%; P I2 = 0%; P I2 = 0%; P = 0.004) showed a significant difference between the sprifermin and placebo injections. Moreover, there were no significant differences between sprifermin and the placebo in the risk of treatment-emergent adverse events (OR = 1.05; 95% CI 0.52–2.14; I2 = 48%; P = 0.89). Conclusion The data from the included studies provide strong evidence to determine the effect of intra-articular sprifermin on joint structure in individuals with KOA and show no specific adverse effects. Nevertheless, intra-articular sprifermin did not likely have any positive effect on symptom alleviation.

Osteoarthritis (OA) is the most common chronic joint disorder worldwide, with a high personal burden for the patients and an important socio-economic impact. Current therapies are largely limited to pain management and rehabilitation and exercise strategies. For advanced cases, joint replacement surgery may be the only option. Hence, there is an enormous need for the development of effective and safe disease-modifying anti-OA drugs. A strong focus in OA research has been on the identification and role of molecular signalling pathways that contribute to the balance between anabolism and catabolism in the articular cartilage. In this context, most insights have been gained in understanding the roles of the transforming growth factor-beta (TGF-β) and the Wingless-type (Wnt) signalling cascades. The emerging picture demonstrates a high degree of complexity with context-dependent events. TGF-β appears to protect cartilage under healthy conditions, but shifts in its receptor use and subsequent downstream signalling may be deleterious in aged individuals or in damaged cartilage. Likewise, low levels of Wnt activity appear important to sustain chondrocyte viability but excessive activation is associated with progressive joint damage. Emerging clinical data suggest some potential for the use of sprifermin, a recombinant forms of fibroblast growth factor 18, a distant TGF-β superfamily member, and for lorecivivint, a Wnt pathway modulator. ispartof: THERAPEUTIC ADVANCES IN MUSCULOSKELETAL DISEASE vol:13 ispartof: location:England status: published

Summary Objective Fibroblast growth factor 18 (FGF18) is involved in chondrogenesis and articular cartilage repair. We investigated tissue distribution and pharmacokinetics of radioactive [3H]sprifermin, a recombinant human FGF18, in rats after a single intravenous (i.v.) or intra-articular (i.a.) injection. Design In two studies (48–96-h [n = 23] and 28-day [n = 12]), 35 male albino (Sprague Dawley) rats received single i.v. or i.a. dose [3H]sprifermin (0.24 mg/kg). Radioactivity was measured in blood, serum, and (in animals receiving i.a. administration) in the knee joint by liquid scintillation counting. Radioactivity in organs, tissues, and distribution in the whole body were measured with whole-body autoradiography. Results After i.v. injection, radioactivity peaked in serum and whole blood after 4 and 24 h, respectively, with greater total radioactivity in serum. After i.a. injection, radioactivity peaked in serum and whole blood after 24 and 48 h, respectively; intact [3H]sprifermin was not detected in vena caval serum and systemic exposure was low, approximately 20% of that with i.v. injection. Following i.v. injection, radioactivity was mainly found in the liver, adrenal glands, kidney, and spleen; following i.a. injection, radioactivity was preferentially concentrated in articular cartilage after initial distribution in the joint capsule, and still evident in the joint after 28 days. Conclusions After i.a. injection of [3H]sprifermin in rats, radioactivity was concentrated in the knee joint, particularly articular cartilage, with low levels in other investigated tissues. Systemic exposure to sprifermin was greater with i.v. than i.a. injection. Subsequent clinical investigation in patients with osteoarthritis has reported consistent results.

Background: Post traumatic osteoarthritis is a disabling condition impacting mostly young and active population. In the present study we investigated the impact of intra-articular sprifermin, a recombinant truncated fibroblast growth factor 18, on the outcome of microfracture treatment, a widely used surgical technique to enhance cartilage healing at the site of injury. Methods: For the purpose if this study, we created a cartilage defect and performed microfracture treatment in fetlock joints of 18 horses, treated joints with one of three doses of sprifermin (10, 30, or 100 mg) or with saline, hyaluronan (HA), and evaluated animals functional and structural outcomes over 24 weeks. For primary outcome measures we performed histological evaluations and performed gene expression analysis of aggrecan, collagen types I and II, and cartilage oligomeric matrix protein (COMP) in three regions of interest. As secondary outcome measures we examined animal’s lameness, performed arthroscopic, radiographic, and CT scan imaging, and gross morphology assessment. Results: We detected the highest treatment benefit following 100 mg sprifermin treatment. Overall histological assessment showed an improvement in the kissing region and expression of constitutive genes showed a concentration dependent enhancement, especially in the peri-lesion area. We detected a significant improvement in lameness scores, arthroscopic evaluations, radiography, and CT scans following sprifermin treatment when results from three dose-treatment groups were combined. Conclusion: Our results demonstrated for the first time, an enhancement in outcomes of the microfracture treatment following sprifermin treatment, suggesting a cartilage regenerative role and a potential benefit of sprifermin treatment in early cartilage injuries.

Sprifermin, recombinant human fibroblast growth factor 18 (rhFGF18), induces cartilage regeneration in knees of patients with osteoarthritis (OA). We hypothesized that a temporal multiphasic process of extracellular matrix (ECM) degradation and formation underlie this effect. We aimed to characterize the temporal ECM remodeling of human knee OA articular cartilage in response to sprifermin treatment. Articular cartilage explants from patients with knee OA (npatients = 14) were cultured for 70 days, with permanent exposure to sprifermin (900, 450, 225 ng/mL), FGF18 (450 ng/mL), insulin-like growth factor-1 (100 ng/mL, positive control) or vehicle (nreplicates/treatment/patient = 2). Metabolic activity (AlamarBlue) and biomarkers of type IIB collagen (PIIBNP) formation (Pro-C2 enzyme-linked immunosorbent assay [ELISA]) and aggrecanase-mediated aggrecan neo-epitope NITEGE (AGNx1 ELISA) were quantified once a week. At end of culture (day 70), gene expression (quantitative reverse transcription polymerase chain reaction) and proteoglycan content (Safranin O/Fast green staining) were quantified. The cartilage had continuously increased metabolic activity, when treated with sprifermin/FGF18 compared to vehicle. During days 7–28 PIIBNP was decreased and NITEGE was increased, and during days 35–70 PIIBNP was increased. At end of culture, the cartilage had sustained proteoglycan content and relative expression of ACAN

Cartilage integration remains a clinical challenge for treatment of focal articular defects. Cartilage exhibits limited healing capacity that declines with tissue maturation. Many approaches have been investigated for their ability to stimulate healing of mature cartilage or integration of repair tissue or tissue-engineered constructs with native cartilage. Growth factors present in immature tissue may enhance chondrogenesis and promote integrative repair of cartilage defects. In this study, we assessed the role of one such factor, fibroblast growth factor 18 (FGF18). Studies using FGF18 have shown a variety of positive effects on cartilage, including stimulation of chondrocyte proliferation, matrix biosynthesis, and suppression of proteinase activity. To explore the role of FGF18 on cartilage defect repair, we hypothesized that treatment with recombinant human FGF18 (sprifermin) would increase matrix synthesis in a defect model, thus improving integration strength. To test this hypothesis, 6 mm cartilage cylinders were harvested from juvenile bovine knees. A central 3 mm defect was created in each explant, and this core was removed and replaced. Resulting constructs were cultured in control or sprifermin-containing medium (weekly 24-h exposure of 100 ng/ml sprifermin) for 4 weeks. Mechanical testing, biochemical analysis, micro-CT, scanning electron microscopy, and histology were used to assess matrix production, adhesive strength, and structural properties of the cartilage-cartilage interface. Results showed greater adhesive strength, increased collagen content, and larger contact areas between core and annular cartilage in the sprifermin-treated group. These findings present a novel treatment for cartilage injuries that have potential to enhance defect healing and lateral cartilage-cartilage integration. © 2018 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 36:2648-2656, 2018.

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 (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.

ObjectivesIn the phase II FGF-18 Osteoarthritis Randomized Trial with Administration of Repeated Doses (FORWARD) study, sprifermin demonstrated cartilage modification in the total femorotibial joint and in both femorotibial compartments by MRI in patients with knee osteoarthritis. Here, we evaluate whether sprifermin reduces cartilage loss and increases cartilage thickness, independent of location.MethodsPatients were randomised 1:1:1:1:1 to three once-weekly intra-articular injections of 30 µg sprifermin every 6 months (q6mo); 30 µg sprifermin every 12 months (q12mo); 100 µg sprifermin q6mo; 100 µg sprifermin q12mo; or placebo. Post-hoc analysis using thinning/thickening scores and ordered values evaluated femorotibial cartilage thickness change from baseline to 24 months independent of location. Changes were indirectly compared with those of Osteoarthritis Initiative healthy subjects.ResultsThinning scores were significantly lower for sprifermin 100 µg q6mo versus placebo (mean (95% CI) difference: 334 µm (114 to 554)), with a cartilage thinning score similar to healthy subjects. Thickening scores were significantly greater for sprifermin 100 µg q6mo, 100 µg q12mo and 30 µg q6mo versus placebo (mean (95% CI) difference: 425 µm (267 to 584); 450 µm (305 to 594) and 139 µm (19 to 259), respectively) and more than doubled versus healthy subjects.ConclusionsSprifermin increases cartilage thickness, and substantially reduces cartilage loss, expanding FORWARD primary results.Trial registration numberNCT01919164.

One possible approach to treat osteoarthritis (OA) is to counteract cartilage degeneration with anabolic compounds that stimulate chondrocyte proliferation and/or extracellular matrix (ECM) production. Several molecules including sprifermin (recombinant human fibroblast growth factor [FGF18]), insulin‐like growth factor‐1 [IGF1] and ‐2 [IGF2], C‐type natriuretic peptide [CNP], and bone metamorphic protein 7 [BMP7] have been shown to have these characteristics both in vitro and in vivo. However, it is not known how these molecules compare each other regarding their effect on phenotype and stimulation of ECM production in primary chondrocytes. The effects of sprifermin, IGF1, IGF2, CNP, and BMP7 were evaluated on bovine articular chondrocytes, first in monolayer to determine their effective concentrations, and then in three‐dimensional (3D) culture at concentrations of 100 ng/ml for sprifermin; 300 ng/ml for IGF1, IGF2, and BMP7; and 10 nM for CNP. In 3D culture, the effects of a permanent exposure or a cyclic exposure consisting of 24 h incubation per week with the compounds were evaluated. All growth factors increased ECM production and cell proliferation to a similar extent but CNP had almost no effect on bovine chondrocytes. Sprifermin was more effective with cyclic exposure, IGF1, and IGF2 with permanent exposure, and BMP7 showed similar results with both exposures. Regarding the cell phenotype, sprifermin appeared to be the only compound favoring the chondrocyte phenotype; it decreased type I collagen expression and had no hypertrophic effect. Together, these results confirmed that sprifermin is a promising disease‐modifying OA drug. © 2019 The Authors. Journal of Orthopaedic Research ® published by Wiley Periodicals, Inc. on behalf of Orthopaedic Research Society. J Orthop Res 38:653–662, 2020

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

Osteoarthritis (OA) is a degenerative joint disorder and is the leading cause of disability of people, which negatively impact people's physical and mental health. Although OA causes great socioeconomic burden and individual suffering, no effective treatment options are provided so far. This is partially resulted from poor regenerative activity of articular cartilage and our incomplete understanding of the underlying mechanism of OA. Traditional drug therapies such as acetaminophen and opioids are effective in relieving pain but do not reverse cartilage damage and are often associated with adverse events. Therefore, it is necessary to find effective OA drugs. In recent years, novel regenerative therapies have received much attention because they can effectively promote tissue repair and regeneration. The fibroblast growth factor (FGF) signaling has been suggested to involve in cartilage homeostasis for decades. The current research shows that sprifermin/recombinant FGF18 significantly reduces the loss of cartilage thickness and volume without serious side effects, thus warrants a continued research for potential new medications of OA. This review mainly highlights the current research progress on FGFs and FGF receptors as a potential therapeutic target for OA.

Sprifermin is a human recombinant fibroblast growth factor 18 (rhFGF18) in clinical development for knee osteoarthritis. Previously, we demonstrated that sprifermin exerts an anabolic effect on chondrocytes in 3D culture with cyclic but not permanent exposure. Here, we hypothesized that permanent exposure to sprifermin de-sensitizes the cells. To test this, a combination of Western-blot and cell staining methods was used. We demonstrate that sprifermin is transiently internalized in chondrocytes along with a transient increase in ERK1/2 activation. We also show that sprifermin is intracellularly degraded, probably together with its receptor FGFR3, thus preventing further stimulation. However, incubation without sprifermin re-sensitizes the cells. Finally, we show that sprifermin endocytosis is clathrin- and dynamin-independent and that receptor activation is not necessary for sprifermin's endocytosis. In this study, we link the role of endocytosis to the cell response and elucidate for the first time a de-sensitization phenomenon to a FGF.

Background:It is challenging to monitor treatment effects after intra-articular (IA) injection with tissue modifying drugs. Assessment of biomarker levels in synovial fluid may be one solution to the challenge. Sprifermin is a truncated form of fibroblast growth factor (FGF) 18 known to induce chondrocyte proliferation and type II collagen formation [1,2]. Data from preclinical investigations show that cartilage formation happens in different phases after therapy with sprifermin, starting with a phase of cartilage degradation during the induction of proliferation of chondrocytes followed by a phase of cartilage formation/production of extracellular matrix.Objectives:The aim was to investigate the effect of IA administrated sprifermin on cartilage turnover activity as compared to placebo in the injected joint by measurement of markers using longitudinal synovial fluid samples of patients participating in the FORWARD study.Methods:Each included patient had baseline and at least one FU sample available. Synovial fluid (SF) from participants receiving injections at three consecutive weeks in six month intervals through to week (wk) 80 (fig.A) available from the phase II clinical trial evaluating the efficacy and safety of intraarticularly delivered sprifermin [3] were selected for the investigations. Biochemical markers were measured in available SF samples of the placebo (containing saline IA, n=38) and the highest sprifermin dose group (100 mcg/IAx4, n=59). Samples were pretreated with ultrasound and centrifugation to decrease viscosity. Markers measured were PRO-C2 (type II collagen formation), huARGS (aggrecan degradation), and FBN-C (fibronectin). Markers are technically validated for synovial fluid measurement. Data were individually normalized to baseline to investigate the median proportional change over time.Results:Baseline mean (SD) levels of the markers in SF at BL were: PRO-C2, 21.4 (13.6) ng/mL, huARGS, 1117 (516) pM and FBN-C, 2556 (1959) ng/mL. PRO-C2 was initially decreased (from BL to wk 2) after injection with sprifermin; however, the level was increased at the beginning of each new injection cycle followed by a decrease after injection of sprifermin (Fig.B). Overall synovial PRO-C2 levels increased over time in therapy with sprifermin, while no change was observed for the placebo arm. huARGS showed a similar pattern as PRO-C2 – there was an overall increase in ARGS over time in the sprifermin group (fig.C). Interestingly ARGS continuously decreased over time in the placebo group. FBN-C is continuously increased after injection’s cycles, whereas no effect was seen in the placebo group (fig.D).Conclusion:Confirmatory of the preclinical investigations a biphasic response on cartilage turnover after injection with sprifermin was observed. Biochemical indications of cartilage formation and chondrocyte proliferation was only modulated in the sprifermin group, and cartilage degradation (ARGS) was temporal induced and reduced by sprifermin and placebo injections, respectively.References:[1]Gigout A, et al. “Sprifermin (rhFGF18) enables proliferation of chondrocytes producing a hyaline cartilage matrix”. Osteoarthr Cartil. 2017;25.[2]Reker D, et al. “Sprifermin (rhFGF18) modulates extracellular matrix turnover in cartilage explants ex vivo”. J Transl Med. 2017;15.[3]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:Anne-Christine Bay-Jensen Shareholder of: Nordic Bioscience A/S, Employee of: Full time employee at Nordic Bioscience A/S., Angela Manginelli Employee of: Merck KGaA, Flavie Moreau Employee of: Merck KGaA, Yi He Employee of: YH is a full time employee of Nordic Bioscience A/S, Yunyun Luo Employee of: Nordic Bioscience A/S, 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., Hans Gühring Employee of: Merck KGaA, Christoph Ladel Employee of: Merck KGaA

Importance Even though osteoarthritis is a chronic and progressive disease, pharmacological agents are mainly studied over short-term periods, resulting in unclear recommendations for long-term disease management. Objective To search, review, and analyze long-term (≥12 months) outcomes (symptoms, joint structure) from randomized clinical trials (RCTs) of medications for knee osteoarthritis. Data Sources and Study Selection The databases of MEDLINE, Scopus, EMBASE, Web of Science, and the Cochrane Central Register of Controlled Trials were searched until June 30, 2018 (MEDLINE alerts through August 31, 2018) for RCTs of patients with knee osteoarthritis that had treatment and follow-up lasting 1 year or longer. Data Extraction and Synthesis Data at baseline and at the longest available treatment and follow-up of 12 months’ duration or longer (or the change from baseline) were extracted. A Bayesian random-effects network meta-analysis was performed. Main Outcomes and Measures The primary outcome was the mean change from baseline in knee pain. Secondary outcomes were physical function and joint structure (the latter was measured radiologically as joint space narrowing). Standardized mean differences (SMDs) and mean differences with 95% credibility intervals (95% CrIs) were calculated. Findings were interpreted as associations when the 95% CrIs excluded the null value. Results Forty-seven RCTs (22 037 patients; mean age range, mostly 55-70 years; and a higher mean proportion of women than men, around 70%) included the following medication categories: analgesics; antioxidants; bone-acting agents such as bisphosphonates and strontium ranelate; nonsteroidal anti-inflammatory drugs; intra-articular injection medications such as hyaluronic acid and corticosteroids; symptomatic slow-acting drugs in osteoarthritis such as glucosamine and chondroitin sulfate; and putative disease-modifying agents such as cindunistat and sprifermin. Thirty-one interventions were studied for pain, 13 for physical function, and 16 for joint structure. Trial duration ranged from 1 to 4 years. Associations with decreases in pain were found for the nonsteroidal anti-inflammatory drug celecoxib (SMD, −0.18 [95% CrI, −0.35 to −0.01]) and the symptomatic slow-acting drug in osteoarthritis glucosamine sulfate (SMD, −0.29 [95% CrI, −0.49 to −0.09]), but there was large uncertainty for all estimates vs placebo. The association with pain improvement remained significant only for glucosamine sulfate when data were analyzed using the mean difference on a scale from 0 to 100 and when trials at high risk of bias were excluded. Associations with improvement in joint space narrowing were found for glucosamine sulfate (SMD, −0.42 [95% CrI, −0.65 to −0.19]), chondroitin sulfate (SMD, −0.20 [95% CrI, −0.31 to −0.07]), and strontium ranelate (SMD, −0.20 [95% CrI, −0.36 to −0.05]). Conclusions and Relevance In this systematic review and network meta-analysis of studies of patients with knee osteoarthritis and at least 12 months of follow-up, there was uncertainty around the estimates of effect size for change in pain for all comparisons with placebo. Larger RCTs are needed to resolve the uncertainty around efficacy of medications for knee osteoarthritis.

Background Sprifermin, a recombinant human fibroblast growth factor 18, is currently being investigated as a potential disease-modifying osteoarthritis (OA) drug. Recently, a dose-dependent increase in femorotibial cartilage thickness, as well as medial and lateral compartment cartilage, over two years was reported 1 . Objectives The aim of this post-hoc analysis is to evaluate potential effects of sprifermin on additional structure endpoints, based on semi-quantitative MRI assessment over 24 months. Methods Patients aged 40–85 years with symptomatic radiographic knee OA, KLG 2 or 3, and medial mJSW ≥2.5 mm in the target knee were randomised (1:1:1:1:1) to receive double-blinded placebo or sprifermin (30 µg or 100 µg), administered as 3 weekly intra-articular injections in cycles every 6 or 12 months. 1.5T or 3T MRIs were acquired at baseline, 6, 12, 18 and 24 month follow-up visits using a standard protocol (ClinicalTrials.gov identifier: NCT01033994). MRIs were read using the Whole-Organ Magnetic Resonance Imaging Score (WORMS) system (time points of baseline, 12 and 24 months) by three trained musculoskeletal radiologists. Analyses of all sprifermin and placebo arms included multiple MRI-defined osteoarthritis features and multi-dimensional assessments: (a) delta-subregional approach (the difference in the number of subregions with worsening as compared to improvement) and (b) delta-sum approach (absolute scores of all subregions). Analyses were performed on a whole knee level and separately for medial, lateral, and patellofemoral compartments. To test for potential dose-response effects, Jonckheere-Terpstra (asymptotic) test was used. P-values were not adjusted for multiple testing. Results 549 patients were included. Dose-dependent treatment effect on cartilage morphology (i.e., less cartilage damage) was observed for the entire knee from baseline to 24 months using both delta sum and delta subregion approaches (table 1). For bone marrow lesions (BMLs), a dose-dependent treatment effect (improvement of BMLs) was observed from baseline to 24 months for the patello-femoral joint using both delta sum and delta subregion approaches but not the other compartments (table 2). No significant effects were seen for baseline to 24 month changes in Hoffa-synovitis, effusion-synovitis, menisci, or osteophytes. Conclusions This post-hoc analysis indicates that sprifermin has a positive effect on cartilage morphology, in addition to the previously reported effect on cartilage thickness. Sprifermin was also associated with BML improvement in the patello-femoral joint. There were no significant effects associated with sprifermin on other joint tissues assessed, and no safety concerns raised. Reference [1] Hochberg MC, et al. Efficacy and Safety of Intra-Articular Sprifermin in Symptomatic Radiographic Knee Osteoarthritis: Results of the 2-Year Primary Analysis from a 5-Year Randomised, Placebo-Controlled, Phase II Study [abstract]. Arthritis Rheumatol 2017;69(suppl 10). Disclosure of Interest F. Roemer Shareholder of: Boston Imaging Core Lab (BICL), LLC., J. Kraines Employee of: EMD Serono, A. Aydemir Employee of: EMD Serono, S. Wax Employee of: EMD Serono, M. Crema Shareholder of: Boston Imaging Core Lab (BICL), LLC., M. Hochberg Consultant for: Bioiberica SA, Bristol Myers Squibb, EMD Serono, Galapagos, IBSA Biotechniq SA, Novartis Pharma AG, Pfizer Inc., Plexxikon, Samumed LLC, Theralogix LLC and TissueGene Inc, A. Guermazi Shareholder of: Boston Imaging Core Lab (BICL), LLC., Consultant for: to MerckSerono, TissueGene, GE, Pfizer, OrthoTrophix, AstraZeneca and Sanofi

Background Sprifermin, a novel recombinant human fibroblast growth factor 18, is currently being investigated as a potential disease-modifying osteoarthritis (OA) drug. Two-year results of the 5 year phase II FORWARD study showed a statistically significant dose-dependent cartilage thickness increase in the total femorotibial joint (TFJ), and in the medial, lateral and central medial sub-region TFJ compartments by quantitative magnetic resonance imaging (qMRI). Objectives Here we report the pre-specified 3 year results. Methods Patients (pts) aged 40–85 years with symptomatic radiographic knee OA, Kellgren-Lawrence grade (KLG) 2 or 3, and medial mJSW ≥2.5 mm in the target knee were randomised (1:1:1:1:1) to receive 3 weekly i.a. injections with double-blinded placebo (PBO) or sprifermin, administered q6mo (0, 6, 12, and 18 months) or q12mo (0 and 12 months). The primary endpoint was the change in TFJ cartilage thickness from baseline (BL) to Year 2 with pre-specified analyses at Year 3. The intent-to-treat (ITT) population (all randomised pts) was used for non-qMRI endpoints; and the modified ITT population (all ITT pts with BL and ≥1 post-treatment MRI up to Year 2) for qMRI endpoints. Results 549 pts were randomised (median age 65 years, 69% women, 80% white, 69% KLG2, and ~70% predominantly medial disease); of which 18.4% (sprifermin) and 24.1% (PBO) discontinued the study within 3 years. TFJ cartilage thickness decreased from Year 2 to 3 in all treatment groups; however, the 0.05 mm difference between sprifermin 100 µg q6mo and PBO was maintained (0.00 vs −0.05 mm; p Conclusions The 3 year results of the FORWARD study are consistent with the 2 year results: although cartilage thickness declined in all treatment groups between Year 2 and 3, the difference at Year 2 with sprifermin 100 µg vs PBO was maintained up to Year 3. Based on qMRI sprifermin is effective at increasing cartilage thickness in a dose-dependent manner in knee OA patients, and has an acceptable safety profile. Disclosure of Interest M. Hochberg Consultant for: Bioiberica SA, Bristol Myers Squibb, EMD Serono, Inc., Galapagos, IBSA Biotechniq SA, Novartis Pharma AG, Pfizer Inc., Plexxikon, Samumed LLC, Theralogix LLC and TissueGene Inc, A. Guermazi Consultant for: OrthoTrophix, GE Healthcare, Merck Serono, AstraZeneca, Sanofi, TissueGene and Pfizer, Employee of: Boston Imaging Core Lab, LLC, H. Guehring Employee of: Merck KGaA, A. Aydemir Employee of: EMD Serono, Inc., S. Wax Employee of: EMD Serono, Inc., P. Fleuranceau-Morel Employee of: EMD Serono, Inc., A. Reinstrup Bihlet Shareholder of: Nordic Bioscience, Employee of: Nordic Bioscience, I. Byrjalsen Employee of: Nordic Bioscience, J. Ragnar Andersen Shareholder of: Nordic Bioscience, Employee of: Nordic Bioscience, F. Eckstein Shareholder of: Chondrometrics GmbH, Consultant for: Merck KGaA, Samumed LLC, Abbvie, Bioclinica, TissueGene, Servier and Roche, Employee of: Chondrometrics GmbH

Objective To determine whether an anabolic drug (sprifermin) is capable of reducing cartilage loss wherever it occurs in a given knee, using a subject-specific, location-independent analysis of cartilage change in patients with knee osteoarthritis (OA). Methods Study participants (n = 168; ages ≥40 years, 69% women) had symptomatic femorotibial OA not confined to the medial compartment. Sprifermin (10, 30, or 100 μg) or placebo was injected intraarticularly 3 times over 3 weeks, both after randomization (baseline) and 3 months later. Coronal magnetic resonance images were acquired at baseline and 3, 6, and 12 months after treatment. The femorotibial cartilage of each subject was segmented, and changes in cartilage thickness were computed across 16 subregions. Location-independent post hoc analysis was used to compute summary scores of negative and positive changes in the subregions, summarized as the total cartilage thinning sum score (ThCTnS) and the total cartilage thickening sum score (ThCTkS), capturing change in either direction in each knee. Ordered values of the magnitude of subject-specific subregional changes in thickness were determined. The ThCTnS and ThCTkS in each sprifermin dose group at 12 months of followup were compared with the values in the matched placebo groups, using the Wilcoxon-Mann-Whitney test. Results The mean ± SD ThCTnS was −591 ± 617 μm (median −360 μm, Q1/Q3 = −820/−200 μm) in patients treated with 100 μg sprifermin (n = 57), and −921 ± 777 μm (median −745 μm, Q1/Q3 = −1,190/−380 μm) in patients given placebo (n = 18). The mean difference in the ThCTnS between the 100-μg sprifermin group and the placebo group was 331 μm (95% confidence interval [95% CI] 24, 685), a difference that was statistically significant (P = 0.03). The mean difference in the ThCTkS in the 100-μg sprifermin group compared with the placebo group was 237 μm (95% CI 34, 440), also a statistically significant difference (P = 0.028). Conclusion Sprifermin not only increases cartilage thickness, but also reduces cartilage loss. Subject-specific, location-independent analysis of both cartilage thinning and thickening represents a sensitive and informative approach for studying the effects of disease-modifying OA drugs.

Augmented microfracture techniques use growth factors, cells, and/or scaffolds to enhance the healing of microfracture-treated cartilage defects. This study investigates the effect of delivering recombinant human fibroblastic growth factor 18 (rhFHF18, Sprifermin) via a collagen membrane on the healing of a chondral defect treated with microfracture in an ovine model. Eight millimeter diameter chondral defects were created in the medial femoral condyle of 40 sheep (n = 5/treatment group). Defects were treated with microfracture alone, microfracture + intra-articular rhFGF-18 or microfracture + rhFGF-18 delivered on a membrane. Outcome measures included mechanical testing, weight bearing, International Cartilage Repair Society repair score, modified O'Driscoll score, qualitative histology, and immunohistochemistry for types I and II collagen. In animals treated with 32 μg rhFGF-18 + membrane and intra-articularly, there was a statistically significant improvement in weight bearing at 2 and 4 weeks post surgery and in the modified O'Driscoll score compared to controls. In addition, repair tissue stained was more strongly stained for type II collagen than for type I collagen. rhFGF-18 delivered via a collagen membrane at the point of surgery potentiates the healing of a microfracture treated cartilage defect. © 2015 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 33:1120–1127, 2015.

Summary Objective Fibroblast growth factor (FGF) 18 has been shown to increase cartilage volume when injected intra-articularly in animal models of osteoarthritis (OA) and in patients with knee OA (during clinical development of the recombinant human FGF18, sprifermin). However, the exact nature of this effect is still unknown. In this study, we aimed to investigate the effects of sprifermin at the cellular level. Design A combination of different chondrocyte culture systems was used and the effects of sprifermin on proliferation, the phenotype and matrix production were evaluated. The involvement of MAPKs in sprifermin signalling was also studied. Results In monolayer, we observed that sprifermin promoted a round cell morphology and stimulated both cellular proliferation and Sox9 expression while strongly decreasing type I collagen expression. In 3D culture, sprifermin increased the number of matrix-producing chondrocytes, improved the type II:I collagen ratio and enabled human OA chondrocytes to produce a hyaline extracellular matrix (ECM). Furthermore, we found that sprifermin displayed a ‘hit and run' mode of action, with intermittent exposure required for the compound to fully exert its anabolic effect. Finally, sprifermin appeared to signal through activation of ERK. Conclusions Our results indicate that intermittent exposure to sprifermin leads to expansion of hyaline cartilage-producing chondrocytes. These in vitro findings are consistent with the increased cartilage volume observed in the knees of OA patients after intra-articular injection with sprifermin in clinical studies.

The management of symptomatic chondral defects is one of the biggest challenges in Orthopaedics. The quest for the ideal orthobiologic treatment modality, in which mechanically functional hyaline cartilage can be regenerated around and in the defect site, is ongoing. The growing understanding of the function of the tissue within joint microenvironment on the one hand is helping to clarify the reasons of the failures, on the other is introducing even more intricate perspectives where a multitude of factors should be ruled to chase therapeutic success. Microfractures (MF) and autologous chondrocyte implantation (ACI) typically result in clinical satisfactory outcome only in selected patients and we are still far from restoring native tissue biology. Preliminary experience with hyaluronic acid, platelet-rich plasma and mesenchymal stem cell as adjuvant therapies for MF and ACI has been positive but high quality prospective clinical trial are lacking. The new perspective of a tissue therapy strategy, based on more mature engineered tissues, holds promise to tackle limitations of standard cell procedures. Furthermore, current research has pointed-up the demand for more targeted therapies as the induction of tolerance with granulocyte colony-stimulating factor or preventing Interleukin-6 (IL-6) downregulation, as combined IL-4 and IL-10 local release, as selective activation of prostaglandin E2 (PGE2) signaling, as intra-articular injection of growth factors such as Sprifermin (Merck kGA, Germany), and as identification of molecules (Kartogenin) that selectively direct mesenchymal stem cells differentiation to chondrocytes. Combining cell and tissue therapies with targeted therapies could represent the next-generation cartilage regeneration strategy to answer both mechanical and environmental requirements of the joint surface.

Objective. We evaluated in a proof-of-concept double-blind placebo-controlled randomized trial the efficacy and safety of intra-articular sprifermin (recombinant human fibroblast growth factor 18) in patients with symptomatic knee OA. Methods. Sprifermin was evaluated as intra-articular injection at 10, 30, and 100μg. Primary efficacy endpoint was change in central medial femorotibial compartment (cMFTC) cartilage thickness at 6 and 12 months using quantitative MRI (qMRI). Primary safety endpoints were nature, incidence and severity of local and systemic treatment-emergent adverse events, acute inflammatory reactions and laboratory assessments. Secondary endpoints included changes in total and compartment femorotibial cartilage thickness and volume by qMRI, joint space width (JSW) from radiographs, and Western Ontario McMaster Universities (WOMAC) pain. Results. 192 patients were randomized and evaluated for safety, 180 completed the trial, 168 evaluated for primary efficacy endpoint. We found no statistically significant dose-response in change in cMFTC cartilage thickness. Sprifermin was associated with statistically significant, dose-dependent reductions in loss of total and lateral femorotibial cartilage thickness and volume, and in JSW narrowing in the lateral femorotibial compartment. All groups improved in WOMAC pain, with statistically significant less improvement at 12 months in patients receiving 100μg sprifermin than placebo. There was no significant difference in SAEs, TEAEs, AIRs between sprifermin and placebo groups. Conclusion. There was no statistically significant relationship between treatment group and reduction in cMFTC cartilage thickness. However, pre-specified structural secondary endpoints showed statistically significant dose-dependent reductions following sprifermin treatment. Sprifermin was not associated with any local or systemic safety concerns. Clinicaltrials.gov identification: NCT01033994. © 2014 American College of Rheumatology. (Less)