Intra-articular Sprifermin Research Articles

Long-term structural and symptomatic effects of intra-articular sprifermin in patients with knee osteoarthritis: 5-year results from the FORWARD study

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,...

Recombinant fibroblast growth factor-18 (sprifermin) enhances microfracture-induced cartilage healing.

Posttraumatic 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, 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 proteinin three regions of interest. As secondary outcome measures, we examined animals' lameness, performed arthroscopic, radiographic, and computed tomography (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.

Intra-articular sprifermin therapy reduces total knee replacements: accumulated evidence from translational and clinical data

Purpose: Osteoarthritis (OA) is a degenerative disease with high prevalence, creating an unmet medical need for drugs to protect and regenerate cartilage. Sprifermin, a truncated form of fibroblast growth factor 18 (rhFGF18), is being investigated as a potential disease-modifying OA drug (DMOAD). Sprifermin has been shown to increase cartilage volume in the knees of OA patients. Studies published about the mode of action clearly demonstrate anabolic effects. Accumulated analysis of data available from preclinical experiments and clinical data was performed to investigate the effects of sprifermin on late stage OA tissues as well as the rate of total knee replacements (TKR) in late stage OA patients.

Evaluating the structural effects of intra-articular sprifermin on cartilage and non-cartilaginous tissue alterations, based on sqMRI assessment over 2 years

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. Patients aged 40-85 years with symptomatic radiographic knee OA, Kellgren-Lawrence grade 2 or 3, and medial minimum joint space width ≥2.5mm in the target knee were randomized (1:1:1:1:1) to receive three double-blinded, once-weekly, intra-articular injections of sprifermin 30μg or 100μg or placebo every 6 (q6mo) or 12 months. 1.5- or 3T 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. 549 patients were included. Dose-dependent treatment effects from baseline to 24 months were observed on cartilage morphology (sprifermin 100μg 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 100μg 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. 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.

Long-term efficacy and safety of intra-articular sprifermin in patients with knee osteoarthritis: results from the 5-year forward study

Purpose: The 5-year Phase II FORWARD study assessed the efficacy and safety of the potential disease-modifying osteoarthritis drug (DMOAD) sprifermin (recombinant human fibroblast growth factor 18) in patients with symptomatic, radiographic knee osteoarthritis (OA). The primary endpoint assessed at Year 2 showed dose-dependent modification of total femorotibial joint (TFTJ) cartilage thickness with sprifermin vs placebo (PBO) by quantitative magnetic resonance imaging (qMRI), and this was found to be sustained at Year 3 follow-up in a subsequent exploratory analysis.

Assessment of cartilage markers in synovial fluid from the forward study provide insight to the biphasic effect of sprifermin

Purpose: 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. The aim was to investigate the effect of intra-articular (IA) administrated sprifermin on cartilage turnover as compared to placebo by measurement of markers in longitudinal synovial fluid samples of patients participating in the FORWARD study. Methods: Synovial fluids (SF) from participants with baseline and at least one follow-up sample (baseline (BL) 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 (saline IA, n=38) and the highest sprifermin dose group (100 mg/IAx4, n=59). Each included patient had baseline and at least one FU sample available. 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 were technically validated for synovial fluid measurement. Data were normalized to baseline to investigate the median 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 a new injection cycle followed by a decrease after injection of sprifermin (Fig.B). Overall 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). Conclusions: Confirmatory of the preclinical investigations we saw a biphasic response on cartilage turnover after injection with sprifermin. Cartilage formation and chondrocyte proliferation was only modulated by sprifermin, and cartilage degradation (ARGS) was temporal induced and reduced by sprifermin and saline injections, respectively.1. Gigout A, Guehring H, Froemel D, Meurer A, Ladel C, Reker D, et al. Sprifermin (rhFGF18) enables proliferation of chondrocytes producing a hyaline cartilage matrix. Osteoarthr Cartil. 2017;25. 2. Reker D, Kjelgaard-Petersen CF, Siebuhr AS, Michaelis M, Gigout A, Karsdal MA, et al. Sprifermin (rhFGF18) modulates extracellular matrix turnover in cartilage explants ex vivo. J Transl Med. 2017;15. 3. Hochberg MC, Guermazi A, Guehring H, Aydemir A, Wax S, Fleuranceau-Morel P, et al. Effect of Intra-Articular Sprifermin vs Placebo on Femorotibial Joint Cartilage Thickness in Patients With Osteoarthritis. JAMA. 2019

Intra-articular sprifermin reduces cartilage loss in addition to increasing cartilage gain independent of location in the femorotibial joint: post-hoc analysis of a randomised, placebo-controlled phase II clinical trial

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...

Efficacy and safety of intra-articular Sprifermin in symptomatic radiographic knee osteoarthritis: pre-specified analysis of 3-year data from a 5-year randomized, placebo-controlled, phase II study

Efficacy and safety of intra-articular Sprifermin in symptomatic radiographic knee osteoarthritis: pre-specified analysis of 3-year data from a 5-year randomized, placebo-controlled, phase II study

Intra-articular sprifermin reduces cartilage loss in addition to increasing cartilage gain independent of femorotibial location: a post-hoc analysis of a randomized, placebo-controlled phase ii clinical trial

Intra-articular sprifermin reduces cartilage loss in addition to increasing cartilage gain independent of femorotibial location: a post-hoc analysis of a randomized, placebo-controlled phase ii clinical trial

Intraarticular sprifermin (recombinant human fibroblast growth factor 18) in knee osteoarthritis: a randomized, double-blind, placebo-controlled trial.

To evaluate the efficacy and safety of intraarticular sprifermin (recombinant human fibroblast growth factor 18) in the treatment of symptomatic knee osteoarthritis (OA). The study was a randomized, double-blind, placebo-controlled, proof-of-concept trial. Intraarticular sprifermin was evaluated at doses of 10 μg, 30 μg, and 100 μg. The primary efficacy end point was change in central medial femorotibial compartment cartilage thickness at 6 months and 12 months as determined using quantitative magnetic resonance imaging (qMRI). The primary safety end points were nature, incidence, and severity of local and systemic treatment-emergent adverse events (AEs) and acute inflammatory reactions, as well as results of laboratory assessments. Secondary end points included changes in total and compartment femorotibial cartilage thickness and volume as assessed by qMRI, changes in joint space width (JSW) seen on radiographs, and pain scores on the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC). One hundred ninety-two patients were randomized and evaluated for safety, 180 completed the trial, and 168 were evaluated for the primary efficacy end point. We found no statistically significant dose response in change in central medial femorotibial compartment 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 had improved WOMAC pain scores, with statistically significantly less improvement at 12 months in patients receiving the 100-μg dose of sprifermin as compared with those receiving placebo. There was no significant difference in serious AEs, treatment-emergent AEs, or acute inflammatory reactions between sprifermin and placebo groups. No statistically significant relationship between treatment group and reduction in central medial femorotibial compartment cartilage thickness was observed; however, prespecified structural secondary end points showed statistically significant dose-dependent reductions after sprifermin treatment. Sprifermin was not associated with any local or systemic safety concerns.