Intraarticular Sprifermin (Recombinant Human Fibroblast Growth Factor 18) in Knee Osteoarthritis: A Randomized, Double‐Blind, Placebo‐Controlled Trial

Abstract

Objective. To evaluate the efficacy and safety of intraarticular sprifermin (recombinant human fibroblast growth factor 18) in the treatment of symptomatic knee osteoarthritis (OA).Methods. The study was a randomized, doubleblind, placebo-controlled, proof-of-concept trial. Intraarticular sprifermin was evaluated at doses of 10 g, 30 g, and 100 g. 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). Results. 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-g 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. Conclusion. No statistically significant relation-ClinicalTrials.gov identifier: NCT01033994.

Deletion of the PH-domain and Leucine-rich Repeat Protein Phosphatase 1 (Phlpp1) Increases Fibroblast Growth Factor (Fgf) 18 Expression and Promotes Chondrocyte Proliferation

“…Fgf18 also promotes chondrogenesis, chondrocyte proliferation and cartilage regeneration in surgically induced models of osteoarthritis (31,32,43,(52)(53)(54)(55)(56). In clinical trials, intra-articular injections of recombinant Fgf18 resulted in dose-dependent increases in total cartilage content, even though thickness of the central medial femorotibial compartment cartilage was unchanged (57). Thus, the effects of Fgf18/Fgfr signaling are complex and may be temporally and spatially controlled.…”

Emerging targets in osteoarthritis therapy

“…FGF-18 via FGFR3 also protects against loading-induced damage in cartilage explants ex vivo [130] and intraarticular administration of FGF18 protects against cartilage damage in a rat model of injury-induced arthritis [131] Thus, there is considerable interest in the potential of anabolic factors such as FGF-18 for enhancing cartilage regeneration with tissue engineering approaches [132]. However a recent proof-of-concept trial with human recombinant FGF-18, sprifermin, showed statistically significant dose-dependent improvement in pre-specified secondary structural end points by MRI, radiographic joint space narrowing, and WOMAC pain scores [133]. …”

The Role of Synovial Macrophages in Rheumatoid Arthritis and Osteoarthritis: Its Implications for Radiosynovectomy

“…In a rat model of OA, intra-articular injections of sprifermin induced a signifi cant, dosedependent reduction in cartilage degeneration. In a recent clinical study, sprifermin had no effect on medial femorotibial compartment cartilage volume, although it did signifi cantly and dose dependently reduce the loss of total and lateral femorotibial compartment cartilage volume [ 82 ]. In stark contrast to the situation in RA, where there is almost an embarrassment of riches when it comes to both biologics and small-molecule targeted therapy, the search for a disease-modifying antiosteoarthritis drug has thus far ended in disappointment, with a number of promising drug candidates failing clinical trials.…”