Sprifermin maintains long-term cartilage structural improvements in knee osteoarthritis
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Improvements in articular cartilage thickness among patients with knee osteoarthritis who received sprifermin, versus placebo, during the FORWARD trial were maintained over a 3.5- to 4-year follow-up period, according to data.
“There is an urgent need for disease-modifying osteoarthritis drugs (DMOADs) that improve symptoms and inhibit structural disease progression,” Felix Eckstein, MD, of Paracelsus Medical University, in Salzburg, Austria, and colleagues wrote in Annals of the Rheumatic Diseases. “Many DMOAD trials have had limited success or yielded negative results, with the heterogeneous nature of OA and insufficient trial follow-up times being potential contributors.”
“FORWARD (FGF-18 Osteoarthritis Randomized Trial with Administration of Repeated Doses) was a 5-year, randomized clinical trial that evaluated the efficacy and safety of sprifermin among 549 patients with symptomatic radiographic knee OA,” they added. “The 2-year and 3-year data were reported recently: Dose-dependent modification of [total femorotibial joint (TFTJ)] cartilage thickness with sprifermin was demonstrated at years 2 and 3, and a mean difference of 0.05mm in TFTJ cartilage thickness between the highest sprifermin dose (100µg every 6 months (q6mo); 0.03mm gain) and placebo (0.02mm loss) was observed.”
To report on the long-term structural and symptomatic efficacy and safety of sprifermin in the FORWARD trial, as well as in a “subgroup at risk” — featuring patients in FORWARD with narrower medial or lateral minimum joint space width and higher pain on the Western Ontario and McMaster Universities Osteoarthritis Index than the overall study population — Eckstein and colleagues reported findings up to year 5, or 3.5 to 4 years after the last sprifermin treatment. Participants in the multicenter, randomized, double-blind, placebo-controlled trial were randomly assigned to receive intra-articular sprifermin 100µg or 30µg every 6 or 12 months, or placebo, for 18 months.
The “subgroup at risk” population included 161 participants with a baseline minimum radiographic joint space width of 1.5 mm to 3.5 mm, and a WOMAC pain score of 40 to 90. A total of 378 patients completed the 5-year follow-up.
According to the researchers, sprifermin demonstrated a significant dose response in total femorotibial joint cartilage thickness (P < .001), as well as a 0.05mm mean difference with the 100-µg dose given every 6 months, compared with placebo (95%CI, 0- 0.1), sustained to year 5. In addition, WOMAC pain scores improved approximately 50% from baseline in all groups. No participants who received 100µg every 6 months underwent replacement of the treated knee.
Regarding safety, 96% to 98% of patients treated with sprifermin, and 98% of those who received a placebo, reported adverse events. Most adverse events were mild, moderate or considered unrelated to treatment, the researchers wrote. Less than 10% of participants withdrew from the study due to adverse events.
In the subgroup at risk, differentiation in WOMAC pain between sprifermin 100µg every 6 months and placebo at year 3 was maintained to year 5 (–10.08; 95% CI, –25.68 to 5.53).
“DMOADs that not only alleviate symptoms but also modify structure are an important and unmet clinical need for knee OA,” Eckstein and colleagues wrote. “Sufficient follow-up in DMOAD trials may be necessary to demonstrate that the structural benefit of a DMOAD is maintained and that structure modification eventually translates into clinical benefit. FORWARD is the longest DMOAD study reported to date.”
“The results of the current analyses show that the efficacy of sprifermin, as measured by both the dose-effect and the mean difference versus placebo in TFTJ cartilage thickness at year 2, was maintained up to year 5, that is, for at least 3.5 years post-active treatment,” they added. “These findings suggest that intra-articular sprifermin has a sustained effect on articular cartilage modification in patients with knee OA, with no detectable systemic exposure or new safety signals observed up to year 5.”
Perspective
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David A. McLain, MD, MACR, FACP, FRCP
One of the major unmet needs in rheumatology, and medicine, for that matter, is for a disease-modifying osteoarthritis drug (DMOAD). Surprisingly, OA is also the most expensive condition for which privately insured patients were hospitalized, accounting for over $6.2 billion in hospital costs. Approximately 27 million Americans have osteoarthritis, which affects more women than men, according to the CDC and leads to $27 billion in expenditures annually in the United States.
By 2030, it is projected that 25% of the U.S. population — nearly 67 million people — will have physician-diagnosed arthritis. Although there is some inflammation in OA, the use of DMARDs and even biologics have shown no significant pain relief over placebo, even in erosive osteoarthritis, as reported by Persson and colleagues in a 2018 meta-analysis published in Rheumatology.
Sprifermin (recombinant human fibroblast growth factor 18) is in clinical development as a potential DMOAD. In vitro studies have shown that sprifermin activates the FGF receptor 3 (FGFR3) on the surface of the chondrocytes. By signaling through this receptor, sprifermin induces cell proliferation and formation of extracellular matrix (ECM) molecules; type 2 collagen (COLII) and aggrecan, while promoting the chondrocyte phenotype (vs. hypertrophic or fibroblast phenotypes).
ECM is composed primarily of the network COLII and an interlocking mesh of fibrous proteins and proteoglycans (PGs), hyaluronic acid (HA) and chondroitin sulfate (CS). Aggrecan is a high molecular weight proteoglycan. It exhibits a bottlebrush structure, in which chondroitin sulfate and keratan sulfate glycosaminoglycan (GAG) chains are attached to an extended protein core.
Together, these results indicate that sprifermin induces cartilage formation by increasing the chondrocyte population and increased ECM production. However, with permanent administration of sprifermin, cell proliferation was strongly stimulated at the expense of ECM production.
As is often seen in medicine, the process of cartilage regeneration is a delicate balance between cellular and extracellular changes. In vivo animal studies have shown that intra-articular sprifermin prevents cartilage degradation and stimulate repair of damaged cartilage in traumatic OA models.
A first-in-man study in OA patients who were scheduled for knee joint replacement, delivered first indications in humans that intra-articular sprifermin may have anabolic effects on joint cartilage by stimulating chondrocyte proliferation. However, in a phase Ib clinical study of intra-articular sprifermin, the primary end point, reduction of cartilage loss, was not met. The present study of sprifermin is a step in the direction of developing a DMOAD given the delicate balance of the dose/response and the time for differences to be seen between treatment and placebo.
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