In our Exclusive Executive Summaries section, we are synthesizing series of current publications around focus topics. These “mini-reviews” provide short overviews over key areas of interest, as well as archives for downloading PDFs of the relevant articles (click the reference# to download the pdf [when available open access]).
Enjoy reading and do not hesitate to contact us for questions or further discussion.
The Sprifermin Program
Several Original Articles published 2013-2021 provide exciting insights into the structural benefits observed with Sprifermin in the Phase I, IIa, and IIb study.
The Sprifermin program is unique amongst potential disease modifying osteoarthritis drug (DMOAD) trials, as it encompasses several large multicenter randomized control trials, providing a tremendously rich resource for designing future DMOAD trials. With 5-year follow-up, FORWARD (Phase IIb) was the longest OA trial, using MR imaging, to date.
The phase I “First in Man” (FIH) randomized control trial (RCT) studied the safety and potential efficacy of intra-articular sprifermin (rhFGF18) in 73 knee osteoarthritis (KOA) patients, scheduled for knee replacement. The study was suggestive of an anabolic effect on medial femorotibial cartilage, and of a reduction of knee replacement rates, without these observations reaching statistical significance (1).
In the following phase IIa “Proof of Concept” POC study, 192 KOA patients were randomized to placebo or 1 of 3 sprifermin doses, injected 3 times over 3 weeks, and the same set of injects again 3 months later (2). In this study, the dose-response in the primary structural endpoint (central medial femorotibial cartilage thickness) was distinguishable, but did not reach statistical significance, at months 3, 6 or 12 follow-up. However, rhFGF18 significantly increase cartilage thickness in the lateral and total (medial and lateral) femorotibial compartment relative to placebo-injected knees (2). There was a substantial reduction in knee pain in all study participants over 12 months, but no statistically significant effect of rhFGF18 in this study relative to placebo. Location-independent analysis of cartilage thickness change (see another Executive Summary on this Page) revealed that rhFGF18 not only increased cartilage thickness (at potentially non-useful locations in the joint), but effectively reduced cartilage loss (3).
In the phase IIb study (FGF-18 Osteoarthritis Randomized Trial with Administration of Repeated Doses / FORWARD), 549 participants were randomized to 4 dose and 1 placebo group, with injection cycles at screening, 6,12, and 18 months (4). The patients included displayed Kellgren Lawrence Grade (KLG) 2-3 (medial or lateral disease), with a medial radiographic joint space width (JSW) of >2.5mm. This study found a statistically significant dose-dependent effect on the primary endpoint (total femorotibial cartilage thickness) as well as the central medial femorotibial subregion at year 2 and 3 (4), but no effect on medial radiographic JSW. Reduction in WOMAC pain (approximately 50%) was again seen in all 5 groups, but not statistically significantly greater than in placebo (4). Post-hoc analysis using location-independent measurement technology (see above) demonstrated a doubling of the cartilage thickening score over 2y with the highest sprifermin dose compared with placebo and with healthy Osteoarthritis Initiative (OAI) reference subjects. There also was a significant reduction of the cartilage thinning score to -0.43mm with the highest sprifermin dose, compared wtih -0.77mm in placebo and with -0.34mm in healthy reference subjects from the OAI (5).
Pertinent with the inclusion criteria, only a small number of FORWARD participants displayed advanced KOA. In a post-hoc analysis of a subcohort at risk (SAR) (6) that included the patients with more severe radiographic disease and pain, femorotibial cartilage thickness gain with the highest sprifermin dose vs. placebo was as high as for the total cohort (0.06 and 0.05 mm at 2 and 3y, respectively) (6) . In this cohort, with clinically and structurally advanced disease, sprifermin treatment translated into a statistically significant and clinically relevant benefit with the highest dose vs. placebo (-8.75 on a 0-100 WOMAC pain scale vs. only 0.97 for the total cohort) (6) . These findings suggest that the anabolic effect on cartilage is not less pronounced in advanced vs. early KOA, whereas translation of structure modification to symptom benefit appears to be more likely when KOA has progressed further.
The 5-year follow-up in FORWARD confirmed that post-treatment cartilage loss was similar amongst the sprifermin- and placebo-treated participants, and that the structural benefit achieved during the treatment period (0.05 mm total femorotibial cartilage thickness between the highest sprifermin dose group vs. placebo) was maintained for another 3 years (7). These findings suggest that the cartilage produced with induction of sprifermin appears to withstand in a normal mechanical environment and provide a lasting benefit after cessation of treatment (7). After 5 years, this structural benefit was also maintained in the SAR, with translation of structure modification into a clinical benefit still apparent after year 5 (7).
More studies pending publication, also see News Section for recent conference contributions
1. Dahlberg LE, Aydemir A, Muurahainen N, Gühring H, Fredberg Edebo H, Krarup-Jensen N, et al.
A first-in-human, double-blind, randomised, placebo-controlled, dose ascending study of intra-articular rhFGF18 (sprifermin) in patients with advanced knee osteoarthritis.
Clin Exp Rheumatol 2016;34:445–50.
2. Lohmander LS, Hellot S, Dreher D, Krantz EFW, Kruger DS, Guermazi A, et al.
Intraarticular sprifermin (recombinant human fibroblast growth factor 18) in knee osteoarthritis: a randomized, double-blind, placebo-controlled trial.
Arthritis Rheumatol (Hoboken, NJ) 2013;66:1820–1831.
3. Eckstein F, Wirth W, Guermazi A, Maschek S, Aydemir A.
Intra-articular sprifermin not only increases cartilage thickness, but also reduces cartilage loss - location-independent post hoc analysis using MR imaging.
Arthritis Rheumatol 2015;67:2916–2922.
4. 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;322:1360–1370.
5. Eckstein F, Wax S, Aydemir A, Wirth W, Maschek S, Hochberg M.
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.
Ann Rheum Dis 2020;79:525–528.
6. Guehring H, Moreau F, Daelken B, Ladel C, Guenther O, Bihlet AR, et al.
The effects of sprifermin on symptoms and structure in a subgroup at risk of progression in the FORWARD knee osteoarthritis trial.
Semin Arthritis Rheum 2021;51:450–456.
7. Eckstein F, Hochberg MC, Guehring H, Moreau F, Ona V, Bihlet AR, et al.
Long-term structural and symptomatic effects of intra-articular sprifermin in patients with knee osteoarthritis: 5-year results from the FORWARD study.
Ann Rheum Dis 2021;80:1062–1069.