Background: A putative disease-modifying osteoarthritis drug, “Sprifermin” was studied by a phase 2B randomized controlled clinical trial (FORWARD RCT - NCT01919164). Given at a 100µg dose, sprifermin increased cartilage thickness, both in absolute terms and compared with placebo [1]. In the full cohort with MRI results (mITT), this effect did, however, not lead to a pain relief greater than placebo [1]. FORWARD contained patients with a variety of radiographic disease stages (KLG 2 or 3, with a medial minimum joint space width (JSW) > 2.5mm). Although all patients had to display > 40mm pain levels at screening, not all of them exceeded that threshold at the actual baseline measurement [2].

Objectives: In this post-hoc analysis, we aim to elucidate whether structural treatment effects on cartilage (thickness) by sprifermin differ between severity strata of symptomatic (WOMAC) and radiographic disease severities (KLG and OARSI JSN grade (max. of med. or lat. compartment). These findings may inform future clinical trials on Sprifermin on at which stage is treatment (most) effective, and at which translation into clinical benefit can be expected.

Methods: Total femorotibial joint (TFTJ) cartilage thickness change at year (Y) 2 follow-up by MRI represented the primary endpoint, WOMAC pain being secondary [1]. Patients aged 40–85 years with primary symptomatic and radiographic TFTJ OA in the target knee (KLG 2 or 3; medial mJSW ≥2.5 mm) were studied. Cartilage thickness was determined quantitatively from 1.5T-3T MRI by expert readers, using proprietary software (Chondrometrics). The current analysis focused on the 2Y MRI TFTJ cartilage thickness change for the two highest sprifermin dose groups (100µg given every 6 or 12 months combined) vs. placebo. The Hedges G (as a sample-size-independent effect size measure) was determined, with 95% CIs obtained by bootstrapping. We studied the modified intent to treat cohort with 24 month data ( ^24M mITT), and the so-called “subcohort at risk” (SAR) [2] with baseline WOMAC pain >40 and more severe radiographic involvement by mJSW criteria.

Results: Of 549 FORWARD patients randomized, 474 completed 2Y follow-up. WOMAC pain and mJSW were well-balanced between the sprifermin-treated and placebo arm. 69% of the ^24M mITT were female; the median age was 67 years (range 45-80), and median BMI 29.6 (18.6-51.3). The treatment effect (difference in cartilage change between combined 100µg vs. placebo cohorts) was 45.6µm for the ^24M mITT (Hedges G=0.63). Participants with a baseline WOMAC pain score ≥ the median displayed a somewhat small treatment effect on TFTJ cartilage (17±7 µm in the 100µg combined vs. -15±55µm in placebo; Hedges G =0.49 [0.11, 0.86] than those with pain < than the median (37±69µm in the combined vs. -27±84µm in the placebo group; Hedges G =0.86 [0.47, 1.25]. Those with baseline KLG2 displayed a marginally greater treatment effect (30±75µm in the 100µg combined vs. -16±46µm in placebo; Hedges G =0.68 [0.36, 1.00]) than those with KLG3 (13±68µm in the combined vs. -33±11µm in the placebo group; Hedges G =0.55 [0.07, 1.03]). A somewhat stronger difference was observed between knees with and without radiographic JSN; those without JSN (grade 0) showed a stronger treatment effect (50±59µm in the combined vs. -11±45µm in the placebo group; Hedges G =1.09 [0.63, 1.54] than those with a JSN grade >0 (7±79µm in the combined vs. -26±84 µm in the placebo group; Hedges G =0.41 [0.07, 0.75]. Given the relatively small sub-group sizes, none of these differences reached statistical significance. Results in the sub-cohort at risk (SAR) were similar, with Hedges G values for cartilage thickness change being 0.84/0.67 for WOMAC pain < vs. > the median, and 1.02/0.67 for KLG2 vs. 3. Results for JSN differed somewhat (0.59/0.76 for no vs. present JSN), but here the no-JSN group only contained n=12 knees. When studying the symptomatic efficacy of sprifermin in the sub-cohort at risk (SAR), the effect size on the WOMAC was strong in KLG3 knees (-34.4±19.9 in the 100µg dose group vs. -10.6±28.6 in the placebo group; Hedges G -1.03 [-1.71, -0.35]), whereas in KLG2 knees the reduction in pain was weaker in the sprifermin treated than in the placebo group (-33.5±17 vs. 36.9± 8; Hedges G 0.20 [-0.45, 0.85]). Observations on symptoms were similar, albeit not as striking, when stratifying knees by JSN status (data not shown).

Conclusion: These post-hoc data suggest that study participants with greater baseline pain and radiographic involvement tend to display a somewhat weaker anabolic structural response by sprifermin treatment (smaller increase in cartilage thickness vs. placebo) than those with less baseline pain or with lesser radiographic osteoarthritis. However, in a subcohort with advanced disease (SAR), the improvement in symptoms was stronger in knees with more advanced radiographic disease. This observation may be compared to a “full” tire gaining little in performance when inflating more air, whereas a “flat” tire improving considerably even with a small injection of it. In summary whereas structural benefits may be numerically greater in knees with less disease, the translation to symptomatic benefit appears to be stronger in knees with more severe disease.

REFERENCES: [1] Effect of Intra-Articular Sprifermin vs Placebo on Femorotibial Joint Cartilage Thickness in Patients With Osteoarthritis: The FORWARD Randomized Clinical Trial. Hochberg MC, Guermazi A, Guehring H, Aydemir A, Wax S, Fleuranceau-Morel P, Reinstrup Bihlet A, Byrjalsen I, Ragnar Andersen J, Eckstein F. JAMA. 2019, 8;322:1360-1370.

[2] The effects of sprifermin on symptoms and structure in a subgroup at risk of progression in the FORWARD knee osteoarthritis trial. Guehring H, Moreau F, Daelken B, Ladel C, Guenther O, Bihlet AR, Wirth W, Eckstein F, Hochberg M, Conaghan PG. Semin Arthritis Rheum. 2021;51:450-456.

Acknowledgements: FORWARD patients, investigators, and study sites & staff. Chondrometrics GmbH readers for performing the cartilage segmentation. Martin Frenzel for help with the statistical analysis.

Disclosure of Interests: Felix Eckstein Chondrometrics GmbH, Chondrometrics GmbH, Merck KGaA, Galapagos, Servier, Kolon Tissuegene, Novartis, 4P Pharma, Formation Bio, Peptinov, Sanofi, Merck KGaA, Galapagos, Kolon Tissuegene, Novartis, 4P Pharma, Peptinov, Sanofi, NIH, FNIH, European Union, European Space Agency, Wolfgang Wirth Chondrometrics GmbH, Chondrometrics GmbH, Casper Clemmensen NBCD, LEO Pharma, Genmab, Merck KGaA, Wendy Ma Formation Bio, Formation Bio, Alyssa Collins Formation Bio, Formation Bio, Chris Knight Formation Bio, Formation Bio, Sandeep Basnet Formation Bio, Formation Bio.

© The Authors 2025. This abstract is an open access article published in Annals of Rheumatic Diseases under the CC BY-NC-ND license ( http://creativecommons.org/licenses/by-nc-nd/4.0/ ). Neither EULAR nor the publisher make any representation as to the accuracy of the content. The authors are solely responsible for the content in their abstract including accuracy of the facts, statements, results, conclusion, citing resources etc.