Low levels of type II collagen formation (PRO-C2) are associated with response to sprifermin: a pre-defined, exploratory biomarker analysis from the FORWARD study

Bay-Jensen, A.-C.; Manginelli, Angela A.; Karsdal, Morten; Luo, Yunyun; He, Yi; Michaelis, M.; Guehring, H.; Ladel, Christoph

doi:10.1016/j.joca.2021.10.008

Cited by 20 publications

(9 citation statements)

References 28 publications

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“…Moreover, we focused on biochemical markers measured at the baseline of the study, and not their longitudinal changes, as this analysis would be more useful to inform future clinical trials. Longitudinal monitoring of biomarkers can give insight in the pharmacodynamic effects or provide early proof of effectiveness of a compound in interventional clinical trials, however often fail to predict progression in the study population in these trials 34 40–42. Therefore, although longitudinal monitoring of individual biomarkers are only modestly predictive (if at all) of knee OA progression, they might have some utility as patient stratification like described herein for enriching OA trials for progressors 29…”

Section: Discussionmentioning

confidence: 99%

Osteoarthritis endotype discovery via clustering of biochemical marker data

et al. 2022

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ObjectivesOsteoarthritis (OA) patient stratification is an important challenge to design tailored treatments and drive drug development. Biochemical markers reflecting joint tissue turnover were measured in the IMI-APPROACH cohort at baseline and analysed using a machine learning approach in order to study OA-dominant phenotypes driven by the endotype-related clusters and discover the driving features and their disease-context meaning.MethodData quality assessment was performed to design appropriate data preprocessing techniques. The k-means clustering algorithm was used to find dominant subgroups of patients based on the biochemical markers data. Classification models were trained to predict cluster membership, and Explainable AI techniques were used to interpret these to reveal the driving factors behind each cluster and identify phenotypes. Statistical analysis was performed to compare differences between clusters with respect to other markers in the IMI-APPROACH cohort and the longitudinal disease progression.ResultsThree dominant endotypes were found, associated with three phenotypes: C1) low tissue turnover (low repair and articular cartilage/subchondral bone turnover), C2) structural damage (high bone formation/resorption, cartilage degradation) and C3) systemic inflammation (joint tissue degradation, inflammation, cartilage degradation). The method achieved consistent results in the FNIH/OAI cohort. C1 had the highest proportion of non-progressors. C2 was mostly linked to longitudinal structural progression, and C3 was linked to sustained or progressive pain.ConclusionsThis work supports the existence of differential phenotypes in OA. The biomarker approach could potentially drive stratification for OA clinical trials and contribute to precision medicine strategies for OA progression in the future.Trial registration numberNCT03883568.

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Section: Discussionmentioning

confidence: 99%

Osteoarthritis endotype discovery via clustering of biochemical marker data

et al. 2022

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“…In OA, C1M was associated with neuropathic pain in patients scheduled for a total joint replacement [ 31 ]. Moreover, markers of cartilage degradation and formation (e.g., urinary CTX-II, PRO-C2, and PIIANP) are predictive of radiographic progression and symptomatic progression [ 15 , 28 , 40 , 41 ].…”

Section: Discussionmentioning

confidence: 99%

Pathological tissue formation and degradation biomarkers correlate with patient reported pain outcomes: an explorative study

Bay‐Jensen

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Samuals

et al. 2023

Osteoarthritis and Cartilage Open

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“…Bay-Jensen and colleagues recently measured PRO-C2, a serum marker of type II collagen formation (with low levels being prognostic of radiographic progression) in the synovial fluid from participants of the FORWARD study and analyzed if the response in subjects with high or low PRO-C2 levels respond differently to sprifermin. It was shown that PRO-C2 increased over time in response to sprifermin, but not to placebo, and that patients with low serum PRO-C2 levels lost more cartilage thickness over time and grew more cartilage in response to sprifermin versus placebo than patients with high PRO-C2 levels [96].…”

Section: Phase 2 Trialsmentioning

confidence: 99%

Sprifermin for Treatment of Osteoarthritis: Recombinant Fibroblast Growth Factor 18 as a Possible Disease-Modifying Knee Osteoarthritis Drug

2022

PPExMed

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Osteoarthritis (OA) is a major cause of pain and disability in adults, affecting approximately 150 million people worldwide. It is most prevalent in knees and hips. Major risk factors are age, female sex, prior joint injury, and obesity. OA causes significant personal and steeply rising socio-economical costs in ageing populations. OA is characterized by progressive cartilage damage and inflammation. In later stages, it affects the subchondral bone, bone marrow, ligaments, tendons, and nerves und eventually leads to joint failure. Symptoms include pain, joint swelling, and stiffness. Therapies are symptomatic and focus on pain relief and measures to improve mobility, or, ultimately, joint replacement. So far, no drugs that could prevent or slow down disease progression are available. Based on promising in vitro and preclinical studies, recombinant fibroblast growth factor (FGF) 18 (sprifermin; Merck Serono) has come into focus as a potential disease-modifying OA drug (DMOAD). Three randomized controlled trials (RCTs) investigating the safety and efficacy of intraarticularly (i.a.) injected sprifermin application in patients with knee OA have been completed so far. Data from these trials, post hocanalyses and follow-ups provide have evidenced that i.a. sprifermin induced a significant and sustained increase in cartilage thickness and volume without specific adverse effects, but in terms of clinical symptoms or physical joint function sprifermin did not cause significant improvements compared to placebo treatment in whole study populations. However, significant pain reduction was observed in a “subgroup at risk” of patients with more severe disease states, indicating that under certain disease conditions the structural benefit improvements could translate into clinical benefit. This calls for larger RCTs allowing e.g., for disease state or risk factor-specific stratification of patients and longer follow-ups to substantiate the efficacy of sprifermin as a possible DMOAD. This review gives an overview on the prevalence, etiology and socio-economic burden of OA, its pathogenesis as well as the current treatment options of the disease. It summarizes the role of FGF-18 in chondrocyte and cartilage (patho)physiology and addresses the question of evidence for the efficacy and safety of i.a. sprifermin injection in patients with knee OA based on trial outcomes and literature data.

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Low levels of type II collagen formation (PRO-C2) are associated with response to sprifermin: a pre-defined, exploratory biomarker analysis from the FORWARD study

Cited by 20 publications

References 28 publications

Osteoarthritis endotype discovery via clustering of biochemical marker data

Osteoarthritis endotype discovery via clustering of biochemical marker data

Pathological tissue formation and degradation biomarkers correlate with patient reported pain outcomes: an explorative study

Sprifermin for Treatment of Osteoarthritis: Recombinant Fibroblast Growth Factor 18 as a Possible Disease-Modifying Knee Osteoarthritis Drug

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