Emerging therapies and future treatment directions in osteoarthritis

Many therapies for osteoarthritis (OA) have been investigated in recent years [1]. Sprifermin showed benefits in a subgroup with advanced disease. Results for lorecivivint were mixed, with the best results observed for an intermediate dose. Canakinumab had good efficacy, but an increased risk of infections.

Prof. Xavier Chevalier (University Paris-Est Créteil, France) discussed several recent trials investigating OA therapies [1]. First, he addressed a post-hoc analysis of the phase 2 FORWARD trial (NCT01919164), in which the efficacy of sprifermin was assessed in patients with knee OA [2]. Sprifermin is a recombinant form of fibroblast growth factor (FGF)18 and therefore a potent agonist of FGF receptor 2 and 3. The post-hoc analysis assessed the effects of sprifermin on an advanced disease subgroup (defined as medial or lateral minimum joint-space width (mJSW) 1.5–3.5 mm and WOMAC pain scores 40–90 units). A high dose of sprifermin (100 μg once every 6 months) had a higher effect on WOMAC pain scores compared with placebo at 3 years of treatment in the advanced disease subgroup (n=161). This effect was not found for the intention-to-treat (ITT) population (n=549). Moreover, total femorotibial joint cartilage thickness improvements in high-dose sprifermin participants were numerically higher in the advanced disease subgroup versus the ITT population. The advanced disease subgroup showed clinical and structural benefits of sprifermin administration. Therefore, this subgroup should be the target of future sprifermin trials, according to Prof. Chevalier.

Second, a phase 2 randomised placebo-controlled trial investigating the effects of Wnt inhibitor lorecivivint on pain and structural progression in knee OA was discussed [3]. A single 2 mL intra-articular injection of lorecivivint (0.03 mg, 0.07 mg, or 0.23 mg) was compared with placebo (n=114). At 52 weeks post injection, the results were mixed. The intermediate dose of lorecivivint (0.07 mg; n=117) showed the best results in terms of pain reduction, represented by the difference between adjusted mean changes from baseline on WOMAC pain score (all participants: 2.4, P=0.405; unilateral symptomatic: 8.7, P=0.049; unilateral symptomatic without widespread pain: 11.2, P=0.025). A small structural effect was observed as well for the intermediate-dose group, represented as the difference between adjusted mean changes of medial joint space width (all participants: 0.06, P=0.529; unilateral symptomatic 0.39, P=0.021; unilateral symptomatic without widespread pain 0.42, P=0.032).

Third, an exploratory analysis of the CANTOS trial was discussed [4]. In this trial, 10,061 participants with high-sensitivity C-reactive protein and a history of myocardial infarction were included. Subjects were randomised to 50, 150, or 300 mg of IL-1β inhibitor canakinumab, administered subcutaneously every 3 months for a period of 5 years, or placebo. The exploratory study derived from CANTOS trial investigated the risk of total hip or knee joint replacement between the placebo and canakinumab arms. At a median of 3.7 years of follow-up, a remarkable reduction of 42% in total joint replacements was observed for the canakinumab recipients compared with placebo subjects. Prof. Chevalier noted that, although these results are highly interesting, the infection risk among canakinumab users was increased.

Prof. Chevalier argued that these trials reflect the individuality of OA treatment efficacy. “We should adapt to the specificity of a patient’s profile. Many confounding factors influence treatment results in OA patients. Therefore, we need more evidence on therapy efficacy in patient subgroups.” In addition, he argued that it is important to recruit the 30% of patients who show actual disease progression. “We should put more effort in recruiting these patients for future trials, based on features like repeated flares, pain, and accelerated cartilage loss.” Prof. Chevalier concluded that treatment should probably be initiated earlier in the disease. “To obtain a disease-modifying effect of a pharmacological treatment, we should probably initiate when the first minimal changes on X-ray are being observed.”

1. Chevalier X. WIN in OA clinical trials. EULAR 2021 Virtual Congress, 2–5 June.
2. Guehring H, et al. Semin Arthritis Rheum. 2021; 51(2):450-6.
3. Hochberg MC, et al. Arthritis Rheumatol. 2020; 72(10):1694-706.
4. Schieker M, et al. Ann Intern Med. 2020; 173(7):509-15.

 

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Posted on 2 August 202117 May 2024