Nature Medicine | Efficacy of Nanobody SLK, which Dual Inhibits IL-17A and IL-17F, in Active Psoriatic Arthritis

This study demonstrates that SLK shows significant clinical efficacy in the treatment of active psoriatic arthritis (PsA) and is well tolerated, providing new directions for future targeted therapies.

 

Literature Overview

This article, titled "Sonelokimab, an IL-17A/IL-17F-inhibiting nanobody for active psoriatic arthritis: a randomized, placebo-controlled phase 2 trial", published in "Nature Medicine", reviews and summarizes the results of a phase 2 clinical trial of the nanobody SLK for active psoriatic arthritis (PsA). The study evaluated the efficacy and safety of SLK under different doses and administration regimens and compared it with placebo and adalimumab (ADA). The results showed that SLK significantly outperformed the placebo on key clinical endpoints, such as ACR50 and PASI90, and also demonstrated higher efficacy on secondary endpoints, such as ACR70+PASI100. Additionally, SLK exhibited good tolerability with a low incidence of adverse events, offering a promising candidate for future PsA treatments.

Background Knowledge

Psoriatic arthritis (PsA) is a chronic inflammatory disease closely associated with the overexpression of IL-17 family cytokines. Currently, although multiple biologics are available for treatment, only about one-third of patients achieve minimal disease activity (MDA) within six months of therapy. Therefore, optimizing dual inhibition strategies targeting both IL-17A and IL-17F may provide more effective disease control. Nanobody SLK, a therapeutic agent derived from camelid heavy-chain antibodies (~40 kDa), may more easily accumulate at inflammatory sites due to its small molecular weight and albumin-binding capability, particularly in hard-to-reach areas such as enthesitis and dactylitis. Previous studies have demonstrated the clinical efficacy of SLK in psoriasis and hidradenitis suppurativa, but its application in PsA has not been extensively studied. This research fills this gap, offering crucial evidence for the potential use of SLK in PsA treatment.

 

 

Research Methods and Experiments

This study is a global, randomized, double-blind, placebo-controlled phase 2 clinical trial (ARGO trial) that enrolled 207 patients aged ≥18 years with active PsA. Patients were randomly assigned to receive SLK at 60-mg or 120-mg, divided into a withdrawal (WI) or non-withdrawal (NI) group, or to receive placebo (PBO) or adalimumab (ADA) as control groups. The primary endpoint was the ACR50 response rate at week 12, while secondary endpoints included ACR20 and PASI90 response rates. The study also evaluated additional clinical endpoints such as ACR70, PASI75, PASI100, MDA, and patient-reported outcomes (e.g., PGA, PsAID-12, PtAAP, BASDAI, HAQ-DI). Safety endpoints included assessments of treatment-emergent adverse events (TEAEs).

Key Conclusions and Perspectives

• At week 12, ACR50 response rates in the 60-mg WI and 120-mg WI SLK groups were 46.3% and 46.5%, respectively, significantly higher than in the placebo group (20.0%)
• At week 12, ACR20 response rates in the 60-mg WI and 120-mg WI SLK groups were 78.0% and 72.1%, respectively, both significantly superior to the placebo group (37.5%)
• At week 12, PASI90 response rates in the 60-mg WI and 120-mg WI SLK groups were 76.9% and 59.3%, respectively, both significantly higher than the placebo group (15.4%)
• At week 24, SLK treatment groups showed sustained improvements in high-threshold composite endpoints such as ACR70+PASI100 and MDA, with 48% of patients in the 120-mg WI group achieving MDA
• SLK was well tolerated, with the most common adverse events including nasopharyngitis, upper respiratory tract infections, injection-site erythema, and headache, and a low incidence of oral candidiasis (2.4%-2.1%)
• In key subgroups (e.g., female patients, weight ≥100 kg, no prior MTX treatment), the efficacy of SLK was consistent, suggesting broad applicability across diverse populations

Research Significance and Prospects

This study provides preliminary evidence supporting the use of SLK in treating active PsA, suggesting that a dual inhibition strategy targeting both IL-17A and IL-17F may surpass current single-target therapies. Due to its small molecular weight and albumin-binding properties, SLK may accumulate more efficiently in inflammatory tissues, especially in hard-to-reach areas, offering new insights for optimizing treatment strategies. Future phase 3 trials with larger cohorts are needed to further confirm the efficacy and safety of SLK and explore its role in different disease subtypes. Moreover, subgroup analyses from this study suggest that SLK is highly effective in female patients and those with higher body weight, providing a basis for personalized treatment strategies. Overall, SLK shows promising potential as a next-generation biologic agent for PsA therapy.

 

 

Conclusion

This study, "Sonelokimab, an IL-17A/IL-17F-inhibiting nanobody for active psoriatic arthritis: a randomized, placebo-controlled phase 2 trial" published in "Nature Medicine", provides crucial evidence supporting the efficacy and safety of SLK in treating active psoriatic arthritis (PsA). The results indicate that SLK significantly outperforms placebo on multiple key clinical endpoints, including ACR50, ACR20, and PASI90, with further improvement observed at week 24. Additionally, SLK shows good tolerability with a low incidence of adverse events, and consistent efficacy across subgroups, including females, patients with weight ≥100 kg, and those not previously treated with MTX. This research not only highlights the therapeutic potential of SLK in PsA but also supports dual-targeting strategies based on nanobodies for future treatment. Although further phase 3 trials are necessary for validation, the initial results of SLK offer new hope for PsA patients and may drive the development of next-generation biologics.

 

Iain B McInnes, Laura C Coates, Philip J Mease, Christopher T Ritchlin, and Joseph F Merola. Sonelokimab, an IL-17A/IL-17F-inhibiting nanobody for active psoriatic arthritis: a randomized, placebo-controlled phase 2 trial. Nature Medicine.