A novel therapeutic approach targeting two key inflammatory cytokines in psoriatic arthritis (PsA) has shown encouraging clinical results, according to a recent phase 2 study published in Nature Medicine. The therapy, sonelokimab, is a nanobody designed to simultaneously inhibit interleukin-17A (IL-17A) and interleukin-17F (IL-17F), two closely related cytokines that play central roles in PsA pathogenesis.
IL-17A and IL-17F are isoforms of the IL-17 cytokine family and are overexpressed across multiple tissues involved in PsA, including skin, synovium, and entheses. Both cytokines form pro-inflammatory homodimers and heterodimers that amplify local and systemic inflammation. Although IL-17A is considered more biologically potent and was the initial therapeutic target in PsA, IL-17F is often preferentially elevated in psoriatic tissues. This differential expression suggests that selective inhibition of IL-17A alone may leave residual IL-17F–driven inflammation unchecked, providing a strong rationale for dual inhibition to achieve more complete disease control.
Sonelokimab belongs to a newer class of biologic therapies known as nanobodies, which are derived from naturally occurring heavy-chain-only antibodies found in camelids. These antibodies lack light chains and the CH1 domain, resulting in smaller molecules with unique structural and functional properties. The antigen-binding variable domain (VHH) retains full specificity and affinity and can be engineered into compact single-domain antibodies measuring approximately 12–14 kDa. Nanobodies offer several potential advantages over conventional monoclonal antibodies, including improved tissue penetration, flexible molecular engineering, and the ability to create multi-specific constructs.
Sonelokimab is composed of three VHH domains that bind IL-17A, IL-17F, and albumin. This trivalent design enables high-affinity neutralization of both IL-17A and IL-17F, effectively blocking signaling from all biologically relevant dimer combinations. The albumin-binding domain prolongs systemic half-life and may promote preferential accumulation in albumin-rich sites of chronic inflammation and tissue edema. With a predicted molecular weight of approximately 40 kDa, substantially lower than the 150 kDa typical of conventional monoclonal antibodies, sonelokimab is hypothesized to achieve enhanced penetration into inflamed and difficult-to-reach tissues, a key consideration in a heterogeneous disease such as PsA.
The phase 2 randomized, double-blind, placebo-controlled trial enrolled 207 patients with active PsA. Participants were randomized to receive sonelokimab at doses of 120 mg every four weeks with induction, 60 mg every four weeks with induction, 60 mg every four weeks without induction, placebo, or adalimumab as an active reference arm. The primary endpoint of an American College of Rheumatology 50% improvement (ACR50) response at week 12 was met by both induction regimens. ACR50 responses were observed in 46.3% of patients receiving 60 mg with induction and 46.5% of those receiving 120 mg with induction, compared with 20.0% in the placebo group, with statistically significant odds ratios favoring sonelokimab.
Secondary endpoints further supported the efficacy of dual IL-17A/IL-17F inhibition. At week 12, ACR20 responses were achieved by 78.0% of patients in the 60-mg induction group and 72.1% in the 120-mg induction group, compared with 37.5% in the placebo arm. Skin responses were similarly robust, with Psoriasis Area and Severity Index 90 (PASI 90) responses reported in 76.9% of patients receiving 60 mg with induction and 59.3% of those receiving 120 mg with induction, versus 15.4% with placebo. By week 24, high-threshold composite outcomes demonstrated sustained and deep responses, with up to 48% of patients in the 120-mg group achieving ACR70 combined with PASI 100, and 61% of patients in the 60-mg group reaching minimal disease activity.
The safety profile of sonelokimab was consistent with that expected for therapies targeting the IL-17 pathway. The most frequently reported treatment-emergent adverse events included nasopharyngitis, upper respiratory tract infection, injection-site erythema, and headache. Mild to moderate oral candidiasis occurred in a small number of patients across the sonelokimab treatment groups, with no new or unexpected safety signals identified.
These findings build on earlier studies demonstrating the efficacy of sonelokimab in plaque psoriasis and hidradenitis suppurativa, a disease characterized by deep, difficult-to-access inflammatory lesions. The results of the PsA phase 2 trial support the continued clinical development of sonelokimab, which is currently being evaluated in two ongoing phase 3 trials: IZAR-1 in biologic-naïve patients with PsA and IZAR-2 in patients with inadequate response or intolerance to tumor necrosis factor inhibitors. If confirmed in phase 3 studies, this nanobody-based dual IL-17A and IL-17F inhibition strategy could represent a meaningful advance in the management of psoriatic arthritis, offering more comprehensive control of both joint and skin disease.
Reference
- McInnes IB, Coates LC, Mease PJ, Ogdie A, Kavanaugh A, Eder L, Schett G, Kivitz A, McGonagle D, Brennan N, Godwood A, Cullen E, Reich K, Ritchlin CT, Merola JF. Sonelokimab, an IL-17A/IL-17F-inhibiting nanobody for active psoriatic arthritis: a randomized, placebo-controlled phase 2 trial. Nat Med. 2025 Dec;31(12):4160-4171.