Recibokibart, an anti-IL-36 receptor monoclonal antibody, for treating generalized pustular psoriasis: Phase 1b trial

Abstract

Inhibiting the interleukin-36 pathway has demonstrated promising results in managing generalized pustular psoriasis (GPP),^1-4 a severe and potentially life-threatening inflammatory skin condition.⁵ Spesolimab is currently the only approved biologic specifically targeting IL-36R for GPP.^{1, 2, 6} Recibokibart, a novel human anti-IL-36R IgG1 monoclonal antibody with unique complementarity-determining region (CDR) sequences⁷ has demonstrated comparable affinity for IL-36R and comparable IC₅₀ for IL-6 secretion on human intestinal fibroblasts to spesolimab (KD: 0.104 nM vs. 0.112 nM, IC₅₀:0.338 nM vs. 0.418 nM). Recibokibart has demonstrated favourable safety and tolerability in two trials involving healthy subjects: a single-dosing study⁸ (NCT05064345) and a multiple-dosing study (NCT05460455). The development of recibokibart would potentially expand the treatment options available for GPP.

We report the safety and efficacy results from an open-label, single-arm phase 1b study (NCT05512598) of recibokibart in patients experiencing an acute GPP flare of moderate-to-severe intensity. This study was conducted in six hospitals in China between January and November 2023. Eligible patients received a single dose of recibokibart at 15 mg/kg intravenously on Day 1. The primary endpoint, focusing on safety, was assessed for up to 90 days, while efficacy, the key secondary endpoint, was evaluated for up to 12 weeks. Disease severity was assessed by GPP-specific scales⁹ including Generalized Pustular Psoriasis Physician Global Assessment (GPPGA), Generalized Pustular Psoriasis Area and Severity Index (GPPASI) and Japan Dermatology Association GPP Severity Index (JDA-SI).

Nine patients were enrolled with eight completing the study. At baseline, the mean (SD) age was 48.0 (9.63) years. Five patients (55.54%) were females. Six patients (66.67%) had the IL36RN gene mutation. All patients had a GPPGA total score of 3 or 4 (moderate or severe) and a GPPGA pustulation score of 3 or 4. The mean (SD) GPPASI and JDA-SI were 37.54 (15.23) and 11.0 (2.45), respectively.

Seven patients (77.78%) reported treatment-emergent adverse events (TEAEs), all of which were graded as mild or moderate. No serious adverse event reported, and no patients withdrew due to TEAEs. Four patients (44.44%) reported drug-related TEAEs. The most common TEAEs (≥2 patients) were anaemia, itching, upper respiratory tract infection, hyperuricemia and hyperlipidaemia.

Recibokibart demonstrated a rapid onset of action. At Week 1, a GPPGA total score of 0/1 (clear/almost clear skin) was achieved in four patients (44.44%). Three patients (33.33%) achieved a GPPGA pustulation score of 0 (no visible pustules) and seven patients (77.78%) achieved the GPPGA pustulation score of 0/1 (no/almost no visible pustules) at Week 1. Additionally, there was an average improvement of 59.06% in GPPASI at Week 1 and 51.30% in JDA-SI score at Week 2. GPPGA, Pustulation score, GPPASI and JDA-SI were all maintained up to Week 12 (Table 1). The photographs taken were consistent with these improvements. Representative photographic documentation for two patients was illustrated in Figure 1. A rapid decrease in mean C-reactive protein level was observed from baseline of 110.01 mg/L to the normal level of 5.30 mg/L at Week 2 (Table 1).

This study was the first clinical study of recibokibart in patients with GPP. Recibokibart was demonstrated favourable safety, and the patients achieved rapid and sustained improvements in the pustules, overall lesions and systemic inflammation following a single dose. Recibokibart could potentially serve as a new safe and effective therapeutic option for patients with GPP. However, the limitations of the small sample size and the single-arm design reduced the generalizability of our findings. The efficacy and safety of recibokibart are currently under further evaluation in a larger, randomized, double-blind, placebo-controlled pivotal clinical trial (NCT06231381), which is expected to provide more robust evidence.

This trial was fully funded by Shanghai Huaota Biopharmaceutical Co., Ltd. Prof. Jiucun Wang was supported by the CAMS Innovation Fund for Medical Sciences (2019-12M-5-066).

Qiaoxia Qian, Chi Ma, Guodong Zhou, Xiaolu Situ, Xiuqiang Ma, Yujie Feng, Shi Chen, Yifan Zhan, Qian Chen, and Xiangyang Zhu are full-time employees of Shanghai Huaota Biopharmaceutical Co. Ltd. C.J. and other authors declare no conflicts of interest.

The study protocol was approved by (1) Shandong First Medical University-Affiliated Skin Disease Hospital Medical Ethics Committee; approval # 20230113XZA002; (2) The Second Affiliated Hospital Zhejiang University School of MedicineEthics Committee; approval # (2023) No. 386; (3) Sun Yat-sen Memorial Hospital of Sun Yat-sen University Medical Ethics Committee; approval # SYSYW-2022-287-02; (4) Peking University Third Hospital Medical Scientific Research Ethics Committee; approval # (2022) No. 186–03; (5) Xiangya Hospital of Central South University Medical Ethics Committee; approval # 202304288; and (6) The First Hospital of Hebei Medical University Ethics Committee; approval # [2023] No. 504–01.

The patients in this manuscript have given written informed consent to the publication of their case details.