Interleukin-17 pathway inhibition with brodalumab in early systemic sclerosis: analysis of a single-arm, open-label, phase 1 trial
Description
Systemic sclerosis (SSc) is an autoimmune disease that causes fibrosis of the skin and internal organs. Despite several studies reporting the role of interleukin-17 (IL-17) in SSc, no consensus exists regarding the role of the IL-17 pathway in SSc pathogenesis and progression. We hypothesize a possible relationship between the activated IL-17 pathway and the pathogenesis of SSc; therefore, this single-center trial assessed the pharmacokinetics, safety, and efficacy of multiple subcutaneous injections of the commonly used dosage of brodalumab, a fully human anti–IL-17 receptor A (IL-17RA) monoclonal antibody, in Japanese patients with SSc. To the best of our knowledge, this is the first study assessing the effect of IL-17RA inhibition with brodalumab on human fibrotic lesions in patients with early diffuse cutaneous SSc with moderate-to-severe skin thickening. Eight patients with early SSc involving moderate-to-severe and progressive skin thickening were enrolled. All patients had diffuse cutaneous SSc and met the ACR/EULAR classification criteria for SSc. Seven of the eight patients were women. All patients were treated with brodalumab. Brodalumab demonstrated a greater than expected rapid and significant reduction in the modified Rodnan Skin Score (mRSS), which decreased rapidly at week 4 and was sustained over 52 weeks. A reduction in dermal thickness in the lesional skin was observed consistently with changes in mRSS. In four of the eight patients with finger digital ulcers at baseline, a decrease in the mean number of digital ulcers from baseline was observed at weeks 24 and 52. No changes were observed in the measures of respiratory function assessed by spirometry. In this trial, brodalumab induced a regulatory T-cell (Treg)–dominant Treg/T helper 17 (Th17) balance, decreased the number of immunoglobulin G+ class–switched memory B cells and plasmablasts, and increased the number of transitional B cells compared with those at baseline. In summary, all patients had a decrease in mRSS that exceeded the minimal clinically important difference, together with a reduction in dermal thickness. This rapid, sustained, and significantly high efficacy of brodalumab in reducing fibrotic lesions in SSc could be attributed to its direct effects on fibroblasts and indirect effects by altering B-cell and T-cell subsets. Brodalumab also ameliorated clinical symptoms without any serious treatment emergent adverse events. These results suggest that brodalumab may represent a new treatment drug for patients with SSc, and it is currently being evaluated in a double-blind, placebo-controlled phase 3 trial with a larger sample size.
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This study included a screening period of up to 30 days from the date of obtaining informed consent to enrollment, a 52-week treatment period for this analysis, and an extension period from administration at week 52 to the date of receiving drug approval. Patients aged 18 to ≤70 years with the ability to provide voluntary written informed consent were enrolled. They were required to meet the criteria for systemic sclerosis (SSc) diagnosis according to the Diagnostic Criteria, Severity Classification, and Clinical Practice Guidelines of SSc at screening; present with the first symptoms of sclerosis other than Raynaud’s phenomenon within 60 months before enrollment; and have SSc presentation involving moderate-to-severe skin thickening, with a modified Rodnan Skin Score (mRSS) of 10 to <30 at screening and at enrollment. They were also required to meet one or more of the following criteria: (1) new diagnosis of diffuse cutaneous SSc within the past 1 year; (2) an increase of ≥3 in mRSS at screening compared with that at the most recent assessment conducted 1-6 months before screening; (3) one newly identified lesion with an increase of ≥2 in mRSS at screening compared with that at the most recent assessment conducted 1-6 months before screening; and (4) two newly identified lesions with an increase of ≥1 in mRSS at screening compared with that at the most recent assessment conducted 1-6 months before screening. On the day of enrollment, considered day 1 (week 0), eligible patients received brodalumab 210 mg subcutaneously at weeks 1 and 2, and every 2 weeks thereafter until week 50, and this analysis was performed at week 52. Restricted concomitant medications included oral corticosteroids (≤10 mg/day of prednisolone), and no change in the dosing regimen was allowed. Prohibited concomitant medications included antifibrotic agents, immunosuppressive agents, imatinib, D penicillamine, and other biological products. At each scheduled visit, brodalumab was administered after completing all planned examinations. In principle, the same evaluator performed the measurements and assessments of mRSS and number of digital ulcers throughout the study. The measures of respiratory function were performed using spirometry. The dermal thickness of the lesion skin was assessed histopathologically. At enrollment, a skin biopsy sample was obtained from one site of a pathologically thickened skin lesion on the left forearm. Biopsy samples at weeks 24 and 52 were taken from the periphery of the site collected at enrollment. The thickness of the dermal layer was measured on hematoxylin-eosin–stained specimen slides and using the microscope image software program cellSens Standard. Peripheral blood lymphocyte subset testing was performed using flow cytometry. A sample size of at least six patients to be treated with brodalumab was specified based on the study type and was not designed to account for the significance level or power.
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Kyowa Kirin Pharmaceutical Development