Interleukin-17 pathway inhibition with brodalumab in early systemic sclerosis: Analysis of a single-arm, open-label, phase 1 trial

• DOI: 10.1016/j.jaad.2023.02.061
• Publication Date: 2023-03-29T07:58:28Z
• Authors: Takemichi Fukasawa; Ayumi Yoshizaki; Satoshi Ebata; Maiko Fukayama; Ai Kuzumi; Yuta Norimatsu; Kazuki M. Matsuda; Hirohito Kotani; Hayakazu Sumida; Asako Yoshizaki-O...; Hisashi Kagebayashi; Shinichi Sato
• Keywords: Open label

To the Editor: Systemic sclerosis (SSc) is an autoimmune disease that causes fibrosis of skin and internal organs, a possible relationship exists between activated interleukin-17 (IL-17) pathway pathogenesis SSc.1Chizzolini C. Dufour A.M. Brembilla N.C. Is there role for IL-17 in systemic sclerosis?.Immunol Lett. 2018; 195: 61-67https://doi.org/10.1016/j.imlet.2017.09.007Crossref PubMed Scopus (42) Google Scholar Therefore, this first single-center trial assessed pharmacokinetics, safety, efficacy multiple subcutaneous injections commonly used dosage brodalumab, fully human anti-IL-17 receptor A monoclonal antibody, Japanese patients with SSc. We enrolled 8 early SSc moderate-to-severe2Asano Y. Jinnin M. Kawaguchi et al.Diagnostic criteria, severity classification guidelines sclerosis.J Dermatol. 45: 633-691https://doi.org/10.1111/1346-8138.14162Crossref (27) progressive thickening (Supplementary Table I, available via Mendeley at https://data.mendeley.com/datasets/dc97t6r54x/1). All had diffuse cutaneous met American College Rheumatology/European League Against Rheumatism (ACR/EULAR) criteria Seven were women (Table I). received brodalumab 210 mg weeks 0 (day 1, enrollment), 2, every 2 thereafter until week 50, analysis was performed 52. Subsequent dosing being continued drug approval. No new vasodilatory or vaso-modulatory medications added. Pharmacokinetics profiles (trough concentration [Ctrough], time to peak [tmax], maximum [Cmax], area under curve [AUC0-τ]) I) not different from those clinical trials other diseases. deaths serious treatment-emergent adverse events (TEAEs) occurred. significant TEAE (nonserious, causing interruption) drug-induced neutropenia (n = 1), resulting concomitant use sulfamethoxazole trimethoprim; causal ruled out. Drug-related TEAEs observed 3 patients: oral candidiasis 3), vulvovaginal arthralgia 1). The modified Rodnan score (mRSS) all decreased quickly 4 remained low through 52 (Fig reduction dermal thickness lesional (left forearm) also consistently changes mRSS Fig A, digital ulcers on toes enrollment weeks. In finger baseline, decrease mean number baseline 24 B, measures respiratory function (data shown). Brodalumab induced regulatory T cell (Treg)-dominant Treg/T-helper 17 (Th17) balance https://data.mendeley.com/datasets/dc97t6r54x/1), immunoglobulin G+ class-switched memory B cells plasmablasts, increased transitional 3, https://data.mendeley.com/datasets/dc97t6r54x/1) compared baseline.Table IBaseline characteristics pharmacokinetics parametersBaseline characteristicsBrodalumab 8)Age, (SD), years53.6 (10.6)Women, n (%)7 (87.5)Disease duration SSc∗Calculated non-Raynaud's sign symptom., (min-max), years2.2 (1.9), (0.3-4.9)Total mRSS, (min-max)23.1 (5.1), (14-29)Anti-Scl-70 antibody positive, (%)3 (37.5)Anti-RNA polymerase III (%)4 (62.5)Anti-centromere antibodies, (%)0 (0.0)Skin both hands extending fingers8 (100.0)Abnormal nail fold capillaries8 (100.0)Fingertip pitting scars and/or tip ulcers4 (50.0)Interstitial pattern bilateral lower lung lobes6 (75.0)Medication history†“Medication history” indicates drugs before initiation brodalumab. Oral corticosteroids listed as restricted study 5 6 them during treatment period.Oral corticosteroids6 (75.0)Immunosuppressive agents1 (12.5)Other‡Treatment identified tocilizumab.1 (12.5)PK parametersBrodalumab 8)Serum trough concentration, μg/mL, 2223.4 (22.9)Tmax, days§Calculated serum concentrations 22 24.3.1 (0.36)Cmax, μg/mL§Calculated 24.37.0 (26.1)AUC0-τ, μg⋅day/mL§Calculated 24.377 (260)AUC, Area curve; Cmax, max concentration; max, maximum; min, minimum; score; PK, pharmacokinetic; RNA, ribonucleic acid; SD, standard deviation; SSc, sclerosis; Tmax, concentration.∗ Calculated symptom.† “Medication period.‡ Treatment tocilizumab.§ 24. Open table tab AUC, concentration. demonstrated exceeded minimal clinically important difference,3Khanna D. Furst D.E. Hays R.D. al.Minimally difference sclerosis: results D-penicillamine study.Ann Rheum Dis. 2006; 65: 1325-1329https://doi.org/10.1136/ard.2005.050187Crossref (121) thickness. As promotes fibroblast proliferation collagen production,1Chizzolini speculated by directly inhibiting action fibroblasts. Studies have reported Th17-dominant Treg/Th17 balance,4Papp G. Horvath I.F. Barath S. al.Altered T-cell repertoire sclerosis.Scand J Rheumatol. 2011; 40: 205-210https://doi.org/10.3109/03009742.2010.528021Crossref (71) rituximab, anti-CD20 improves features SSc.5Ebata Yoshizaki A. Oba K. al.Safety rituximab (DESIRES): double-blind, investigator-initiated, randomised, placebo-controlled trial.Lancet 2021; 3: e489-e497https://doi.org/10.1016/S2665-9913(21)00107-7Abstract Full Text PDF (70) Thus, inhibition indirect effects subsets may ameliorate fibrotic lesions. Study limitations include its open-label design small sample size. Further studies are necessary confirm safety Dr Fukasawa reports funding present manuscript Kyowa Kirin Co, Ltd. addition, has patent PCT/JP2020/036156 issued. consulting fees (over past 36 months) C, Kagebayashi employee (contract) Sato along personal months Drs Yoshizaki-Ogawa, Kotani, Sumida, Matsuda, Fukayama, Ebata, Norimatsu, Kuzumi report Medical writing support provided Annirudha Chillar, MD, PhD, Cactus Life Sciences (part Communications) funded Ltd, Japan.