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

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