Lupus Science & Medicine
plasma cells produce a variety of characteristic autoan- tibodies and are, therefore, critically involved in SLE pathogenesis. Studies have shown an increased number of plasmablasts in the blood of patients with active SLE. 5 CD38 is a type II glycoprotein that is highly and uniformly expressed on antibody-producing plasmablasts and plasma cells. In an ex vivo study of CD38 expression on various immune cells in peripheral blood mononuclear cells (PBMCs) from patients with SLE, the highest CD38 expression was observed on plasma cells and plasmab- lasts, followed by natural killer (NK) cells, plasmacytoid dendritic cells (pDCs), a regulatory T cell subpopulation and naïve T cells. 6 These findings suggest that CD38 is a well-suited target for therapeutic investigation in SLE. 7 A case report of daratumumab, an anti-CD38 antibody, in SLE demonstrated preliminary evidence of efficacy and proof of mechanism. In two patients with severe, life-threatening manifestations of SLE, profound clinical responses were accompanied by substantial depletions of autoantibodies, reduction in plasmablasts and decrease in type I interferon (IFN) activity. 8 Furthermore, the clin- ical benefits of daratumumab have also been reported in other autoantibody-driven diseases, such as primary Sjorgen disease, anti-neutrophil cytoplasmic antibody- associated vasculitis and immune thrombocytopenia, highlighting the importance of CD38 in autoimmunity. 9 Mezagitamab (also known as TAK-079) is an investiga- tional fully human immunoglobulin G1 (IgG1) mono- clonal antibody (mAb) that binds with high affinity to CD38. 10 The available non-clinical, first-in-human data and preliminary clinical data in patients with multiple myeloma demonstrated an acceptable safety profile and encouraging pharmacodynamic (PD) effects in reducing target cells expressing CD38. 11–13 These observations supported investigation of mezagitamab in SLE, a disease characterised by high prevalence of cells with dysregu- lated CD38 expression. Presented here are the results of the phase 1b trial (NCT03724916) investigating the safety, pharmacokinetics (PK) and PD of mezagitamab in patients with moderate to severe SLE.
Eligible patients needed to meet either the 2012 Systemic Lupus International Collaborating Clinics classification criteria or the American College of Rheu- matology classification criteria for SLE. Additional key inclusion criteria included having SLE Disease Activity Index 2000 (SLEDAI-2K) score ≥ 6 and being positive for anti-dsDNA antibodies and/or anti-ENA antibodies. Patients were required to receive stable background SLE therapy for ≥ 12 weeks (with stable dosing for ≥ 8 weeks) prior to screening and throughout the study. Allowed SLE concomitant medications were immunosuppres- sants (azathioprine, mycophenolate mofetil and metho- trexate), antimalarials and corticosteroids. Key exclusion criteria were a concurrent diagnosis of drug-induced SLE or any concomitant rheumatologic or autoimmune disease that would confound efficacy assessments, active neuropsychiatric SLE or active lupus nephritis docu- mented by an acute flare within 3 months of screening. Additional exclusion criteria were positive hepatitis B surface antigen or hepatitis C antibody or HIV antibody/ antigen; an opportunistic infection or an acute or chronic infection requiring hospitalisation within ≤ 12 weeks and ≤ 30 days of screening, respectively. This study was conducted with the highest respect for the individual patients, in accordance with the study protocol, ethical principles of the Declaration of Helsinki, the International Council for Harmonisation of Tech- nical Requirements for Pharmaceuticals for Human Use Harmonised Tripartite Guideline for Good Clinical Prac- tice and all applicable local regulations. The investigator explained the study, including its objectives and potential risks and benefits, to patients using the informed consent form approved by the institutional review boards or inde- pendent ethics committees (Advarra Institutional Review Board (Pro00029715), Western Institutional Review Board (2019P000259), Oklahoma Medical Research Foundation (OMRF) (19-10), UCSD Human Research Protections (Project # 190227), Partners Human Research Committee (Protocol # 2019P000964)). Each patient signed and dated the informed consent form before any protocol-specific screening procedures. Primary endpoints were safety and tolerability, including the incidence, type and grade of adverse events (AEs) as well as the percentage of patients with ≥ 1 AE, leading to study treatment discontinuation. Secondary endpoints included PK and PD. Exploratory endpoints assessed the effects of repeated administration of mezagitamab on SLE disease activity using clinical rating scales such as SLEDAI-2K and Cutaneous Lupus Erythematosus Disease Area and Severity Index (CLASI) and biomarkers. The study was not statistically powered for any efficacy hypothesis testing. The sample size for each study cohort was deemed sufficient to fulfil the primary and secondary study objectives in each cohort. Receptor occupancy assay The CD38 receptor occupancy flow cytometry assay was developed to evaluate changes in T cells, B cells, NK
METHODS Study design
This phase 1b double-blind, placebo-controlled, multi- centre study evaluated the safety, PK and PD of mezagi- tamab across three sequentially enrolling cohorts in a study population receiving standard principal investigator- directed background therapy for persistent moderate to severe SLE (online supplemental figure 1). Each cohort aimed to enrol eight patients in a 3:1 randomisation scheme (mezagitamab: placebo). Patients were assigned to either mezagitamab or placebo administered as a subcutaneous injection every 3 weeks for 12 weeks (total of four doses). Treatment compliance was calculated as (actual number of doses taken)/(planned number of doses)×100. Patients were assessed every 4 weeks for 12 weeks during the safety follow-up period.
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McDonnell SRP, et al . Lupus Science & Medicine 2024; 11 :e001112. doi:10.1136/lupus-2023-001112
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