Clinical trials and drug discovery
Mezagitamab in systemic lupus erythematosus: clinical and mechanistic findings of CD38 inhibition in an autoimmune disease
Scott R P McDonnell , 1 Van Anh Nguyen , 1 Noah M Walton, 1 Carsten Merkwirth, 1 Feng Hong, 1 Deborah Berg, 2 Elena Tomaselli Muensterman , 2 Richard A Furie 3
To cite: McDonnell SRP, Nguyen VA, Walton NM, et al . Mezagitamab in systemic lupus erythematosus: clinical and mechanistic findings of CD38 inhibition in an autoimmune disease. Lupus Science & Medicine 2024; 11 :e001112. doi:10.1136/ lupus-2023-001112 ► Additional supplemental material is published online only. To view, please visit the journal online (https://doi.org/10.1 136/ lupus-2 023-001112).
ABSTRACT Objective To evaluate safety and mechanism of action of mezagitamab (TAK-079), an anti-CD38 monoclonal antibody, in patients with moderate to severe systemic lupus erythematosus (SLE). Methods A phase 1b double-blind, placebo-controlled, multicentre study was conducted in patients with SLE receiving standard background therapy. Eligible patients were adults who met the 2012 SLICC or ACR criteria for diagnosis, had a baseline SLE Disease Activity Index 2000 (SLEDAI-2K) score of ≥6 and were positive for anti- double-stranded DNA antibodies and/or anti-extractable nuclear antigens antibodies. Patients received 45 mg, 90 mg or 135 mg of mezagitamab or placebo every 3 weeks over 12 weeks. Primary endpoints were safety and tolerability. Secondary endpoints included pharmacokinetics and pharmacodynamics. Exploratory assessments included disease activity scales, deep immune profiling and interferon pathway analysis. Results 22 patients received at least one dose of either mezagitamab or placebo. In patients exposed to mezagitamab (n=17), drug was well tolerated. Adverse event (AEs) were balanced across treatment groups, with no treatment emergent AEs exceeding grade 2. Responder analyses for Cutaneous Lupus Erythematosus Disease Area and Severity Index (CLASI) and SLEDAI- 2K did not reveal any observable differences across treatment groups. However, there was a trend for more profound skin responses among patients with higher CLASI scores (>10) at baseline. Pharmacodynamic analysis showed median CD38 receptor occupancy up to 88.4% on CD38+ natural killer cells with concurrent depletion of these cells up to 90% in the 135 mg group. Mean reductions in IgG and autoantibodies were less than 20% in all dose groups. Cytometry by time of flight and type 1 interferon gene analysis revealed unique fingerprints that are indicative of a broad immune landscape shift following CD38 targeting. Conclusions Mezagitamab had a favourable safety profile in patients with moderate to severe SLE and elicited a pharmacodynamic effect consistent with CD38+ cell depletion. These findings reveal novel insights into the drug’s mechanism of action and support the continued investigation of mezagitamab in autoimmune diseases.
INTRODUCTION Systemic lupus erythematosus (SLE) is a heterogeneous autoimmune disease char- acterised by dysregulation of cells of T and B-cell lineage as well as other components of the innate immune system. 1 2 A hallmark of the disease is the production of patho- genic autoantibodies to double-stranded DNA (dsDNA) and/or extractable nuclear antigens (ENA), phospholipids, blood cells and other antigens. 3 Inflammation leading to tissue damage in SLE is incited primarily by these pathogenic autoantibodies through immune complex deposition and direct anti- body–target interactions. SLE can affect virtu- ally any organ in the body. Most therapeutic agents that are used for treatment of SLE have demonstrated limited success in reducing autoantibodies (particu- larly anti-ENA antibodies) because they do not specifically target antibody-producing cells. 4 Short-lived plasmablasts and long-lived ⇒ Mezagitamab induces broad immune landscape changes consistent with CD38+ cell depletion and reduction in type 1 interferon signalling. HOW THIS STUDY MIGHT AFFECT RESEARCH, PRACTICE OR POLICY ⇒ Mezagitamab may have utility in various autoim- mune diseases driven by CD38-expressing cells. WHAT IS ALREADY KNOWN ON THIS TOPIC ⇒ High expression of CD38 on leukocytes of system- ic lupus erythematosus (SLE) patients makes it a potential treatment target for intervention in this disease. WHAT THIS STUDY ADDS ⇒ Mezagitamab, an anti-CD38 antibody, has a favour- able safety profile in patients with moderate to se- vere SLE.
SRPM and VAN are joint first authors. ETM and RAF are joint senior authors.
Received 22 November 2023 Accepted 15 February 2024
1 Takeda Development Center Americas Inc, Lexington, Massachusetts, USA 2 Clinical Sciences, Takeda Pharmaceuticals America Inc, Lexington, Massachusetts, USA 3 Department of Rheumatology, Northwell Health, Great Neck, New York, USA Correspondence to Dr Elena Tomaselli Muensterman; elena. muensterman@takeda.com © Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY. Published by BMJ.
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McDonnell SRP, et al . Lupus Science & Medicine 2024; 11 :e001112. doi:10.1136/lupus-2023-001112
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