Clinical trials and drug discovery
safety results were consistent with those observed in the first-in-human study, 12 which informed the dose selection in the present study. The starting dose of 45 mg for the initial dosing cohort (ie, cohort A) was selected based on the favourable safety profile and PD target effect (ie, a sustained reduction of plasmablasts) observed after 0.6 mg/kg dose was administered to healthy participants. Because levels of CD38-expressing plasmablasts are gener- ally higher in patients with SLE compared with healthy volunteers, 20 higher doses were selected for subsequent cohorts to achieve desired PD effects. Target engagement of mezagitamab on CD38 antigen was evaluated via receptor occupancy on CD38+ NK cells, which serves as a surrogate PD marker due to the abun- dance in peripheral blood and high expression of the receptor. 18 Target engagement by mezagitamab on CD38+ NK cells was dose dependent, but not saturated at the doses tested. Return to baseline for receptor occupancy on CD38+ NK cells paralleled partial recovery of this cell population by the time of the next dose administration. Given the importance of these effector cells in driving antibody-dependent cellular cytotoxicity, their recovery is essential for mezagitamab’s cytotoxicity against antibody- producing cells. The therapeutic hypothesis for investigating mezagi- tamab in SLE was based on targeting CD38-expressing cells, such as plasma cells and plasmablasts, thus reducing the production of all types of pathogenic autoantibodies that could be present in patients. Reductions in autoan- tibodies for which patients were positive at baseline did not appear to be correlated with efficacy measures as assessed by disease activity instruments, such as CLASI and SLEDAI-2K—a finding consistent with published literature. 21 22 Lack of concordance could also have been due to insufficient depletion of plasma cells resulting in limited reductions in immunoglobulins. In addition, the small size of the study and heterogeneity of disease manifestations could have contributed. Since each auto- antibody may have a distinct pathogenic contribution to disease activity 3 and a number of patients were positive for more than one autoantibody, a uniform suppression of all autoantibodies may be required to evaluate the rela- tionship between autoantibody reduction and clinical improvement. These observations, coupled with find- ings from the receptor occupancy assay, suggest that the dosing regimen of mezagitamab in SLE was not optimal to produce maximal pharmacological effects. Despite the small sample size and the heterogeneity of the study population, an exploratory objective was to assess the effects of mezagitamab on disease activity using conventional SLE disease activity instruments. The study was not powered to formally compare changes in clinical scores across groups. In addition, efficacy analyses were further hampered because of the COVID-19 pandemic, which resulted in a high number of discontinuations and missed doses, further reducing the number of avail- able patients for efficacy assessments within each cohort. Furthermore, as with most SLE studies, patients were on
multiple concomitant medications, including oral corti- costeroids, which were not tapered during the study, thus contributing to an inflated treatment response. This was a limitation and was evident by the relatively high placebo response observed in this study. Clinical response (particularly in CLASI score) in the absence of immunoglobulin reductions in some patients warranted investigation into consequences of CD38 inhi- bition that are unrelated to antibody-producing target cells. In addition to NK cell depletion observed in the receptor occupancy assay, CyTOF analysis identified effects on other immune cell populations, including reductions in Bregs. Changes in these upstream regula- tory cell types may have significant impact on effector cells and more broadly on the immune landscape. To this end, unbiased cluster analysis identified (among others) two clusters representing populations with features of effector CD4 and CD8 T cells, which have been impli- cated in SLE pathophysiology. Both populations appear to increase in response to treatment, although this was most pronounced only at the highest tested dose, highlighting again that an optimised dosing regimen for mezagitamab in SLE could further increase its pharmacological effects. Assessment of biomarkers associated with cutaneous lupus was undertaken to gain a mechanistic under- standing of profound CLASI responses. Available results indicated apparent reduction in whole blood type I IFN gene expression in mezagitamab 135 mg-treated patients over the course of the trial compared with placebo-treated patients in whom reductions were not observed. As skin biopsies were not performed in this trial, evaluation of tissue IFN expression and tissue-resident immune cells implicated in its produc- tion (such as pDCs and keratinocytes) could not be conducted. Since mezagitamab did not impact pDC levels in whole blood, additional investigation is needed to elucidate a link between mezagitamab’s mechanism of action, the observed reduction in IFN gene signature and the CLASI responses. Overall, this phase 1b study demonstrated mezagitam- ab’s favourable safety profile, expected PD effects and encouraging mechanistic data in patients with moderate to severe SLE. These findings support continued investi- gation of mezagitamab in autoimmune diseases. Acknowledgements The authors thank the patients who took part in this study and their families, as well as the principal investigators, sub-investigators, study coordinators and members of the Lupus Research Alliance. They thank all members of Takeda mezagitamab SLE project team for their contributions to the study. They acknowledge Kristina Allikmets (employee of Takeda Development Center Americas, Inc.) and Jason Homsy (previously an employee of Takeda Development Center Americas, Inc.) for their leadership in the study concept, design and conduct. They also thank Mary Farmer, Tien Bo and Ishani Patel (employees of Takeda Development Center Americas, Inc.) for the critical review of the manuscript. Contributors All authors were involved in drafting the article and/or revising it critically for important intellectual content, and all authors approved the final version to be published. SRPM and VAN contributed equally to this work. Analysis conception and design: SRPM, VAN, ETM. Acquisition of data: SRPM, VAN, NMW, CM, FH. Analysis and interpretation of data: SRPM, VAN, NMW, CM, FH, DB, ETM, RAF. ETM acted as guarantor in the manuscript.
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McDonnell SRP, et al . Lupus Science & Medicine 2024; 11 :e001112. doi:10.1136/lupus-2023-001112
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