Safety and tolerability of inebilizumab (MEDI-551), an anti-CD19 monoclonal antibody, in patients with relapsing forms of multiple sclerosis: Results from a phase 1 randomised, placebo-controlled, escalating intravenous and subcutaneous dose study

Mark A Agius, Gabriela Klodowska-Duda, Maciej Maciejowski, Andrzej Potemkowski, Jing Li, Kaushik Patra, Jacob Wesley, Soraya Madani, Gerard Barron, Eliezer Katz, Armando Flor, Mark A Agius, Gabriela Klodowska-Duda, Maciej Maciejowski, Andrzej Potemkowski, Jing Li, Kaushik Patra, Jacob Wesley, Soraya Madani, Gerard Barron, Eliezer Katz, Armando Flor

Abstract

Background: B cells may be involved in the pathophysiology of multiple sclerosis (MS). Inebilizumab (formerly MEDI-551) binds to and depletes CD19+ B cells.

Objectives: To assess safety, tolerability, pharmacokinetics, pharmacodynamics and immunogenicity of inebilizumab in adults with relapsing MS.

Methods: This phase 1 trial randomised 28 patients 3:1 (21, inebilizumab; 7, placebo) to inebilizumab (2 intravenous (IV) doses, days 1 and 15: 30, 100 or 600 mg; or single subcutaneous (SC) dose on day 1: 60 or 300 mg) or matching placebo, with follow-up until at least week 24 or return of CD19+ B-cell count to ⩾80 cells/µL.

Results: Complete B-cell depletion was observed across all doses. Infusion/injection (grade 1/2) reactions occurred in 6/15 patients receiving inebilizumab IV, 2/5 placebo IV and 1/6 inebilizumab SC. Serious adverse events occurred in three patients receiving inebilizumab: pyrexia, mixed-drug intoxication (unrelated to inebilizumab; resulted in death) and urinary tract infection. Mean number of cumulative new gadolinium-enhancing lesions over 24 weeks was 0.1 with inebilizumab versus 1.3 with placebo; mean numbers of new/newly enlarging T2 lesions were 0.4 and 2.4, respectively.

Conclusion: Inebilizumab had an acceptable safety profile in relapsing MS patients and showed a trend in reductions in new/newly enlarging and gadolinium-enhancing lesions.

Keywords: B cells; intravenous administration; pharmacodynamics; pharmacokinetics; subcutaneous administration.

Conflict of interest statement

Declaration of Conflicting Interests: The author(s) declared the following potential conflicts of interest with respect to the research, authorship and/or publication of this article: The University of California at Davis received funding, with M.A.A. as principal investigator, for the conduct of this study. M.A.A. has also served as a consultant for Novartis, Roche, Sanofi and Serono and has received research funding from Biogen, Celgene, Novartis, Roche and Sanofi. G.K.-D. has received research funding for the conduct of this study and has had travel, accommodation and/or investigator meeting expenses paid by MedImmune. M.M. has received lecture fees from Biogen, Novartis and Merck. A.P. received research funding for the conduct of this study and has served as a consultant and on an advisory board for MedImmune. J.L., K.P., J.W., S.M., G.B., E.K. and A.F. are employees of MedImmune and may own stock and/or stock options in AstraZeneca. M.A.A., G.K.-D., M.M. and A.P. received no honoraria or other form of financial support related to the development of this manuscript.

Figures

Figure 1.
Figure 1.
Study design. The number of patients in each group included those who received inebilizumab and those who received placebo. The SC cohorts received inebilizumab or placebo on day 1 only; the IV cohorts received inebilizumab or placebo at days 1 and 15. Long-term follow-up occurred for patients with reduced B-cell counts at week 24. IV: intravenous; LTFU: long-term follow-up; SC: subcutaneous.
Figure 2.
Figure 2.
Patient disposition. In all, 28 patients were randomised, 27 patients completed through end of treatment (day 169/week 24) and 24 patients completed the study. aSubject did not complete the study owing to investigator decision. IV: intravenous; SC: subcutaneous.
Figure 3.
Figure 3.
Mean inebilizumab concentrations versus time. Data below the lower limit of quantification (LLOQ) (0.1 µg/mL; as shown by dashed line) are plotted at half of the LLOQ, for illustrative purposes only. Error bars represent standard deviation of the mean. Arrows indicate dosing events (IV on days 1 and 15; SC on day 1). IV: intravenous; LLOQ: lower limit of quantification; SC: subcutaneous.
Figure 4.
Figure 4.
Median CD20 B-cell counts over time following inebilizumab administration. Data after week 24 reflect only patients who had not achieved B-cell repletion. Data used to calculate median value were collected from ⩾2 patients. *One subject in the 60-mg SC cohort and two subjects in the 600-mg IV cohort did not fully reach repletion to the lower limit of normal during the long-term follow-up period and received other standard-of-care MS therapies. IV: intravenous; SC: subcutaneous.
Figure 5.
Figure 5.
Effect of inebilizumab on plasma cell signature in whole blood. Mean values are plotted. Signature scores were calculated by determining the median fold change of the panel of genes at each time point for each subject within a dose cohort. Results were reported as fold change in PC signature compared with the value at baseline (pretreatment) with the baseline value set to 1. Values 1 represent an increase in the PC signature compared with pretreatment levels. PC: plasma cells; WB: Western blot.
Figure 6.
Figure 6.
Magnetic resonance imaging outcomes by week 24. Gd+: gadolinium-enhancing.

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