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. 2022 Apr 26;8(2):20552173221091475.
doi: 10.1177/20552173221091475. eCollection 2022 Apr-Jun.

A double-blind, placebo-controlled, single-ascending-dose intravenous infusion study of rHIgM22 in subjects with multiple sclerosis immediately following a relapse

Benjamin M Greenberg  1 , James D Bowen  2 , Enrique Alvarez  3 , Moses Rodriguez  4 , Anthony O Caggiano  5 , Arthur E Warrington  4 , Ping Zhao  5 , Andrew Eisen  6
Affiliations

A double-blind, placebo-controlled, single-ascending-dose intravenous infusion study of rHIgM22 in subjects with multiple sclerosis immediately following a relapse

Benjamin M Greenberg et al. Mult Scler J Exp Transl Clin. .

Abstract

Background: Recombinant human immunoglobulin M22 (rHIgM22) has promoted remyelination in animal models and was well tolerated in people with clinically stable multiple sclerosis.

Objective: Safety/tolerability of a single rHIgM22 dose was investigated following an acute relapse and to determine whether this enhanced CNS/CSF concentrations.

Methods: Adults (N = 27) with acute relapse were assigned to rHIgM22 (0.5 or 2.0 mg/kg) or placebo. Study included screening/steroid administration periods and 10 study visits over 6 months. rHIgM22 CSF concentrations were assessed on days 2 and 29. Pharmacokinetic and safety samples were taken for up to 60 days. Assessments included adverse events and other clinical measures. Brain magnetic resonance imaging was performed with/without gadolinium.

Results: rHIgM22 CSF levels were consistent with dose-dependent concentration on both days 2 and 29. Infusion was generally well tolerated during an acute relapse. Immunogenicity was mild. Most adverse events did not appear to be dose dependent, were mild/moderate, and were events often associated with multiple sclerosis.

Conclusion: Although limited by high variability and small sample size, the data suggest enhanced CNS uptake associated with a drop in CSF levels. This study demonstrated safety of an antibody directed to myelin and oligodendrocytes in the course of active demyelinating disease. Further research into rHIgM22 is warranted.ClinicalTrials.gov: NCT02398461 https://clinicaltrials.gov/ct2/show/study/NCT02398461?term=M22&draw=2&rank=8.

Keywords: human immunoglobulin; immunogenicity; relapsing multiple sclerosis; remyelination; treatment.

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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: Xxxxxxx. B.M. Greenberg has received consulting fees from Alexion, Novartis, EMD Serono, Viela Bio, Genentech/Roche, Greenwich Biosciences, Axon Advisors, Rubin Anders, ABCAM, Signant, IQVIA, Sandoz, Druggability Technologies, Genzyme, Immunovant, and PRIME Education. He has received grant funding from PCORI, NIH, NMSS, The Siegel Rare Neuroimmune Association, Clene Nanomedicine, and the Guthy Jackson Charitable Foundation for NMO. He serves as an unpaid member of the board of the Siegel Rare Neuroimmune Association. He receives royalties from UpToDate. J.D. Bowen has received compensation for activities such as advisory boards, lectures, and consultancy with the following companies and organizations: AbbVie, Alkermes, Biogen IDEC, Bristol Myers Squibb, Celgene, EMD Serono, Genentech, Genzyme, Novartis, and Roche. E. Alvarez has received compensation for activities such as advisory boards, lectures, and consultancy with the following companies and organizations: Actelion/Janssen, Alexion, Bayer, Biogen, Celgene/BMS, EMD Serono/Merck, Genentech/Roche, Genzyme, Novartis, and TG Therapeutics. He has also received research support from Biogen, Genentech/Roche, Novartis, TG Therapeutics, Patient-Centered Outcomes Research Initiative, National Multiple Sclerosis Society, National Institutes of Health, and Rocky Mountain MS Center. M.R. Rodriguez and A.E.W. Warrington: The Mayo Clinic owns patents and has licensed rHIgM22 to Acorda Therapeutics. If the antibody proves to be effective, then royalties may be received. A. Caggiano, Ping Zhao and A. Eisen were employees of Acorda Therapeutics at the time of the study, and A. Caggiano and A. Eisen own stock in Acorda.

Figures

Figure 1.
Figure 1.
Study design. MRI, magnetic resonance imaging; rHIgM22, recombinant human immunoglobulin M22.
Figure 2.
Figure 2.
Mean plasma concentration (SD) of rHIgM22 over 60 days. rHIgM22, recombinant human immunoglobulin M22.
Figure 3.
Figure 3.
Box plots of CSF rHIgM22 Cmax and AUC0−last AUC0−last, area under the concentration-time curve from time 0 to the concentration at last time point; Cmax, maximum measured concentration; CSF, cerebrospinal fluid; rHIgM22, recombinant human immunoglobulin M22.
Figure 4.
Figure 4.
CSF rHIgM22 concentration and CSF/serum albumin index vs brain Gd uptake index at day 2. (a) CSF rHIgM22 concentration for 0.5-mg/kg rHIgM22 dose. Spearman r = −0.86 (P = 0.01). (b) CSF rHIgM22 concentration for 2.0-mg/kg rHIgM22 dose. Spearman r = −0.54 (P = 0.22). (c) CSF/serum albumin index for 0.5-mg/kg and 2.0-mg/kg rHIgM22 dose. The data were fitted using locally estimated scatterplot smoothing (LOESS) regression because the distribution was not normally distributed. CSF, cerebrospinal fluid; Gd, gadolinium; rHIgM22, recombinant human immunoglobulin M22.
Figure 5.
Figure 5.
Hypothesis to account for pathway of rHIgM22 into the brain after an acute relapse. After an acute relapse, the BBB becomes more permeable, allowing large proteins (albumin and rHIgM22) to enter the CNS. The increase in albumin concentration is reflected in higher albumin concentrations in the CSF, with a positive correlation between albumin uptake index and Gd uptake index I. In contrast, rHIgM22 binds to white matter so does not remain in the CSF, resulting in a negative correlation with Gd uptake index. BBB, blood-brain barrier; CNS, central nervous system, CSF, cerebrospinal fluid; Gd, gadolinium; rHIgM22, recombinant human immunoglobulin M22.
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