A double-blind, placebo-controlled, single ascending-dose study of remyelinating antibody rHIgM22 in people with multiple sclerosis

Abstract

Objective: The objective of this paper is to assess, in individuals with clinically stable multiple sclerosis (MS), the safety, tolerability, pharmacokinetics (PK) and exploratory pharmacodynamics of the monoclonal recombinant human antibody IgM22 (rHIgM22).

Methods: Seventy-two adults with stable MS were enrolled in a double-blind, randomized, placebo-controlled, single ascending-dose, Phase 1 trial examining rHIgM22 from 0.025 to 2.0 mg/kg. Assessments included MRI, MR spectroscopy, plasma PK, and changes in clinical status, laboratory values and adverse events for three months. The final cohort had additional clinical, ophthalmologic, CSF collection and exploratory biomarker evaluations. Participants were monitored for six months.

Results: rHIgM22 was well tolerated with no clinically significant safety signals. Noncompartmental PK modeling demonstrated linear dose-proportionality both of C_max and AUC_0-Last. The steady-state apparent volume of distribution of approximately 58 ml/kg suggested primarily vascular compartmentalization. CSF:plasma rHIgM22 concentration increased from 0.003% on Day 2 for both 1.0 and 2.0 mg/kg to 0.056% and 0.586% for 1.0 and 2.0 mg/kg, respectively, on Day 29. No statistically significant treatment-related changes were observed in exploratory pharmacodynamic outcome measures included for the 21 participants of the extension cohort.

Conclusions: Single doses of rHIgM22 were well tolerated and exhibited linear PK, and antibody was detected in the CSF.

Keywords: Clinical trial; demyelination; disease-modifying therapies; multiple sclerosis.

Figure 1.

Study timeline, evaluations and enrollment. Panel (a) is a schematic of study design, and evaluations conducted in the first five dose-escalation cohorts are noted above the timeline. Additional procedures added to the sixth cohort included the consumption of heavy water and two lumbar punctures to obtain cerebrospinal fluid (CSF) as noted below the timeline. Panel (b) depicts the enrollment and disposition of the participants. In the five dose-escalation cohorts, individuals received single doses of monoclonal recombinant human antibody immunoglobulin (Ig)M22 (rHIgM22) ranging from 0.025 to 2.000 mg/kg. Each cohort planned for eight active rHIgM22 and two placebo patients. The sixth cohort included three groups of seven patients each, who received placebo, 1.0 mg/kg or 2.0 mg/kg rHIgM22.PK: pharmacokinetics; MRI: magnetic resonance imaging; MRS: magnetic resonance spectroscopy; D2O: non-radioactive heavy water.

Figure 2.

Patient Global Impression of Change (PGIC) trend toward improvement. The 21 participants in the sixth cohort were administered this questionnaire to assess the change (if any) in activity limitations, symptoms, emotions and overall quality of life, related to their condition since baseline. More individuals receiving monoclonal recombinant human antibody IgM22 (rHIgM22) reported improvements in their status than did individuals receiving placebo throughout the study.