NeuroImmunology

Abstract

Multiple sclerosis (MS) is a typical CD4 T cell-mediated autoimmune disease of the central nervous system (CNS) that leads to inflammation, demyelination, axonal damage, glial scarring and a broad range of neurological deficits. While disease-modifying drugs with a good safety profile and moderate efficacy have been available for 20 years now, a growing number of substances with superior therapeutic efficacy have recently been introduced or are in late stage clinical testing. Daclizumab, a humanized neutralizing monoclonal antibody against the α-chain of the Interleukin-2 receptor (IL-2Rα, CD25), which had originally been developed and approved to prevent rejection after allograft renal transplantation, belongs to the latter group.

 

Clinical efficacy and safety of daclizumab in MS has so far been tested in several smaller phase II trials and recently two large phase II trials (combined 912 patients), and has shown efficacy regarding reduction of clinical disease activity as well as CNS inflammation. A phase III clinical trial is ongoing till March 2014 (DECIDE study, comparison with interferon (IFN) β-1a in RRMS). Furthermore, the existing safety data from clinical experience in kidney transplantation and in MS appears favorable.

 

Apart from the promising clinical data mechanistic studies along the trials have provided interesting novel insights not only about the mechanisms of daclizumab treatment, but in general about the biology of IL-2 and IL-2 receptor interactions in the human immune system. Besides blockade of recently activated CD25+T cells daclizumab appears to act through additional mechanisms including the expansion of immune regulatory CD56bright natural killer (NK) cells, the blockade of cross-presentation of IL-2 by dendritic cells (DC) to T cells, and the reduction of lymphoid tissue inducer cells.

Via Krishan Maggon

ABSTRACT

Objective: To evaluate the safety, tolerability, and pharmacokinetics (PK) of BIIB033 (anti-LINGO-1 monoclonal antibody) in healthy volunteers and participants with multiple sclerosis (MS).

Methods: In 2 separate randomized, placebo-controlled studies, single ascending doses (SAD; 0.1–100 mg/kg) of BIIB033 or placebo were administered via IV infusion or subcutaneous injection to 72 healthy volunteers, and multiple ascending doses (MAD; 0.3–100 mg/kg; 2 doses separated by 14 days) of BIIB033 or placebo were administered via IV infusion to 47 participants with relapsing-remitting or secondary progressive MS. Safety assessments included adverse event (AE) monitoring, neurologic examinations, conventional and nonconventional MRI, EEG, optical coherence tomography, retinal examinations, and evoked potentials. Serum and CSF PK as well as the immunogenicity of BIIB033 were also evaluated.

Results: All 72 healthy volunteers and 47 participants with MS were included in the safety analyses. BIIB033 infusions were well tolerated. The frequency of AEs was similar between BIIB033 and placebo. There were no serious AEs or deaths. No clinically significant changes in any of the safety measures were observed. BIIB033 PK was similar between healthy volunteers and participants with MS. Doses of ≥10 mg/kg resulted in BIIB033 concentrations similar to or higher than the concentration associated with 90% of the maximum remyelination effect in rat remyelination studies. The incidence of anti-drug antibody production was low.

Conclusions: The emerging safety, tolerability, and PK of BIIB033 support advancing BIIB033 into phase II clinical development as a potential treatment for CNS demyelination disorders.

Classification of evidence: This study provides Class I evidence that BIIB033 is well tolerated and safe (serious adverse event rate 0%, 95% confidence interval 0–7.6%).

Via Krishan Maggon

Alzheimer’s disease (AD) is the most common form of dementia, afflicting more than 30 million people worldwide. Currently, there is no cure or way to prevent this devastating disease.

Via Krishan Maggon