Treating Multiple Sclerosis with Monoclonal Antibodies: A 2010 Update

Mathias Buttmann

Expert Rev Neurother. 2010;10(5):791-809.

Abstract and Introduction

Abstract

Treating multiple sclerosis (MS) with monoclonal antibodies (mAbs) has been marked by both progress and setbacks in the past 2 years, which are reviewed here. The natalizumab section of the article centers around progressive multifocal leukoencephalopathy (PML), and discusses PML risk in relation to treatment duration, bioassays for individual risk prediction, the concept of drug holidays, clinical course and treatment of PML, as well as safety-related regulatory actions. The rituximab section critically analyzes recent clinical trial results, discusses the clinical relevance of anti-idiotypic mAbs and makes a short excursion to neuromyelitis optica. Following this, the newer anti-CD20 mAbs ocrelizumab and ofatumumab, which are currently being tested in Phase II for MS, are reviewed and compared. The alemtuzumab section highlights novel data on mechanisms of action, potentially allowing individual risk prediction, and new results from the CAMMS223 trial, as well as the current status of the pivotal MS studies. The daclizumab section summarizes new open-label data, shedding more light on the adverse-effect profile of the drug in MS patients, and reports on its Phase III status. Subsequently, a failed ustekinumab trial and LY2127399 are reviewed. Taking into account late Phase II and III data on novel oral agents, the final section attempts to provide a detailed perspective on disease-modifying MS therapy in the medium term.

Introduction

The 2 years since the publication of a review on the treatment of multiple sclerosis (MS) with monoclonal antibodies (mAbs) in the March 2008 issue of this journal have seen significant progress in the field. This article critically highlights the advancements and setbacks of the past 2 years. It is intended as a nonredundant update for readers of the previous article, which we therefore recommend is read first.^[1]

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Sidebar

Key Issues

As of 9 February 2010, 35 cases of progressive multifocal leukoencephalopathy (PML) were diagnosed in more than 64,000 patients having received natalizumab (NATA) in the post-marketing setting, translating into an overall post-marketing incidence of 0.52 (0.36–0.73) per 1000 patients. As of mid-February 2010, eight out of 35 PML cases ended in fatality.
The risk of PML increases with increasing NATA treatment duration.
Measures to determine the individual risk of NATA-associated PML are being developed.
Currently, there is no evidence that NATA drug holidays decrease the risk of PML. Therefore, they cannot be recommended as a general treatment strategy at present.
The impressive clinical efficacy of alemtuzumab (ALEM) in patients with relapsing–remitting MS (RRMS) in the Phase II CAMMS223 trial was sustained over 4 years, with thyroid autoimmunity arising in the phase of immune reconstitution in part of the patients. Anti-ALEM antibodies did not influence therapeutic effects or adverse reactions.
Measurement of IL-21 might help to determine the risk of thyroid autoimmunity before starting ALEM to some clinically relevant extent, although this requires further confirmation.
A Phase III program testing ALEM in patients with RRMS is running and first results are to be expected for 2011.
Although rituximab (RTX) did not meet its primary end point in the Phase II/III OLYMPUS trial, conducted in 439 patients with primary progressive MS, a preplanned post hocsubgroup analysis indicated that patients aged under 51 years and with gadolinium-enhancing MRI lesions at baseline profited from B-cell depletion with this anti-CD20 monoclonal antibody (mAb).
There is currently no evidence that anti-idiotypic antibodies to RTX impede the clinical efficacy or increase the risk of adverse effects in patients with MS.
The clinical MS trial program for RTX is currently not being pursued; however, the newer anti-CD20 mAbs ocrelizumab and ofatumumab are undergoing Phase II trials for RRMS.
Based on an interim analysis of the Phase II SELECT trial, the anti-CD25 mAb daclizumab recently entered Phase III as a monotherapy for patients with RRMS.
Ustekinumab, an inhibitory mAb against the p40 subunit of IL-12 and -23, did not reduce MRI disease activity in comparison to placebo in 249 patients with RRMS over 23 weeks but was associated with a higher rate of nonserious adverse events.
LY2127399, a fully human mAb neutralizing BAFF, is currently being tested in a RRMS Phase II trial. A clinical trial program investigating double blockade of BAFF and APRIL by the recombinant TACI immunoglobulin fusion protein ataticept was recently terminated owing to higher disease activity in the verum group.

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