A Randomized, Placebo-Controlled Trial of Natalizumab for Relapsing Multiple Sclerosis

• Polman et al., NEJM 354 (9): 899-910, 2006
• PMID: 16510744

(see also: Rudick et al., NEJM 354 (9): 911-923, 2006)

Natalizumab is a monoclonal antibody against alpha-4 integrins. The alpha-4 family of adhesion molecules on lymphocytes (most importantly T-cells) binds to Ig-superfamily receptors (notably VCAM-1) on endothelium during early phases of the extravasation process. By blocking these interactions, T-cells can be prevented from entering tissue and thus inflammation can be prevented.

Natalizumab has been tested in Crohn’s disease and multiple sclerosis. The drug has been largely successful, but a series of major adverse events last year temporarily halted all trials (see references 25-27 in title paper). A subsequent evaluation of the data concluded that studies could continue, but this situation raises serious issues about the balance between drug risks and drug benefits. Adhesion molecule inhibition promises to be a potent strategy for blocking inflammation, especially where organ- and process-specific targets can be found (e.g. alpha-4 integrins are reportedly most relevant in the brain and gut). However, the consequences of such therapies must be considered. Certainly we are in an era where the concept of "do no harm" must be viewed in context (i.e. drug toxicity is a given), but inducing death in any fraction of patients where there was no imminent risk seems like an excessive trade-off.

While monoclonal antibodies are clearly powerful drugs, they may sometimes be too powerful, taking too long to wash out if an adverse event is reported and/or too potently inhibiting the target systems. Note similarities between this case and the reactivation of tuberculosis in patients treated with infliximab (Remicade). Perhaps the use of less-specific yet more pharmacokinetically manipulable drugs, e.g. designer small molecules, is the answer in such cases, or else more advanced monitoring need be implemented. Remicade has been successful with the added safety net of proper TB screening - could natalizumab succeed safely if we ensure proper PML screening?