[Physician Comment] Multiple sclerosis: Anti-cancer drug beats current first-line treatment in phase 3 trial

Image: PD/Relapsing-remitting MS

 Study author, Dr. Jeffrey Cohen, talks to 2 Minute Medicine. Mellen Center, Cleveland Clinic, Cleveland, OH, USA* 

“The CARE-MS I trial confirmed the superiority of alemtuzumab over interferon beta-1a, previously noted in a Phase 2 study, on reducing relapses and MRI lesion activity in patients with early, active relapsing-remitting MS not previously treated with disease modifying medications.  Benefit on slowing worsening of impairment/disability was not demonstrated.  

However, the accompanying CARE-MS II study, which enrolled patients with continued activity while on disease modifying therapy, did show benefit on slowing worsening impairment/disability.  Alemtuzumab slowed brain atrophy in both studies.  

The potent efficacy of alemtuzumab will make it a useful addition to the treatment algorithm for MS. However, because of some safety issues, it probably will not be used as the initial therapy for the majority of patients. The high price of MS medications is a significant issue.  Hopefully, as treatment options accumulate, the prices will decrease.”

 *Other authors include Alasdair J Coles, Douglas L Arnold, Christian Confavreux, Edward J Fox, Hans-Peter Hartung, Eva Havrdova, Krzysztof W Selmaj,Howard L Weiner, Elizabeth Fisher, Vesna V Brinar, Gavin Giovannoni, Miroslav Stojanovic, Bella I Ertik,StephenLLake, David H Margolin, Michael A Panzara, and principal investigator D Alastair S Compston

Key study points: 

1. Compared to interferon beta-1a, alemtuzumab was associated with a significantly reduced relapse rate and less MRI disease activity in the context of early relapsing-remitting MS in patients without prior treatment.
2. Alemtuzumab was associated with treatable but potentially severe adverse events, particularly secondary autoimmune disorders, which might limit its broad application.

Primer: Multiple sclerosis (MS) is a demyelinating, inflammatory disease affecting neurons in the central nervous system. It is generally believed to be an autoimmune disorder, although this has yet to be directly proven. The course of MS involves cycles of relapse and remission, ultimately progressing to a secondary phase where deficits increase even without relapses.

Alemtuzumab (brand name: Campath) is a humanized monoclonal antibody against CD52, which is found on lymphocytes and monocytes. It is approved for use in treating B-cell chronic lymphocytic leukemia. However, since 1991, it has also been investigated as a treatment for MS. Pulsed doses of alemtuzumab deplete the lymphocyte pool and allow it to reconstitute in different proportions. This “reset” of the immune system may be beneficial for MS.

Previous smaller studies and a phase 2 trial suggested that alemtuzumab reduces the rate of relapse and disability accumulation compared to interferon beta-1a, a first-line disease-modifying therapy.

 Background reading:

1. BBC article on the pair of papers published in the Lancet on alemtuzumab for MS
2. The accompanying paper looking at alemtuzumab for patients who have already received first-line treatment
3. Kinetics of B-cell reconstitution after alemtuzumab depletion
4. IL-21 and secondary automimmunity after treatment with alemtuzumab for MS
5. Mechanism of action of alemtuzumab
6. The phase I/II trial for alemtuzumab vs. interferon beta-1a

This [randomized controlled/phase III] study: Patients with early relapsing-remitting MS were randomly assigned to either alemtuzumab treatment (n = 386) or interferon beta-1a treatment (n = 195).

The alemtuzumab group had a lower rate of relapses than the interferon beta-1b group: 22% vs 40% (rate ratio 0.45 [95% CI 0.32-0.63]; p<0.0001). No difference in accumulation of disability was found between the two groups (hazard ratio 0.70 [95% CI 0.40 – 1.23]; p=0.22). On MRI, the alemtuzumab group had lower proportions of patients with new or enlarging T2-hyperintense lesions (48% vs. 58%; p=0.04) or with gadolinium enhancing lesions at 24 months (7% vs 19%; p<0.0001). Both of these MRI findings are indicators of disease activity.

Alemtuzumab also appeared to slow the loss of brain volume (-0.867% vs. -1.488%; p<0.0001).

The most common adverse events in the alemtuzumab group were infusion-associated reactions. Infections were also more common in the alemtuzumab group than the interferon beta-1a group. Autoimmune disorders involving the thyroid and platelets were also observed, consistent with previous studies. With proactive monitoring, these autoimmune complications were detected and successfully treated.

A double-blind design was not practical in this study due to differences in the modes of administration of the drugs. Although clinicians and patients were aware of treatment assignments, those performing clinical assessments or interpreting MRIs were blinded to the treatment groups.

In sum: Alemtuzumab shows promise as a treatment of early relapsing-remitting MS. It significantly reduces the rate of relapse and slows disease progression on MRI. It is associated with some treatable, but potentially serious adverse events.

The efficacy of alemtuzumab in this study raises the possibility that it could be useful in other inflammatory or autoimmune conditions. Indeed, it is being investigated as a lymphocyte-depleting immunosuppressant for conditions such as graft-versus-host disease. However, beyond lymphocyte-depletion alone, the efficacy of pulsed alemtuzumab here suggests that the paradigm of depleting and then reconstituting lymphocytes should specifically be investigated.

Alemtuzumab has been withdrawn from the European and American markets as Genzyme pursues licensing it as a treatment for MS. There are concerns that price increases might make it unaffordable for patients and even some healthcare systems.  

Click to read the study in The Lancet

Click to read an accompanying editorial in The Lancet

By [TJ] and [MP] 

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