HONOLULU—The humanized monoclonal antibody campath-1H (alemtuzumab) clearly suppresses the inflammation present in secondary progressive multiple sclerosis (MS) and makes the disease less likely to relapse. Disability continues to worsen, however, because campath-1H does not slow the axonal degeneration associated with secondary progressive MS.

It has been hypothesized, however, that starting treatment far earlier in the course of MS, when inflammation is much more of a factor in the development of the disease, may prevent axonal degeneration and, in turn, the progression of disability. That is exactly what investigators from the United Kingdom found when they performed long-term follow-up of 58 patients with MS who received campath-1H.

Of the 17 patients with earlier stage relapsing-remitting MS, who underwent treatment within a few years of disease onset, none became more disabled; indeed, most showed some recovery from previous disability. Most of the 36 patients with secondary progressive MS became increasingly disabled.

“And so we have switched strategy completely and now only treat patients with early active MS who have not entered the progressive phase,” said Alastair Compston, PhD, during a presentation at the 55th Annual Meeting of the American Academy of Neurology. Dr. Compston is Professor of Neurology at the University of Cambridge, United Kingdom.

PULSE THERAPY

In the study, campath-1H therapy consisted of a one-week intravenous pulse, which initially caused profound T-cell depletion. However, a subsequent rise in thymic activity led to recovery of CD8+ counts after 30 months and of CD4+ counts after 60 months. The restored T cells showed a reduction in mitogenic proliferation and interferon-gamma secretion.

At therapy initiation, the mean intervals since MS onset and progression in the secondary progressive group were 12 years and four years, respectively. The patients with relapsing-remitting MS had had their disease for an average of 2.7 years and had not yet entered the progressive phase. In the year preceding campath-1H therapy, their mean relapse rate was three per year and their mean score on the Expanded Disability Status Scale (EDSS) rose by 2.4 points.

“This is a bit of an uncontrolled study,” Dr. Compston acknowledged. Some patients opted out before treatment, he explained, because they were concerned about adverse effects.

BENEFITS OF EARLY INTERVENTION

The relapse rate was reduced even among the patients with secondary progressive MS during follow-up, which averaged seven years in that group. However, in addition to their increasing disability, these patients began to show signs of continuing brain atrophy starting in the second year of follow-up.

In contrast, campath-1H virtually eliminated relapse activity in the patients with relapsing-remitting MS, who were followed for an average of 13 months; during that time, their relapse rate decreased to 0.1 per year—in fact, only one patient in the group relapsed. Furthermore, their mean EDSS score fell to 0.5, indicating less disability.

However, campath-1H triggered an acute cytokine release syndrome in all patients that was associated with dramatically increased neurologic symptoms. These symptoms, the result of nitric oxide release and coincident lymphocyte toxicity, were fortunately fully reversible either spontaneously or with appropriate intervention.

“What we did not expect … is that a proportion of [the] patients, about one quarter of them, developed Graves’ disease in the second year of therapy,” reported Dr. Compston. No significant infective adverse effects were observed, though.

The study findings suggest that campath-1H is more efficacious during the early phase of MS, Dr. Compston concluded. The results are being confirmed in a multicenter randomized trial in the United States and Europe. The trial will compare campath-1H to recombinant interferon beta-1a during three years in patients with relapsing-remitting MS of less than three years’ duration and an EDSS score of less than 3.5.

NR

—Timothy Begany

Suggested Reading
Rovaris M, Filippi M. Interventions for the prevention of brain atrophy in multiple sclerosis: current status. CNS Drugs. 2003;17:563-575.

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