September 24, 2008 (Montreal, Quebec) — Alemtuzumab (Campath, Genzyme/Bayer Healthcare Pharmaceuticals), currently under investigation for the treatment of relapsing and remitting multiple sclerosis (RRMS), appears to have remarkable efficacy, even compared with high-dose interferon beta-1a, a new study shows.

If these phase 2 results are confirmed in phase 3 trials that are now ongoing, "this could be a powerful drug," lead author Krzysztof W. Selmaj, MD, PhD, DSc, chair of the neurology department at the Medical University of Lodz, in Poland, told Medscape Neurology & Neurosurgery.

However, adverse effects remain a concern with this drug. In this trial, alemtuzumab therapy was associated with higher rates of immune thrombocytopenic purpura, thyroid dysfunction, infusion reactions, and predominantly mild and moderate infections than with interferon beta-1a.

The phase 2 results were presented here at the World Congress on Treatment and Research in Multiple Sclerosis: 2008 Joint Meeting of the American, European, and Latin America Committees on Treatment and Research in Multiple Sclerosis (ACTRIMS, ECTRIMS, LACTRIMS). The trial was supported by Genzyme.

Monoclonal Antibody

Alemtuzumab is a humanized monoclonal antibody that targets CD52 on the surface of both T and B cells. It is currently approved for use in B-cell chronic lymphocytic leukemia (B-CLL) and is in phase 3 trials for the treatment of RRMS.

"We need better drugs for MS patients," Dr. Selmaj told Medscape Neurology & Neurosurgery in an interview here; current drugs are "quite modest" in their effects, he said. As a monoclonal antibody, alemtuzumab influences immune and pathologic processes very specifically. "This monoclonal antibody interacts with lymphocytes, and . . . we hypothesize that lymphocytes are instrumental in multiple sclerosis."

CAMMS223 was a phase 2 study in which 334 treatment-naive patients with early active RRMS were randomized to receive alemtuzumab 24 mg, alemtuzumab 12 mg, or interferon beta-1a 44 µg. Alemtuzumab was delivered via intravenous injection in yearly cycles that included once-daily administration for 5 days at month 0 and again for 3 days at month 12. Some patients also received 3 days of therapy at month 24. Interferon was given 3 times per week via subcutaneous injection.

Dr. Selmaj presented 36-month follow-up results in which data on both alemtuzumab dosing groups were pooled. The cumulative number of relapses over time was reduced by 74%, and the time to sustained accumulation of disability (SAD) was reduced by 71% with alemtuzumab, compared with interferon (P < .0001 for both).

In addition, while the Expanded Disability Status Scale (EDSS) increased by a mean of 0.38 points among those on interferon, it actually decreased by 0.39 points for those on alemtuzumab.

The proportion of patients who remained relapse free was 50% with interferon, vs 80% with alemtuzumab (P < .0001). At 3 months, 67% of patients on interferon and 86.3% on alemtuzumab were free of SAD, while 74% on interferon vs 91% on alemtuzumab were SAD free at 6 months (P < .005 for both).

Similarly, 39% of those on interferon vs 71% of those on alemtuzumab were both relapse and SAD free for 3 months, while 43% of interferon patients vs 74% of alemtuzumab patients were relapse and SAD free for 6 months (P < .0001 for both).

"These are figures that have not been seen in any clinical trials in MS, ever,” said Dr. Selmaj.

Data "Phenomenal"

Rhonda Voskuhl, MD, professor in the department of neurology and director of the Multiple Sclerosis Research and Treatment Program at the University of California, Los Angeles, moderated the session where these results were presented. She shared Dr. Selmaj's enthusiasm about the efficacy results. "The data looked phenomenal," she told Medscape Neurology & Neurosurgery.

Although among the best and safest treatments to date for MS, interferon beta-1a still reduces relapses only by about one-third, she said. "The fact that alemtuzumab looked so much better than interferon beta is very exciting."

Adverse effects were a concern with alemtuzumab, however. Overall, 13 patients taking alemtuzumab at either dose experienced grade 3 infections, vs only 1 on interferon. There were no grade 4 or 5 infections.

More alarmingly, 23% of patients on alemtuzumab experienced autoimmune thyroid dysfunction, compared with 3% on interferon. Immune thrombocytopenic purpura (ITP) occurred in 6 of the 216 patients on alemtuzumab and only 1 on interferon. The interferon-treated patient developed intracranial hemorrhage before ITP was diagnosed and subsequently died. The other 5 cases of ITP were identified early and either reversed spontaneously or responded to treatment.

"The thrombocytopenia does not have acute symptoms," said Dr. Selmaj. "They develop over time, a couple of weeks. So, it is believed that we'll be able to detect patients who are at risk of thrombocytopenia; they can be withdrawn from the [drug], and they can be given steroids, which, under normal conditions, will bring platelet count into the normal range."

Nevertheless, Dr. Voskuhl believes the risk for such an adverse event relegates the drug primarily to second-line therapy. "MS is a disease that affects really young people who don't have that much disability at [the outset]," she said, "so, until they fail 1 of these other treatments, it doesn't want to make you use [alemtuzumab] as a first-line treatment if [it has] these significant adverse events."

Two phase 3 studies with alemtuzumab are currently under way. Platelet counts will be monitored closely.

This research was funded by Genzyme. Dr. Selmaj reports he has received funds from Genzyme.

World Congress on Treatment and Research in Multiple Sclerosis: 2008 Joint Meeting of the American, European, and Latin America Committees on Treatment and Research in Multiple Sclerosis (ACTRIMS, ECTRIMS, LACTRIMS): Abstract 55. Presented September 19, 2008.

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