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Daclizumab Plus Interferon Found Safe and Effective Combination Therapy for Active MS

ARTICLE IN BRIEF

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In a randomized, placebo-controlled trial, combined interferon and daclizumab therapy was safe and effective at 48 weeks in patients with relapsing-remitting MS.

Daclizumab (Zenapax) helped control brain lesions in patients with active relapsing-remitting multiple sclerosis (RRMS) who participated in a placebo-controlled trial of interferon. Reported at the AAN annual meeting in Chicago on April 16, the findings suggest that patients need to be on the drug to gain benefit, because the added effect of daclizumab disappears once treatment is stopped, said the lead author, Michael D. Kaufman, MD, director of the Multiple Sclerosis Center and Carolinas Medical Center in Charlotte, NC.

“The results suggest that this treatment, when administered for 24 weeks, does not change the fundamental nature of the disease over the long term,” Dr. Kaufman said. “Both our study and an earlier study suggest that daclizumab is safe in patients taking interferon and is a good fit with interferon.”

Daclizumab is an injectable immunosuppressant approved for prevention of allograft rejection associated with kidney transplant. Two small pilot studies investigated the effect of the drug in MS using MRI outcome as an endpoint. In a study of 10 patients with active MS, sponsored by the NIH and reported in 2004 in The Proceedings of the National Academy of Science, daclizumab significantly reduced the number of new or contrast-enhancing lesions on MRI and also reduced the number of relapses. A second study of nine patients, reported in Neurology in 2007, found that adding daclizumab to interferon significantly reduced new and contrast-enhanced lesions. The protocol allowed for withdrawal of interferon, and after interferon was withdrawn, MRI activity increased in some patients, but when interferon was resumed, good control of lesions was again seen.

“This study suggests that the efficacy of interferon and daclizumab are complementary and all of the beneficial effect upon MRI activity is not due to daclizumab alone,” Dr. Kaufman noted.

STUDY PROTOCOLS

The current study enrolled 230 patients with active RRMS. Active MS was defined in those who had either one or more gadolinium-enhancing lesions or one or more relapses within the past 12 months. Patients continued interferon treatment and were randomized to receive high-dose daclizumab (2 mg/kg every two weeks); low-dose daclizumab (1 mg/kg every two weeks); or placebo. Mean age of patients was 40.8 years in the placebo group, 38.2 years in the low-dose daclizumab group, and 40.4 years in the high-dose daclizumab group. The ratio of females to males in each group was roughly 3:1. Patients were treated for 24 weeks and followed for an additional 48 weeks.

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DR. MICHAEL D. KAUFMAN: “This study suggests that the efficacy of interferon and daclizumab are complementary and all of the beneficial effect upon MRI activity is not due to daclizumab alone.”

The 24-week data, reported last October at a meeting of the European Committee for Treatment and Research in Multiple Sclerosis by Xavier Montalban, MD, showed that high-dose daclizumab had a significant effect on new and enlarging gadolinium-enhancing lesions at each time point during 24 weeks of treatment, while low-dose daclizumab had a significant effect at only one time point. At 24 weeks, there was a 72 percent reduction in new or enlarging gadolinium-enhancing lesions in the high-dose daclizumab group, in contrast to a 25 percent reduction in the low-dose group.

“These results should be viewed with a caveat: the number of gadolinium-enhancing lesions was significantly higher in the low-dose group at baseline, which may be part of the reason that the low dose had a less robust effect,” Dr. Kaufman speculated.

The adjusted annualized relapse rate at 24 weeks was reduced by 30 percent in the low-dose group and 34 percent in the high-dose group. The annualized relapse rate unadjusted for baseline relapse rate was 42 percent in the low-dose group and 51 percent in the high-dose group.

At 48 weeks, the difference favoring daclizumab had disappeared. “This implies that you have to be on the drug to get benefit,” Dr. Kaufman told Neurology Today.

SAFETY CONCERNS

Safety concerns about combining a monoclonal antibody with interferon have increased because of problems with a comparable antibody, natalizumab (Tysabri), when added to interferon. This study raised no new safety concerns for the combination of interferon plus daclizumab, however.

The overall rate of infection was similar in patients receiving active drug and placebo, but the rate of cutaneous reactions was higher in those who received daclizumab. A higher rate of serious infections also occurred with daclizumab. Serious infections in the daclizumab groups included pulmonary infections (three), sinusitis (one), and sepsis (two). “However, there was no particular pattern of infections related to daclizumab,” Dr. Kaufman said.

The drug will be studied further. “In the future, daclizumab may be useful in patients who fail on other drugs for MS,” Dr. Kaufman said.

Daclizumab binds to the high-affinity receptor of interleukin-2 (IL-2), which down-regulates activated T cells and impedes their proliferation. Dr. Kaufman said that another mechanism of action may be related to the increased binding of IL-2 to its intermediate affinity receptor, which results in activation of natural killer CD56-bright cells that then kill activated T cells.

QUESTIONS ABOUT THE STUDY

Jack Antel, MD, who was not involved with the study, questioned the basis for the statement that the observed effects are not due to daclizumab alone, as all patients were on interferon. Dr. Antel is chair of the department of neurology and neurosurgery at Montreal Neurologic Hospital and Institute at McGill University in Montreal.

Dr. Kaufman responded that the best evidence for both drugs having an effect when given concurrently comes from the 2007 report in Neurology by John W. Rose, MD, and co-investigators at the University of Utah in Salt Lake City, and not the current study.

He added that Dr. Rose added daclizumab to interferon and noted a drop in the occurrence of gadolinium-positive lesions. “In his open-label trial, he then stopped the interferon so that they were taking only daclizumab, an action that was followed by an increase in gadolinium-positive lesions, and that, in turn, was reversed by adding back interferon.”

Dr. Antel also wanted to know more about how interferon and daclizumab work together. Dr. Kaufman noted that there is no evidence that interferon and daclizumab work together on a mechanistic level. “Their effects could be additive, synergistic, or overlapping. I never meant to imply a mechanistic interaction; only that the treatment effect appeared to be better when the drugs were used together than with either drug alone. Again, this is based on the data by Rose, et al., not the current study,” he emphasized. “Since there were so few patients in Dr. Rose's study, this is a hypothesis and not fact.”

REFERENCES

• Bielekova B, Richert N, McFarland HF, Martin R, et al. Humanized anti-CD25 (daclizumab) inhibits disease activity in multiple sclerosis patients failing to respond to interferon beta. Proc Natl Acad Sci 2004;101(23):8705–8708.
    • Rose JW, Burns JB, Carlson NG, et al. Daclizumab phase II trial in relapsing and remitting multiple sclerosis: MRI and clinical results. Neurology 2007;69:785–789.