SAN DIEGO—In new studies, investigators detailed how treatment with natalizumab (Tysabri) benefited patients with multiple sclerosis (MS).
In one study of quality-of-life measures, treatment with natalizumab showed improvement over baseline.
“To my knowledge,” said Richard Rudick, MD, Chairman of the Division of Clinical Research at the Cleveland Clinic Foundation in Ohio, “this is the first time we have ever observed positive findings in quality-of-life measures in a phase III multiple sclerosis study.”
Natalizumab is a monoclonal antibody that reduces the frequency of MS relapses and was approved in the United States before it was withdrawn by the Food and Drug Administration (FDA) after cases of progressive multifocal leukoencephalopathy (PML) followed this treatment.
PML, a rare and frequently fatal, demyelinating disease of the CNS, was diagnosed in three people enrolled in those studies. The drug was withdrawn from the market in February 2005, but is again being reviewed by the FDA to determine if it can be returned to market.
Dr. Rudick combined results of the Natalizumab Safety and Efficacy in Relapsing Remitting Multiple Sclerosis study, dubbed AFFIRM, which showed that natalizumab slowed the progression of relapsing-remitting multiple sclerosis compared to placebo (N Engl J Med 2006;354:899-910). In the SENTINEL trial – or, Safety and Efficacy of Natalizumab in Combination with Interferon Beta-1a in Patients with Relapsing Remitting Multiple Sclerosis – the combination of natalizumab and interferon beta-1a (Avonex) was more effective than interferon beta-1a alone (N Engl Med 2006;354:911-923). [These studies, which were sponsored by Biogen IDEC and Elan Pharmaceuticals, were featured in the April 18 issue of Neurology Today, page 1.]
In AFFIRM, researchers enrolled 942 patients and 800 completed the quality-of-life measurements – 264 were on placebo and 536 on natalizumab. In the physical well-being domain, they observed a 1.3-point drop in scores of patients on placebo but a 0.7 improvement in scores for those on natalizumab (p = .003), Dr. Rudick said.
In the mental well-being part of the quality-of-life measure, a similar pattern was observed. Patients on placebo had a 0.5-point drop in scores, while those on natalizumab improved by 2 points, which was a significant difference (p = .011 level), he said.
In the SENTINEL study, the same trends were seen. In patients on combination treatment, there was a 1.03-point improvement in physical well-being scores compared to a decrease of 0.97 in controls who did not receive natalizumab. That was a significant difference (p = .001). In the mental well-being part, patients on combination treatment improved scores by 0.18 compared with a decrease of 0.96 for those not taking natalizumab. That difference was not significant.
In a second study reported at the meeting, J. Theodore Phillips, MD, PhD, Director of the Multiple Sclerosis Center at Texas Neurology in Dallas, reported: “Natalizumab significantly suppressed MRI changes attributed, at least in part, to irreversible axonal damage.”
In the prospective double-blind study, 942 people with relapsing multiple sclerosis were randomized to receive placebo or 300 mg natalizumab intravenously every four weeks. They were followed for measures of disability progression including the Expanded Disability Status Scale (EDSS) score and Multiple Sclerosis Functional Composite.
After two years, there was a 42 percent reduction in disease progression, the primary endpoint, for patients treated with natalizumab compared to those who received placebo.
The extent of confirmed change in the EDSS score was also significantly better for the natalizumab group. There was “essentially no change” in disability (0.04 points) for natalizumab-treated patients over two years compared to a “small worsening” of 0.41 points for those given placebo.
About three times fewer patients who received natalizumab reached EDSS milestone scores of 4.0 or 6.0 compared to those on placebo. Functional composite scores were statistically superior at all time points for natalizumab-treated patients compared to placebo-treated patients. The component functional scores were also all significantly better with natalizumab versus placebo.
The mean number of new T1-hypointense sclerosis lesions seen on cranial MRI in two years was 76 percent lower for the natalizumab group than the placebo group. The mean change in volume of T2-hyperintense lesions was also significantly lower with natalizumab.
The elephant in the room, however, remains the side effect profile of natalizumab. In a poster presentation, Paul O'Connor, MD, Associate Professor of Neurology at the University of Toronto, noted that even after patients stopped natalizumab, the relapse rate continued to be lower over the long-term than baseline.
“I think that is due to a carryover effect of the drug,” Dr. O'Connor said. His analysis of the controlled studies and open-label safety extension studies of natalizumab included 2,321 patients, representing 3,804 person-years of use of natalizumab, and they were compared with 1,135 patients who were given placebo. During these studies, about 97.3 percent of placebo patients and 96 percent of natalizumab patients had adverse effects, notably headache, relapse of multiple relapse, nasopharyngitis, or fatigue.
The study included the two cases of PML, one fatal. He said a third case was discovered in a subsequent review of cases in a patient with Crohn disease who had previously been treated for astrocytoma. “We are pretty sure that the drug is partly to blame for these cases,” Dr. O'Connor said.
Aside from the opportunistic infections, he said there did not seem to be other safety issues with natalizumab. He said the safety profile was similar to placebo; the incidence of serious infections did not increase with extended use of natalizumab; and there was no rebound in multiple sclerosis disease activity when the antibody was discontinued.
He said the FDA will review the new data on natalizumab in June to determine marketability. “We need further studies on safety to be comfortable in prescribing this drug for patients with multiple sclerosis,” he said.
“I still do not think natalizumab is ready for prime-time use,” said Timothy Vollmer, MD, Chairman of the Division of Neurology at Barrow Neurological Institute at St. Joseph's Hospital in Phoenix, AZ. “The incidence of PML remains at 0.2 percent and we still have no way of determining which patients are likely to develop this opportunistic infection, and once this infection becomes active in the brain we have limited ways of treating it,” said Dr. Vollmer, who was not involved in the studies.
While the incidence is rare, Dr. Vollmer explained, it is also quite deadly. “For that reason, if the FDA brings natalizumab back to the market, I would restrict its use to my patients who have the most aggressive form of relapsing multiple sclerosis,” he said. “For those patients, the risk-benefit ratio would make it feasible to prescribe the drug.”
He estimated that about 80 percent of patients with MS have the relapsing form of the disease and about 10 to 15 percent of those patients have aggressive characteristics of the disease. He said there is no evidence that natalizumab has any impact on patients with progressive multiple sclerosis.
Dr. Vollmer said natalizumab is a remarkable, well-tolerated agent in that it is directed at the single pathway that is involved in MS. However, by effectively preventing cytokines from damaging neurons, natalizumab appears to prevent these immune system watchdogs from keeping surveillance on JC-virus in a small number of patients. JC-virus, he said, is part of the human viral package that virtually all individuals carry, usually without any problems.
Uncontrolled infection with JC-virus can occur in severely immunosuppressed individuals such as transplant patients, patients undergoing chemotherapy, or patients with HIV infection and can result in PML.
He said that until scientists can determine who is most likely to develop PML or how the infection can be successfully treated, he would be hesitant to widely prescribe natalizumab.
ARTICLE IN BRIEF
- ✓ Three studies – on quality-of-life measures, MRI disease progression, and safety – reported that natalizumab benefited patients with multiple sclerosis.