Philadelphia, PA—Extending the dosing interval of natalizumab to every 6 to 8 weeks may lower the risk for progressive multifocal leukoencephalopathy (PML) without affecting efficacy in patients with multiple sclerosis (MS).
A review of 601 patients receiving extended dosing of natalizumab at MS centers in the United States found no cases of PML, said Joseph Herbert, MD, Director of the MS and Neurorehabilitation Care Center, New York University, NY, at the 2014 American Academy of Neurology meeting.
The risk of PML in recipients of natalizumab who are seropositive for JC virus (JCV) antibodies is 0.7% without previous immunosuppression and 1.3% with previous immunosuppression. The current guidelines for the treatment of MS call for a standard 300-mg dose of natalizumab administered every 4 weeks.
It is thought that saturation of the alpha-4 integrin receptor underlies susceptibility to PML, because it leads to the excessive reduction in tissue compartment trafficking of the immune cells that are required for JCV surveillance. The saturation of the alpha-4 integrin receptor on circulating lymphocytes depends on the serum concentrations of natalizumab. After a single 300-mg dose of natalizumab infusion, alpha-4 integrin saturation reaches >80% and does not fall below 75% over 4 weeks.
“Our hypothesis is that probably we’re oversaturating the receptor, and thereby we’re being too aggressive about reducing the normal immune surveillance that takes place,” said Dr Herbert. “The original dosing, 300 mg every 4 weeks, was based on the premise that you needed to maintain maximal saturation of the receptor. Usually with a biological there should be a weight-based calculation.”
Dr Herbert and colleagues hypothesized that extending the dose of natalizumab may produce intermediate alpha-4 integrin saturation that is still “MS protective” yet will permit anti-JCV lymphocyte immune surveillance in the central nervous system and/or the peripheral circulation.
They looked at data from 601 patients treated with extended natalizumab dosing at 6 large MS centers in the United States. They defined extended dosing as every 4 weeks and 3 days to every 8 weeks and 5 days.
The annualized relapse rate was 0.12, 0.18 among patients receiving early extended dosing, and 0.08 among those receiving late extended dosing. A total of 62% of patients had no clinical or radiologic evidence of disease activity. Extended dosing was discontinued in 32% of patients. There were no new cases of PML over 680 JCV antibody–positive person-years.
Thinner patients metabolize natalizumab more poorly and are more susceptible to PML, said Dr Herbert. “We’re going to have to develop algorithms that tie in the individual dose, the frequency of the dose, and the patient’s individual metabolism, body mass index, and JCV index, and determine the optimal integrin saturation that you’re trying to achieve in the serum for each patient,” he noted.
Dr Herbert said that he presents extended dosing of natalizumab as an option to his patients, and many of his patients are using a dosing schedule of every 6 to 8 weeks. “I explain to patients that what we’re doing is not proven, and so far there have been no PML cases,” he said. “When the patients hear it explained, and they see that you’re considering the risk, and you’re taking some kind of action to minimize it, the majority of patients, even the JCV positive, are opting to stay on the drug. That may change once the first case of PML occurs.”