BARCELONA—Extended-interval dose therapy with natalizumab may reduce the risk of progressive multifocal leukoencephalopathy (PML), reduce annualized relapse rate, and decrease the likelihood of new T2 lesions in high-risk patients with multiple sclerosis (MS), according to Lana Zhovtis-Ryerson, MD, a neurologist at New York University Langone MS Comprehensive Care Center in New York City.
Lana Zhovtis-Ryerson, MD
Previous attempts to mitigate the risk of PML associated with natalizumab by altering the optimal dosing frequency through drug holidays compromised the efficacy of treatment, Dr. Zhovtis-Ryerson explained at the 31st Congress of the European Committee for Treatment and Research in MS (ECTRIMS). “Our hypothesis is that extending the dosing frequency up to eight and a half weeks may be safely enacted without clinical or radiographic worsening, and perhaps reduce PML risk,” she said.
Rebound of MS clinical activity tends to occur at 10 to 12 weeks following natalizumab withdrawal, Dr. Zhovtis-Ryerson said, suggesting that natalizumab-receptor saturation may be more germane to the drug’s disease-modifying effects than serum concentration. “Less frequent natalizumab dosing may result in submaximal receptor saturation, leading to a balance where there is adequate exclusion of white blood cells from the CNS, allowing the drug to be MS-protective,” she reported. At the same time, a PML-protective effect may occur because enough of the cells are entering the CNS to maintain immune surveillance of the John Cunningham virus (JCV) that causes PML.
Dr. Zhovtis-Ryerson and colleagues at nine MS centers in the United States examined 1,093 patients with MS who received standard-interval dose therapy with natalizumab and 905 patients with MS who received extended-interval dose therapy with natalizumab. Patients in the standard-interval dose group received 300-mg infusions of natalizumab every four weeks, while those in the extended-interval dose group waited up to eight weeks and five days between doses.
None of the patients in the extended-interval dose group developed PML during the study period, compared with four participants who developed PML in the standard-interval dose group. The study population had a total of 1,052 JCV-positive patient years. Post-market algorithms as reported by Biogen show an expected incidence of 2.5 cases of PML per 1,000 patients who are JCV-antibody positive, said Dr. Zhovtis-Ryerson.
The results are not statistically significant, but demonstrate a distinct trend, she added. The extended-dose interval group in this study would be considered to be at theoretically high risk of PML because of a combination of several risk factors, including testing positive for the JC antibody and having a high JCV index, a history of prior immunosuppression, and longer duration of therapy (ie, more than 24 months).
Annualized relapse rates were low in both groups, but “surprisingly,” the number of patients who showed clinical relapses was slightly lower in the extended-interval dose group, Dr. Zhovtis-Ryerson observed. Extended-dose interval schedules may be considered for patients with MS who are treated with natalizumab and are at high risk for PML, she added.
The investigators plan to continue monitoring the current cohort and to add pharmacodynamic studies evaluating CD34 cells and receptor saturation and concentration, Dr. Zhovtis-Ryerson said. A prospective, randomized trial of extended interval dosing with natalizumab is also needed, she concluded.
—Linda Peckel