Previous analysis has suggested that an extended dosing regimen can reduce the risk of progressive multifocal leukoencephalopathy for patients with relapsing multiple sclerosis.
Alfred Sandrock, Jr., MD, PhD
The first patent has been enrolled in a global phase 3b study to evaluate the safety and efficacy of extended interval dosing with natalizumab (Tysabri, Biogen) compared to the standard interval dosing, in patients with relapsing multiple sclerosis (MS).1
Currently, patients on the disease-modifying therapy use the treatment in a 300-mg dose every 4 weeks, which is the FDA-approved regimen. The extended interval dosing period being assessed in this study, called NOVA (NCT03689972), is 6 weeks.
“For more than a decade, natalizumab has been considered a highly effective treatment option for patients with relapsing forms of MS,” Alfred Sandrock, Jr., MD, PhD, the executive vice president and chief medical officer at Biogen, said in a statement.
The study will be a 2-year, prospective, randomized, interventional, controlled, open-label, rater-blinded study. It plans to enroll 480 patients with MS worldwide, with a primary end point of the number of new or newly enlarging T2 hyperintense lesions at 48 weeks. Patients in the trial who switch to extended interval dosing after 1 year of standard interval dosing with natalizumab will be evaluated in relation to those that continue the standard regimen.
The trial is expected to be completed in December 2020.
“The NOVA study may generate valuable data that we hope will answer questions for the scientific community about the efficacy of natalizumab when its dosing schedule is extended to every 6 weeks, and in conjunction with prior safety analyses, may inform on the drug’s benefit-risk profile,” Sandrock said.
Use of natalizumab, a monoclonal antibody against α4-integrin, has been associated with an increased risk of progressive multifocal leukoencephalopathy (PML), a rare but serious opportunistic brain infection caused by the JC virus.2 The highest estimated risk—an incidence of 11.1 cases per 1000 patients (95% CI, 8.3 to 14.5)—is in patients who have tested positive for anti—JC virus antibodies, who had taken immunosuppressants before the initiation of natalizumab, and who had received 25 to 48 months of natalizumab treatment.3
“You could ask the question: Is it a wise idea to keep a patient who had relapsing disease—and now has secondary progressive MS—on natalizumab, particularly if they’re JC virus antibody--negative? I don’t know if that makes a lot of sense at this point, and that’s an unknown. Based on the data from the trial, we’d say it’s probably not a great idea because the data didn’t really support it,” Clyde E. Markowitz, MD, the director of the Multiple Sclerosis Center at the University of Pennsylvania, told NeurologyLive.
Markowitz questioned if the safety profile could be improved by changing the frequency of infusions, noting that that very question is currently being explored. He said that a small group of clinicians in the United States assessed an extended dosing schedule and were able to show that it may reduce the risk of PML. “They didn’t have enough patients to really answer that question,” he explained.
“But when it comes to patients with progressive disease, I don’t know that this is going to be the right approach. That’s the problem,” he added.
According to Biogen, previous analysis from the TYSABRI Outreach: United Commitment to Health (TOUCH) REMS program, which explored the impact of extended interval dosing’s impact on PML risk compared to standard interval dosing, indicated that extended interval dosing with natalizumab has suggested a significant reduction in the risk of PML.
1. First patient enrolled in Biogen’s phase 3b study to evaluate extended interval dosing (EID) with natalizumab in multiple sclerosis [press release]. Cambridge, MA: Biogen Inc; Published January 3, 2019. investors.biogen.com/news-releases/news-release-details/first-patient-enrolled-biogens-phase-3b-study-evaluate-extended. Accessed January 9, 2019.
2. FDA Drug Safety Communication: New risk factor for Progressive Multifocal Leukoencephalopathy (PML) associated with Tysabri (natalizumab). FDA website. fda.gov/Drugs/DrugSafety/ucm288186.htm Published January 20, 2012. Accessed January 9, 2019.
3. Bloomgren G, Richman S, Hoterman C, et al. Risk of natalizumab-associated progressive multifocal leukoencephalopathy. N Engl J Med. 2012;366:1870-1880. doi: 10.1056/NEJMoa1107829