6-Week Dosing of Natalizumab Effective, May Reduce PML Risk

Disease Spotlight | <b>Disease Spotlight: Multiple Sclerosis</b>

Efficacy data from a trial examining extended dosing adds to real-world data that demonstrates a significant reduction in the probability of progressive multifocal leukoencephalopathy infection.

Results from the phase 3b NOVA study (NCT03689972) showed no statistically significant differences in efficacy when extending the approved 4-week (QW4), 300-mg natalizumab (Tysabri, Biogen) intravenous (IV) dosing schedule to a 6-week (QW6) schedule in patients with relapsing-remitting multiple sclerosis (MS). The study findings complement real-world data that suggest a QW6 dosing schedule may significantly reduce the risk of developing progressive multifocal leukoencephalopathy (PML). 

The randomized, controlled, open-label, rater-blinded study enrolled 500 participants, all of whom had at least 1 year of disease stability on the QW4 IV dosing schedule. In studying each treatment arm, investigators saw a mean number of new or newly enlarging T2 hyperintense lesions at week 72 of 0.20 in the Q6W group compared with 0.05 in the Q4W group (P = .0755), showing no clinical significance. The higher lesion count in the Q6W group was largely attributed to a patient who developed lesions 3 months after discontinuing treatment and another who developed asymptomatic PML. The efficacy data coincide with an updated safety analyses of the Tysabri Outreach: Unified Commitment to Health (TOUCH) Prescribing Program which showed an 88% reduction in the probability of developing PML infection in the Q6W dosing group (hazard ratio [HR] 0.118; P <.0001) when compared with the Q4W dosing regimen.

“The NOVA study provides the first prospective, randomized efficacy data of every 6-week dosing with natalizumab, building on its well-established clinical profile and the real-world findings,” Maha Radhakrishnan, MD, chief medical officer, Biogen, said in a statement.1 “In addition to the safety analyses from the TOUCH Prescribing Program, which showed significant reduction in the probability of PML, the results from NOVA deliver a more comprehensive understanding of the 6-week dosing regimen of natalizumab.”

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Secondary end points showed no clinically meaningful differences between the dosing regimens, according to investigators, as relapse rates were low, 0.00010 (Q4W) and 0.00013 (Q6W), with relapse-free rates at 97.9% and 97.2%, respectively. Additionally, 1.1% of patients in the Q4W group developed hypointense lesions compared with 1.4% in the Q6W group. Notably, 0.5% of participants in both groups has gadolinium-enhancing T1 lesions. 

The occurrence of adverse events (AEs) and serious adverse events were consistent in both the Q4W and Q6W treatment arms, confirming the existing safety profile for IV natalizumab. The patient in the Q6W arm who developed asymptomatic PML was at higher risk, according to investigators, with an anti-JC virus antibody index greater than 1.5 and over 2 years of natalizumab treatment. Future research is necessary to monitor PML risk and better understand associated risk factors with the treatment.

Results from the ongoing NOVA study follow findings from another study, which concluded that natalizumab may offer an effective treatment option to minimize the risk of postpartum relapses in pregnant women with MS, who typically pause treatment with disease-modifying therapy during pregnancy. According to study findings published in Neurology, results showed particular benefit for women who were at a low risk for PML infection.2 

DMT reinitiation with natalizumab protected against postpartum relapse (HR, 0.11 [95% CI, 0.04-0.32]; P <.0001), while continuation of natalizumab use into pregnancy reduced the odds of relapse during pregnancy (odds ratio [OR], 0.76 per month [95% CI, 0.60-00.95]; P = .017). In general, investigators found reinitiation with high-efficacy DMT was independently protective against postpartum relapse and reduced the hazard of relapse by 88.9% (HR, 0.111 [95% CI, 0.0382-0.322]; P <.0001 compared to no treatment reinitiation). Additionally, those who breastfed were also less likely to experience disease relapse (HR, 0.61 [95% CI, 0.41-0.91]; P = .016).2

In April of this year, Biogen announced that the FDA had sent a complete response letter for the submission of a supplemental biologics license application for the novel subcutaneous administration of natalizumab. The news followed the announcement earlier in April that the European Union had granted marketing authorization for the use of subcutaneous natalizumab for relapsing MS. 

REFERENCES
1. Biogen announces results from phase 3b NOVA study evaluating every six-week dosing with natalizumab in relapsing-remitting multiple sclerosis. News release. August 2, 2021. https://www.biospace.com/article/releases/biogen-announces-results-from-phase-3b-nova-study-evaluating-every-six-week-dosing-with-natalizumab-in-relapsing-remitting-multiple-sclerosis/
2. Yeh WZ, Widyastuti PA, Van der Walt, A, et al. Natalizumab, fingolimod, and dimethyl fumarate use and pregnancy-related relapse and disability in women with multiple sclerosis. Neurology. 2021;96:e2989-e3002. doi:10.1212/WNL.0000000000012084