Just weeks after receiving an EU marketing authorization, the FDA has issued a complete response letter to Biogen for its sBLA related to the subcutaneous administration of natalizumab (Tysabri).
Biogen has announced that the FDA has sent it a complete response letter (CRL) for its submission of a supplemental biologics license application (sBLA) for the novel subcutaneous administration of its approved relapsing multiple sclerosis (MS) agent natalizumab (Tysabri). The CRL, indicating that the agency cannot approve the filing as submitted, is currently being evaluated by Biogen as it determines the next steps.1
This news comes just weeks after the early April announcement that the European Union had granted marketing authorization for the subcutaneous administration of natalizumab for relapsing MS.2 This subcutaneous version of the disease-modifying therapy (DMT) is also delivered in a dose of 300 mg every 4 weeks. Biogen has noted that it plans to pursue filings for this route of administration in additional countries.
“We are committed to MS and pursuing innovations such as new routes of administration to help provide options that could address the individual needs of patients,” said Maha Radhakrishnan, MD, chief medical officer, Biogen, in a statement accompanying the announcement.1 “This response from the FDA does not affect the intravenous administration of TYSABRI, a well-established high-efficacy treatment with a well-characterized safety profile, which over the last 15 years has treated more than 200,000 people worldwide with relapsing MS.”
Neither the company nor the regulatory agency clarified the specific details of the CRL for natalizumab. The recombinant humanized IgG4k monoclonal antibody was originally approved by the FDA in November 2004 for the treatment of relapsing forms of MS and has since been granted indications for treating moderately to severely active Crohn's disease.
Also this month, data from a recent study presented by Carrie Hersh, DO, MSc, assistant professor, neurology, Cleveland Clinic Lou Rovo Center for Brain Health, at the 2021 American Academy of Neurology (AAN) Annual Meeting, April 17-22, suggest that natalizumab treatment improved mental and social health in patients with multiple sclerosis.3 The recent EU decision to approve this new route of administration was made based on supporting data from the DELIVER (NCT00559702) and REFINE (NCT01405820) studies.
DELIVER was a 32‐week, open‐label, phase 1b multicenter study of natalizumab‐naive patients (n = 76) with relapsing‐remitting MS (n = 24) or secondary progressive MS (SPMS; n = 52) randomized to receive 300-mg natalizumab by subcutaneous injection, intramuscular injection, or intravenous (IV) infusion. Pharmacokinetic and pharmacodynamic data were evaluated over 8 weeks after the first natalizumab treatment (Part 1) and over 24 weeks with repeated dosing every 4 weeks, beginning at week 8 (Part 2).4
All told, following subcutaneous or intramuscular administration, peak serum concentrations were approximately 40% of those observed with IV administration and showed no major differences in elimination characteristics. The mean bioavailability relative to IV administration was 57.1% to 71.3% with subcutaneous natalizumab and 48.7% with intramuscular. The mean trough serum concentrations were similar between IV and subcutaneous administration, but lower with intramuscular natalizumab. Post-single or -multiple doses of natalizumab, pharmacodynamic response was comparable across administration routes and disease stages. As well, no meaningful differences were observed between groups in the incidence or nature of overall adverse events (AEs), serious AEs, administration site reactions, hypersensitivity reactions, or anti-natalizumab antibodies.
REFINE, on the other hand, was an exploratory, dose- and frequency-blinded, prospective, dose-ranging study in relapsing-remitting MS. It included 290 individuals evenly randomized to 300-mg doses administered by IV every 4 weeks (n = 54), subcutaneously every 4 weeks (n = 45), by IV every 12 weeks (n = 52), and subcutaneously every 12 weeks (n = 54), as well as 150-mg doses administered every 12 weeks by IV (n = 47) or subcutaneously (n = 38).5
All told, the 12-week dosing arms were all associated with increased clinical and MRI disease activity and closed early, with at least 39.5% of patients in each arm meeting rescue criteria. In the 300-mg IV and subcutaneous 4-week dosing arms, the mean cumulative number of combined unique active MRI lesions was 0.23 and 0.02, respectively; annualized relapse rates were 0.07 and 0.08, respectively; and trough natalizumab serum levels and α4-integrin saturation were comparable between groups. AEs were reported for 223 of 289 patients (77.2%), most of which were mild in severity and deemed not related to study treatment. The overall study population reported AEs considered related to study treatment during the randomized treatment period at a rate of 27.3%. The most common treatment-related AEs were consistently low in both the IV and SC 4-week administration treatment arms.
At the time of EU approval, Sven G. Meuth, MD, PhD, professor of neurology, and director, Clinic of Neurology, University Hospital of Düsseldorf, said in a statement that the subcutaneous administration “expands choices when it comes to controlling MS disease activity. I believe the SC administration offers an opportunity to receive comparable efficacy and safety to the intravenous formulation with reduced administration time which may be meaningful for patients. For physicians, the SC administration offers the ability to prescribe and administer TYSABRI in their practice, providing more locations where patients can be treated.”2