New eBook: The role of real-world evidence in FDA approvals. Download now.

FDA Decision Alerts December 14, 2020

CDER-Approved NDA for VILTEPSO® (viltolarsen)

Christina Purpura and Jen Polinski
Contributing writers, Aetion

On August 12, 2020, the FDA approved Nippon Shinyaku’s VILTEPSO® (viltolarsen) for Duchenne muscular dystrophy (DMD). Here are the key findings from the FDA’s Summary Review and Clinical Review of the drug:

  • The agency’s accelerated approval is based on the results of a phase 2, two-period, dose-finding study. Study NS-065/NCNP-01-201 (“Study 201”/NCT02740972; n=16) included low and high dose cohorts: 40 or 80 mg/kg/week, respectively. The sponsor used the change in dystrophin, which is a surrogate endpoint, as the major efficacy outcome. For both doses, the FDA determined that the drug produced statistically significant increases of dystrophin.
  • The sponsor also submitted the results of a natural history study, but this approach failed to win the approval of the FDA. The sponsor compared changes in functional tests from baseline in Study 201’s treatment groups to the patients in the natural history study. The FDA did not accept the sponsor’s approach due to the variability in the natural history of the disease, imprecision of population matching, and selection bias.
  • The FDA’s recommended dosage is 80 mg/kg/week. (The sponsor wrote: “Although the truncated dystrophin levels are similar between the two doses, the 80 mg/kg/week may be appropriate for approval based on marginally higher amounts of dystrophin by mass spectrometry method.” The sponsor later added: “There was also no notable difference in safety between the two doses.”) In the 80 mg/kg/week, the median increase in dystrophin levels was 1.9 percent, as measured by mass spectrometry.
  • At the time of submission, 32 patients were exposed to the sponsor’s drug. The primary safety data is from Study 201. Other contributions to the safety database include the 144-week extension of Study 201, called Study 202 (NCT03167255; n=16), and the phase 1/2 study, NS-065/NCNP-01 (NCT02740972; n=16). The studies found that cough, injection site reaction, pyrexia, and upper respiratory tract infection were the most frequent adverse events (AEs). The FDA concluded that additional AEs, or those of a greater magnitude, were likely to occur after the product goes to market. 
The sponsor’s natural history study is described below.

 

Natural history study

Purpose: To support a secondary objective of Study 201, the sponsor drew on a natural history study to evaluate changes in functional tests (Time Function Tests, 6-Minute Walk Test, and North Star Ambulatory Assessment) from baseline. In 2015, the FDA warned against such an approach. 

 

What was done: The sponsor used the Cooperative International Neuromuscular Research Group (CINRG)’s natural history database to match patients in Study 201. (Patients for Study 201 were recruited from the CINRG’s network.) The natural history study included 65 patients (nine with exon 53 skipping, which were the type of patients in Study 201). The sponsor compared change after 24 weeks on both functional outcomes as well as strength assessments. They found no clinically meaningful difference between either Study 201 treatment group compared to the natural history control group.

 

Outcome: The FDA did not accept the sponsor’s approach. The FDA cited the variability in the natural history of the disease and flaws in the sponsor’s statistical matching process that likely led to biases in estimating clinical benefits. The FDA wrote: “[G]iven the variability in the natural history of the DMD, comparisons to a natural history cohort, even when matched controls are utilized, does not appear reliable.” At the same time, the agency looked for correlation or trends in changes in dystrophin and functional tests. The agency did not find a correlation in the magnitude of increase in dystrophin to functional tests. 

 

In addition, the FDA critiqued the sponsor’s selection and use of dystrophin production as the surrogate endpoint. The sponsor lacked sufficient evidence to show that dystrophin production produces clinical benefit, the FDA concluded.  

FDA Decision Alerts

Subscribe to our newsletter for insights and updates on research and applications for real-world evidence in life sciences and value-based health care.

eBook

The role of real-world evidence in FDA approvals

View now
arrowcalendarchevronclosecollapsecountdownfacebookflickrinstagramlinelinkedinlocationpinsearchsocialtwitteryoutube