Barclays: Changes to Ph3 SMA Trial are a Net-Positive, in Our View
Barclays: BIIB/IONS: SMA Trial Changes Open Window for Early Readout
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Changes to Ph3 SMA Trial are a Net-Positive, in Our View
We discovered updates to the Ph3 ENDEAR study of nusinersen in SMA (link) that include changes to the primary endpoint and timelines for secondary endpoints that offer the potential for the trial to stop earlier then current guidance of 1H:17. After speaking with IONS, we believe these changes are a net positive for the program allowing for early stopping of the trial with minimal risk to quality/importance of the results or the chances of a positive outcome. We also found comments attributed to the FDA regarding endpoints and regulatory hurdles in SMA that we believe are supportive for the profile nusinersen has shown to date. The changes to the trial and FDA comments are listed below.
An Additional Primary endpoint
One of the key changes was the addition of second primary endpoint “proportion of motor milestone responders, up to 13 months” to the original primary endpoint “time to death or permanent ventilation, up to 13 months”. While the addition of a co-primary endpoint could raise concern, we believe the motor function improvements with nusinersen are well established vs. patients on supportive care where, unfortunately, these children rarely meet even modest milestones. Therefore we see this endpoint as having a low hurdle and offering another potential claim for marketing purposes.
Changes to Secondary Endpoints Mainly Support a Faster Readout
While there were changes to certain secondary endpoints (see below), the broadest change was measuring these endpoints “at” 13 months, which now reads “Up to” 13 months. We see these changes mainly as providing the option for the sponsors to stop the trial early if they choose rather than waiting for the last patient to reach the 13 month time point.
These Changes in Line with Prior Comments From IONS and BIIB
We believe these changes are in line with the goals IONS/BIIB have outlined regarding the potential to get nusinersen to patients as quickly as possible while maintaining the integrity of the Ph3 data. When speaking with IONS it was confirmed that these changes received FDA sign-off.
Previous comments from IONS:
“All of our positive regulatory interactions give us the confidence that we are on the right track to achieve approval for nusinersen as early as possible.”
“While we're working closely with Biogen to execute what we believe is the best strategy to gain the most rapid approval possible for nusinersen, we're pleased we're pleased with the interactions we're having with regulators. We're moving on a path designed to achieve the earliest possible approval.” 4/21/16
Previous comments from BIIB:
“We want to do this as quickly as possible but not quicker. And what that means is we want to be as fast as we can, but we have to have a data package that clearly demonstrates that this drug has efficacy and is safe for the kids. And the -- so we're trying to balance those two. And we'll get this done as quickly as we can. But as you know, that's not an easy call to make.” 1/11/16
Cited comments from a recent FDA meeting with the FAST MOVEMENT, an SMA advocacy group (link)
Dr. Janet Woodcock (Director, Center for Drug Evaluation and Research (CDER)) commenting on Accelerated Approval vs Full Approval in SMA:
-Accelerated Approval only requires a surrogate endpoint, not an expected outcome but one that can determine if they’re on the right path to an outcome.
-In SMA you don’t need a surrogate endpoint because the disease is well known.
-Accelerated Approval wouldn’t be appropriate. Full approval would be granted based on any improvement or after analysis of an expressed outcome.
Dr. Billy Dunn (Director, Division of Neurology Products, CDER) commenting on Full Approval in SMA:
-Full approval would be appropriate if a drug can stabilize them.
-It is clinical meaningful to have a change in function of life
-It can vary in disease but we are very open-minded, we like ideas and like to think outside of the box
Changes to Ph3 ENDEAR study of nusinersen