Second-Guessing FDA? Sage Zulresso Denied Add-On Status In Medicare

Medicare’s doubts about trial design for Sage’s postpartum depression therapy suggests even ‘breakthrough’-designated products can struggle with the ‘substantial clinical improvement’ standard for NTAP status. Denial of enhanced payment for Zulresso ends a long winning streak by innovators.

Biopharma companies have fared very well with applications for enhanced Medicare payment for innovative drugs used by hospitals during the Trump Administration, but the rejection of Sage Therapeutics, Inc.’s request for NTAP (new-technology add-on payment) status for Zulresso (brexanalone) is a reminder that the process can still have some unexpected difficulties for sponsors.

Zulresso became the first biopharma product to be rejected for NTAP status in the past three years when the US Centers for Medicare & Medicaid Services issued its final rule updating policies for in-patient prospective payments for 2021. The rejection came even as CMS highlighted an all-time high of 24 NTAP products for the coming year (including those continuing with the enhanced payments from 2020). (See sidebar.)

The rejection is based on CMS’ view that the “Breakthrough” designated therapy for a first-of-its kind indication does not represent a “substantial clinical improvement” that justifies NTAP status. Zulresso won approval for postpartum depression in March 2019. (Also see "Zulresso Postmarket Commitment Hints At Easier Dosing In Postpartum Depression" - Pink Sheet, 20 Mar, 2019.)

The decision comes as CMS is taken steps to streamline adoption of “Breakthrough” designated devices in both the outpatient and inpatient settings – with the IPPS rule including several devices granted NTAP coverage on an abbreviated pathway for “Breakthrough” products.

However, CMS specifically did not apply that pathway to drugs, noting its underlying concerns with prescription drug costs as a factor. (Also see "Medicare New Technology Add-On Payment Awards For Hospital Drugs On The Rise " - Pink Sheet, 11 Aug, 2019.)

Sage Used Placebo, Not Active Controls

The Zulresso rejection shows that policy choice can and will have a practical impact. CMS’ fundamental issue is that Sage’s trials all used a placebo control, and the agency believes other antidepressants may work just as well.

“We remain concerned that all of the studies submitted by the applicant used placebo as control and did not compare the use of Zulresso to the use of existing treatments,” CMS says. “There are multiple medications approved to treat major depressive disorders (of which PPD is a subtype).”

“As noted by the applicant in their comments, patients who were taking antidepressants at a stable dose for at least 14 days prior to enrollment were allowed to participate in the Zulresso clinical trials if they met other inclusion/exclusion criteria, and analysis of this subgroup showed statistically significant LS mean differences in change in HAM-D at hour 60 compared to baseline,” CMS acknowledges.

However, “given that these Phase III studies were not designed to compare the use of Zulresso to currently available treatments, we do not believe that the analysis of a subgroup is sufficient evidence that the use of Zulresso provides a substantial clinical improvement over the use of existing technologies, especially since traditional antidepressants may take 4-6 weeks to have full therapeutic effect (not 14 days).”

Endpoints Might Not Be Clinically Meaningful, CMS Says

CMS also questions the robustness of the results compared to placebo. “The primary endpoint of improvement in HAM-D scores from baseline at the conclusion of the 60-hour infusion was met in both Phase III studies submitted by the applicant, demonstrating the efficacy of the use of Zulresso in rapidly reducing depressive symptoms compared with placebo at this timepoint (60-hour infusion).”

“However, we note that the study authors observed variable placebo response across the three placebo-controlled trials, with robust placebo response in studies 2 and 3. For example, in the third study, placebo had a stronger effect than treatment at 30 days. We also note that the secondary endpoint of HAM-D remission at 30 days was not statistically significant in any of the treatment groups or in the integrated analysis when compared to placebo.”

“We also remain concerned as to whether study participants had time-limited PPD that might have resolved with the passage of time and whether the outcomes chosen for these studies translate into clinically significant observable improvements in maternal functioning and child interaction,” CMS continued. Therefore, “we are unable to determine that Zulresso represents a substantial clinical improvement over existing technologies, and we are not approving new technology addon payments for Zulresso for FY 2021.”