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Sage Therapeutics Announces Positive Interim, Topline Xuranolone Safety, And Tolerability Data From Open-Label SHORELINE Study In Patients With MDD

Zuranolone was generally well-tolerated at the 30 mg dose and by the initial patients treated with the 50 mg dose with an adverse event profile consistent with that seen in earlier trials Nearly half of trial

· 10/15/2020 06:36

Zuranolone was generally well-tolerated at the 30 mg dose and by the initial patients treated with the 50 mg dose with an adverse event profile consistent with that seen in earlier trials

Nearly half of trial participants with positive response to initial 14-day course of zuranolone 30 mg did not need an additional zuranolone treatment course 

For those who needed retreatment with the 30 mg dose, safety, tolerability and efficacy results were similar to those seen in the initial treatment course

Sage Therapeutics, Inc. (NASDAQ:SAGE), a biopharmaceutical company committed to developing novel therapies with the potential to transform the lives of people with debilitating brain disorders, today reported interim, topline results from a July data cut of the ongoing Phase 3 open-label SHORELINE Study. This clinical study was designed to naturalistically follow patients with major depressive disorder (MDD) and evaluate the safety and tolerability of zuranolone 30 mg in adults for up to one year. In May 2020, the protocol was amended to include a 50 mg dose of zuranolone. For the primary endpoint of safety and tolerability, the data analyzed to date show that zuranolone was generally well-tolerated in the 30 mg dose and among the initial patients treated with the 50 mg dose. Adverse events reported in the trial during the period analyzed were generally consistent with results seen in previous clinical trials.

Secondary endpoints included response and remission as evaluated by the 17-item Hamilton Rating Scale for Depression (HAMD-17) and the number of times a patient received retreatment. At the time of this analysis, patients with a clinical response (decrease in HAMD-17 baseline score of ≥50%) to the initial 14-day course of zuranolone 30 mg used a mean number of 1.9 treatments per year. As the first naturalistic, longitudinal, clinical development trial conducted in MDD, the SHORELINE Study provides real world insight into the potential use of zuranolone, if successfully developed and approved as an as-needed treatment for MDD, and builds on the data assembled in the LANDSCAPE clinical program. The Company plans to report comprehensive data from the 30 mg dose in the first half of 2021 and will include additional subsets of data within the primary and secondary endpoints. Select data will be reserved for presentation at medical and scientific conferences and in peer-reviewed journal articles.

"This data from the SHORELINE Study show that medically-oriented, as needed treatment for depression has the potential to be a compelling option for many patients diagnosed with MDD," said Jeff Jonas, M.D., chief executive officer at Sage Therapeutics. "Approximately 70% of patients who participated in the study only needed one or two treatment courses, a total of two to four weeks of treatment with zuranolone 30 mg, which we believe will be the minimally effective dose, if our development efforts are successful."

Zuranolone 30 mg: Summary of July Results from SHORELINE Study 

Sage's Phase 3 SHORELINE Study is evaluating the safety and tolerability of zuranolone 30 mg and 50 mg in adults 18-75 who have MDD as defined by a baseline HAMD-17 total score ≥20. The original study design included a zuranolone 30 mg dose administered once nightly for 14 days.

  • 725 people with MDD (HAM-D ≥ 20) were treated with a first dose of zuranolone 30 mg once daily for 14 days.
  • The mean baseline HAM-D score (± SD) at entry into the study was 25.3 ± 4.1 (n=725).
  • Of the 725 patients treated, 143 (19.7%) did not achieve response to the first course and exited the study. Subjects were required by protocol to achieve response to continue into the naturalistic follow-up period.
    • At Day 15 of the initial course of patients who only received 30 mg in the study, the mean change from baseline was -14.9 ± 7.1 (n=640); 458 (71.6%) patients achieved response and 255 (39.8%) achieved remission (HAM-D ≤ 7).
    • 304 (42%) patients were on pre-existing antidepressant therapy (ADT) which was continued, while 421 (58%) were on no ADT; there were no meaningful differences in efficacy outcomes between the two groups.

Safety and tolerability of initial treatment:

  • In this first course of treatment with zuranolone 30 mg, the adverse events experienced by patients were similar in nature and frequency to those previously reported for completed zuranolone studies, with 447 (61.7%) patients reporting at least one adverse event.
  • The most common adverse events (reported ≥ 5%) were: somnolence (69; 9.5%), headache (63; 8.7%), and dizziness (39; 5.4%). Most adverse events were mild or moderate.
  • Similar adverse events were reported regardless of the presence or absence of ADT.
  • Causes of adverse event-related discontinuations during the 14-day course of treatment were varied, with the most common being dizziness, anxiety, or nausea (n=2 each). The overall rate of discontinuation due to treatment-emergent adverse events was 2.2%
  • No events of loss of consciousness were reported at any time during the study.

Retreatment:

Among the 494 patient responders from the initial treatment cycle continuing in the study, 274 (55.5%) of patients used zuranolone in retreatment one or more times, while the remaining 220 (44.5%) were not retreated during their participation in the study.

  • Of the 494 patients continuing in the study, 220 (44.5%) patients used only the single initial zuranolone course, while 132 (26.7%) used a total of 2 courses, 66 (13.4%) used a total of 3 courses, 51 (10.3%) used a total of 4 courses, and 27 (5.5%) used a total of 5 courses.
  • The number of zuranolone retreatments used were similar regardless of the presence or absence of ADT.
  • For patients using one or more retreatments with zuranolone, overall AE rates in treatment courses with greater than 50 patients were 151 (53.7%), 56 (38.1%), and 28 (35.9%) for the second, third, and fourth treatment courses, respectively.
  • For those patients that used one or more retreatments, outcomes on efficacy measures and safety events were similar to those observed in the initial treatment course; and the presence or absence of ADTs did not change the results.

Initial Experience with Zuranolone 50 mg Dosing: 

In May 2020, standard dosing with zuranolone in the SHORELINE Study was increased to 50 mg. Patients who started treatment at the 30 mg dose and were retreated after May 2020 started receiving zuranolone 50 mg rather than 30 mg. A new cohort of patients starting treatment at 50 mg was also initiated in May 2020.

  • In this interim sample of patients who received zuranolone 50 mg after having received 30 mg previously (n=48), higher rates and levels of intensity with AEs of >5% (sedation, somnolence) were noted. Most adverse events were mild or moderate.
  • In the 76 (38%) patients with safety data available from the 50 mg cohort, the adverse event profile was similar to that seen in patients who received 30 mg zuranolone. Events >5% of somnolence, dizziness, sedation, headache and tremor were observed to be more frequent in the 50 mg cohort, but were similar in severity to the events seen with 30 mg. Most adverse events were mild or moderate.
  • For new 50 mg cohort (n=52) the mean HAM-D baseline score was 25.1 ± 3.1.
  • At Day 15 of the initial course in this group, the mean HAM-D change from baseline was -15.9 ± 6.6; 39 (75.0%) achieved response and 25 (48.1%) achieved remission.