SAGE-547 Demonstrates Favorable Tolerability
Pharmacodynamic Activity Corroborated by Continuous EEG Findings
Phase 3 STATUS Trial Expected to Initiate by Mid-2015
Conference Call Scheduled Today at
Phase 1/2 Trial Design
The Phase 1/2 open-label clinical trial evaluated the safety, efficacy, tolerability and pharmacokinetics of two IV-administered dose regimen cohorts (target plasma exposures of approximately 200 nM, the standard dose regimen, and approximately 300 nM, the higher dose regimen) of SAGE-547 as an adjunctive therapy for the treatment of patients with SRSE at 18 trial sites in
Phase 1/2 Trial Results
Of the total evaluable patients, 77 percent (17/22) were successfully weaned off their anesthetic agents while SAGE-547 was being administered during the maintenance phase, 81 percent (13/16) of those on the standard dose regimen, and 67 percent (4/6) of those on the higher dose regimen. In addition, 77 percent of the total evaluable patients successfully weaned off SAGE-547 without recurrence of SRSE in the 24-hour period following treatment.
Continuous EEG was evaluated as an exploratory endpoint in 14 patients. SAGE-547 administration was associated with a significant increase in EEG suppression with peak suppression occurring approximately one hour into the loading phase (mean = 19.6, p < 0.001; paired t-test comparison of baseline to mean suppression ratio during the one hour after the start of infusion) and terminal suppression being significantly greater than that observed during the pre-SAGE-547 baseline period (mean = 9.8 percent, p < 0.005; paired t-test). This effect was seen regardless of underlying third-line agents employed, indicating clear evidence of additive pharmacodynamic activity.
At baseline, all patients were evaluated using the Global Clinical Improvement Scale (CGI-S) and the Glasgow Coma Scale (CGS). At baseline, 23 patients were rated as "most extremely ill" and two were rated as "severely ill." By day 29, the group of patients that were successfully weaned off of third-line IV general anesthesia and SAGE-547 had improved by three points to "mildly ill," while the non-responder group demonstrated only a one-point improvement. Similarly, this responder group continued to improve over the 29 days of follow-up, demonstrating an overall seven-point improvement in the GCS (mean score of 11 at day 29). Importantly, seven patients had a full (no GCS deficit) score of 15 (41 percent) at day 29. By contrast, of the patients that were not successfully weaned, only one had a GCS rating of 15 at day 29. In the responder group, four patients had recurrence of status epilepticus, with one patient in the one-to-two-week period and three patients in the two-to-four-week period.
Overall, tolerability to SAGE-547 was demonstrated in the context of the serious nature of SRSE. Overall, 64 percent of patients experienced at least one serious adverse event, though none were drug-related as determined by the Safety Review Committee. Individual serious adverse events reported in at least two patients were respiratory failure, pulmonary embolism, sepsis, convulsion and renal failure. Independent of treatment response, six patient deaths occurred within the study period, all driven by underlying medical conditions. A total of 207 adverse events were reported in 23 patients. The most common adverse events (reported in four or more patients) were fever, hypotension, diarrhea, peripheral edema, anemia and blood urea nitrogen (BUN) increase. One case each of fever and BUN increase were deemed related to SAGE-547 by the investigator.
Phase 1/2 Trial Subject Profile
The trial employed broad inclusion criteria, primarily excluding patients only with major damage to the brain, such as anoxic injury, devastating stroke or the presence of a large lesion. A status epilepticus patient who failed therapy with first- and second-line antiepileptic agents and had failed to be weaned from third-line IV general anesthesia administered over 24 hours was eligible to be included in the trial.
Of the 25 total patients enrolled in the trial, 11 males and eight females with a mean age of 44 were enrolled in the standard dose cohort, while five males and one female with a mean age of 42 were enrolled in the higher dose cohort. The mean duration of status epilepticus prior to treatment with SAGE-547 was eight days overall, with a mean duration of nine days in the standard dose cohort and seven days in the higher dose cohort.
Of the 25 total patients, the underlying etiology of SRSE was attributed to infections in six patients, brain hemorrhage in four patients, worsening of seizures in three patients, unknown causes in three patients, primary or metastatic brain tumors in two patients and toxic ingestion in two patients. SRSE was caused by each of the following in one case: anti-NMDA encephalitis, stroke, sickle cell anemia, PRES and Lupus.
Responses were unrelated to underlying condition, age, gender, status epilepticus severity at baseline as determined by Status Epilepticus Severity Score (STESS), duration of status epilepticus prior to enrollment and concomitant treatment.
The Phase 1/2 clinical trial results will be presented on
Phase 3 Development Program
SAGE plans to initiate the STATUS Trial, a Phase 3 randomized, double-blind, placebo-controlled clinical trial of SAGE-547 for the treatment of patients with SRSE, by mid-2015. SAGE has begun enrollment in its Phase 3 open-label expanded access protocol, designated Study 302. Study 302 will make SAGE-547 available to patients in
Conference Call Information
SAGE will host a conference call and webcast today at
SAGE-547 is an allosteric modulator of both synaptic and extra-synaptic GABAA receptors. GABAA receptors are widely regarded as validated drug targets for a variety of disorders, with decades of research and multiple approved drugs targeting these receptor systems. SAGE-547 is an intravenous agent entering Phase 3 clinical development as an adjunctive therapy, a therapy combined with current therapeutic approaches, for the treatment of super-refractory status epilepticus (SRSE), as well as in exploratory Phase 2a clinical trials for the treatment of essential tremor and as an adjunctive therapy for the treatment of severe postpartum depression. SAGE plans to begin enrollment of its planned Phase 3 clinical trial, called the STATUS Trial, in mid-2015. SAGE-547 has been granted both Fast Track and orphan drug designations by the
About Status Epilepticus
Status epilepticus (SE) is a life-threatening seizure condition that occurs in approximately 150,000 people each year in the U.S., of which 30,000 SE patients die.i We estimate that there are 35,000 patients with SE in the U.S. that are hospitalized in the intensive care unit (ICU) each year. An SE patient is first treated with benzodiazepines, and if no response, is then treated with other, second-line, anti-seizure drugs. If the seizure persists after the second-line therapy, the patient is diagnosed as having refractory SE (RSE), admitted to the ICU and placed into a medically induced coma.
Currently, there are no therapies that have been specifically approved for RSE; however, physicians typically use anesthetic agents to induce the coma and stop the seizure immediately. After a period of 24 hours, an attempt is made to wean the patient from the anesthetic agents to evaluate whether or not the seizure condition has resolved. Unfortunately, not all patients respond to weaning attempts, in which case the patient must be maintained in the medically induced coma. At this point, the patient is diagnosed as having SRSE. Currently, there are no therapies specifically approved for SRSE.
Various statements in this release concerning SAGE's future expectations, plans and prospects, including without limitation, SAGE's expectations regarding SAGE-547 as a treatment for SRSE, essential tremor and severe postpartum depression, statements concerning the potential safety and efficacy of SAGE-547 and durability of response, the final protocol design, statistical power and timing of a planned Phase 3 clinical trial and an open-label, expanded access protocol for SAGE-547, and whether the results from the planned Phase 3 clinical trial together with other available clinical data for SAGE-547 will be sufficient to support submission of an NDA for this product candidate, constitute forward-looking statements for the purposes of the safe harbor provisions under The Private Securities Litigation Reform Act of 1995. In particular, it should be noted that
i DeLorenzo, Robert J., Pellock, John M., Towne, Alan R., Boggs, Jane G. Epidemiology of Status Epilepticus. J Clin Neuro 1995; 12(4): 316-325.
CONTACT: Investor Contact:
Paul Cox, SAGE Therapeuticspaul.firstname.lastname@example.org 617-299-8377 Media Contact: Dan Budwick, Pure Communicationsdan@purecommunicationsinc.com 973-271-6085
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