Date: 2015-05-14
Type of information: Results
phase: 1-2
Announcement: results
Company: Sage Therapeutics (USA - MA)
Product: SAGE-547
Action
mechanism: allosteric modulator. 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 CNS disorders, with decades of research and multiple approved drugs targeting these receptor systems. SAGE-547 is an intravenous agent in Phase 1/2 clinical development as an adjunctive therapy, a therapy combined with current therapeutic approaches, for the treatment of super-refractory status epilepticus (SRSE), as a treatment for essential tremor.
Disease: super-refractory status epilepticus (SRSE)
Therapeutic area: CNS diseases - Neurological diseases
Country: USA
Trial
details: The Phase 1/2 open-label trial of SAGE-547 as an adjunctive therapy was designed to provide clear data around safety, exposure and the ability of SAGE-547 to effectively halt SRSE. The trial enrolled adult patients with SRSE who have not responded to conventional therapy with continuous intravenous antiepileptic agents and who remain in a state of persistent seizure following one or more weaning attempts from general anesthesia. In the trial, patients are administered SAGE-547 intravenously for five days while weaning from anesthesia is attempted and are monitored for four weeks following treatment with SAGE-547. (NCT02052739) 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.
Latest
news: * On May 14, 2015, Sage Therapeutics announced that SAGE-547 demonstrated robust activity, with a 77 percent response rate in evaluable patients with super-refractory status epilepticus (SRSE), in a successfully completed Phase 1/2 clinical trial. SAGE-547 also demonstrated favorable tolerability and a benefit-risk profile supporting development in this acutely ill patient population. 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 the United States. Patients were administered SAGE-547 intravenously for five days while weaning from third-line IV general anesthesia administered to achieve burst suppression. Patients were then monitored for 30 days from treatment initiation. The trial enrolled 25 total patients. Of these patients, 22 were evaluable for efficacy, 16 at the standard dose regimen and six at the higher dose regimen. Patients were judged to be non-evaluable if their treatment was disrupted or if no weaning attempts from general anesthesia were made. 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. 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 the United States, aged two years or older, who are affected with SRSE and is designed to evaluate the safety of SAGE-547. The results from the STATUS Trial, along with other results from the SAGE-547 development program, may form the basis of a New Drug Application (NDA) submission for SAGE-547. * On November 10, 2014, Sage Therapeutics announced that in a Phase 1/2 clinical trial of SAGE-547, an allosteric modulator of both synaptic and extra-synaptic GABAA receptors, all primary and secondary endpoint targets were achieved in patients with super-refractory status epilepticus (SRSE), a critical condition in which the brain is in a state of persistent seizure. In 73 percent of patients, treatment with SAGE-547 allowed for patients to be successfully weaned off their anesthetic agent. Top-line data reported from 12 patients, eight males and four females with a mean age of 54, enrolled in the study show that all 12 patients met the primary endpoint, safety and tolerability. Of the 11 patients evaluable for efficacy, eight patients met the key efficacy endpoint of being successfully weaned off their anesthetic agents while SAGE-547 was being administered, and eight patients were successfully weaned off SAGE-547 without recurrence of SRSE. The mean duration of status epilepticus prior to treatment with SAGE-547 was 11 days. With an overall response rate of 73 percent, SAGE-547 was generally well tolerated and no drug-related serious adverse events, as determined by the Safety Review Committee, were reported in treated patients. Mean exposure levels of SAGE-547 were approximately 200nm.The trial will continue enrollment under protocol amendment. The FDA recently approved a protocol amendment for the Phase 1/2 trial submitted by Sage Therapeutics that will enable the company to treat pediatric patients as young as two years old and to increase the dose of SAGE-547 being administered to patients. Sage Therapeutics is continuing to enroll patients as an expansion cohort in this trial, and this enrollment will proceed in parallel with Sage Therapeuticss regulatory initiatives. The company looks forward to working with the FDA on the appropriate design of a pivotal trial. This trial could be initiated in the first half of 2015 pending on discussions with the FDA. In addition to the top-line Phase 1/2 trial results, Sage Therapeutics reported that seven patients, four males and three females with a mean age of 12.5, have been treated with SAGE-547 by independent centers under emergency-use Investigational New Drug (IND) Applications. Five of these patients treated with SAGE-547 achieved resolution of SRSE either during the course of or soon after SAGE-547 treatment. The overall response rate was 71 percent, similar to the observed response rate in the Phase 1/2 clinical trial.
