CAMBRIDGE, Mass.—SAGE Therapeutics announced Nov. 10 that its epilepsy candidate SAGE-547, an allosteric modulator of both synaptic and extra-synaptic GABAA receptors, met all primary and secondary endpoint targets in a Phase 1/2 clinical trial of 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.
“We believe SAGE-547 has the potential to dramatically improve the therapeutic approach for patients with SRSE, and the efficacy and safety results from this trial support our continued development of SAGE-547 as a treatment for this disorder,” said Dr. Jeff Jonas, CEO of SAGE. “We look forward to working with the U.S. Food and Drug Administration (FDA) on the appropriate design of a pivotal trial, which we anticipate initiating in the first half of 2015 pending our discussions with the FDA. We believe SAGE-547 has the potential to be the first therapy intended specifically for the treatment of SRSE, and that is very exciting for patients and clinicians managing this life-threatening disease.”
Analysts at Leerink Partners noted that the success rate of SAGE-547 in this trial of 73 percent is well above the approximately 30-percent success rate achieved by current SRSE standard-of-care practices.
“In the study, the mean duration of status epilepticus prior to treatment with SAGE-547 was 11 days, so individuals treated with '547 already failed benzodiazapenes, anti-epileptics, and anesthesia,” the analysts wrote. “Thus, at [more than twice] the success rate of the standard-of-care in a highly refractory patient population, we believe the data announced this morning could be sufficient for SAGE to attain breakthrough therapy status.”
Leerink did note that with four of four patients seeing treatment success in the last update of this Phase 1/2 trial and five of six patients in the emergency Investigational New Drug (IND) program showing resolution of SRSE in that same update, the more recent top-line results suggest that in the new set of eight patients, the response rate is modestly lower (four of those eight, or 50 percent).
“Most important to us, however, the success rate in [13 of 18] patients appears to separate clearly from the standard-of-care, which would have been expected to resolve status in [six of 18] individuals, and therefore de-risks a Phase 3 in our view for which we currently assume a 75-percent probability of success,” the analysts wrote.
Getting more specific about the study results thus far, SAGE notes that in the top-line data reported from 12 patients—eight males and four females with a mean age of 54—enrolled in the study, all of those patients met the primary endpoint, safety and tolerability. Of the 11 patients evaluable for efficacy, eight 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. 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 200 nm. In the trial, patients have been administered SAGE-547 intravenously for five days while weaning from anesthesia is attempted and are monitored for four weeks following treatment with SAGE-547.
In addition to the top-line Phase 1/2 trial results, SAGE 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 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.
SAGE also noted that the FDA recently approved a protocol amendment for the Phase 1/2 trial submitted by SAGE 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 is continuing to enroll patients as an expansion cohort in this trial, and this enrollment will proceed in parallel with SAGE's regulatory initiatives.
“We are pleased that we were able to complete this portion of our development plan ahead of our projected timelines and would like to thank all of our investigators, patients and their families involved in this trial,” said Dr. Steve Kanes, chief medical officer of SAGE. “We are also pleased that the approved protocol amendment to our Phase 1/2 trial will enable us to explore the potential of SAGE-547 in a broader population, particularly in very young children affected with this disorder that have no other treatment options.”