SAGE-547 response rate in SRSE Phase 1/2 trial not impacted by patient characteristics
Potential pharmacodynamic biomarker identified for SAGE-547 informs STATUS Trial protocol
Analyses from hospital chargemaster claims data set show significant burden of illness of SRSE in the U.S.
GABA mechanism confirmed as potential target for essential tremor; significant tremor reduction observed in 25-patient trial
CAMBRIDGE, Mass., April 17, 2016 -- Sage Therapeutics, Inc. (NASDAQ:SAGE), a clinical-stage biopharmaceutical company developing novel medicines to treat life-altering central nervous system (CNS) disorders, today announced data from five abstracts to be presented at the 68th American Academy of Neurology (AAN) Annual Meeting, taking place April 15-21, 2016 in Vancouver, BC. Data from the open-label Phase 1/2 trial of SAGE-547 in super-refractory status epilepticus (SRSE) demonstrated that the 77% key efficacy endpoint response rate was not related to age, gender, ethnicity, co-morbid medical condition, or underlying antiepileptic or third line agents. Data suggest that for patients on three third-line agents one additional day of weaning is needed, a change adopted in the ongoing Phase 3 trial. Chargemaster claims data set analyses provided valuable insights into the estimated burden of illness of SRSE in the U.S. In addition, significant reductions in kinetic tremor scores were observed in an exploratory study of SAGE-547 designed to evaluate the GABA mechanism as a potential treatment for essential tremor. Sage intends to study its next-generation GABAA modulator, SAGE-217, for essential tremor in a Phase 2 trial later this year, subject to successful completion of the ongoing Phase 1 clinical trials.
“Sage is taking on SRSE, a condition considered by many to be too challenging for clinical research due to the complexity of the treatment setting, the neurological ICU, and the dire circumstances of the patients. Our team identified creative solutions designed to address these challenges in the drug development pathway, and we applied these learnings when we moved from the Phase 1/2 trial into our ongoing Phase 3 STATUS trial,” said Jeff Jonas, M.D., Chief Executive Officer of Sage. “While the treatment setting is less daunting in essential tremor, the unmet need is significant. We look forward to executing on our plans to advance our GABAA modulator, SAGE-217, into a Phase 2 clinical trial in essential tremor later this year, with the ultimate goal of expanding the options for patients where limited treatments exist.”
"SRSE is a devastating, life-threatening condition that is widely misunderstood, likely underdiagnosed, lacks widely adopted clinical treatment standards, and has an incidence rate and cost of care that have been historically difficult to ascertain. The research underway at Sage, some of which is being presented this year at AAN, helps to provide a more disciplined understanding of the disease as well as highlighting the importance of further development of SAGE-547 for SRSE," said Steve Kanes, M.D., Ph.D., Chief Medical Officer of Sage.
SAGE-547 in Super-Refractory Status Epilepticus (Abstracts P4.210 and P4.197)
- Detailed data regarding effects of underlying disorders, and treatment approaches was presented from the open-label Phase 1/2 study of SAGE-547 in SRSE in a peer-reviewed setting for first time.
- Demonstrated that the 77% (17/22 in evaluable patients) key efficacy endpoint response rate (being successfully weaned off the anesthetic agents while SAGE-547 was being administered at the maintenance dose) was not related to age, gender, ethnicity, co-morbid medical condition, underlying medical condition, or previous antiepileptic or third line agent treatment.
- Subsequent post-hoc analysis involving duration of the weaning period (five days versus six days) showed that 16 of 22 (73%) evaluable subjects were successfully weaned off both anesthetic agents and SAGE-547 within five days of starting the SAGE-547 infusion without the need to reinstate anesthetic agents in the following 24-hour period, while 18 of 22 (82%) evaluable subjects were weaned off both anesthetic agents and SAGE-547 within six days of starting the SAGE-547 infusion without the need to reinstate anesthetic agents in the following 24-hour period, which is the key efficacy endpoint of the Phase 3 clinical trial.
- At baseline, patients were rated to be among the most extremely ill patients in the hospital, with ongoing status epilepticus averaging 9 days (range 3-20 days) before treatment.
- 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. 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.
- An exploratory pharmacodynamic biomarker was identified that was significantly correlated with the plasma concentration of SAGE-547 despite high baseline variability and presence of background medications.
- Sage is currently enrolling the STATUS Trial, a global Phase 3 randomized, double-blind, placebo-controlled clinical trial in SRSE with top-line results expected in the second half of 2016.
Incidence and Cost of Super-Refractory Status Epilepticus (U.S.) (Abstract P4.214)
- Working closely with academic collaborators, Sage estimated the burden of illness of SRSE in the U.S. based on cases classified as SRSE using a treatment algorithm applied to a database of patient-level demographics, resource utilization (diagnostic and therapeutic services, diagnoses, procedures), and hospital data, for 2012.
- Mean length of stay (LoS), based on the cases classified in the study as SRSE using the primary algorithm, was 16.5 days with significant utilization of the ICU (mean LoS 9.3 days). LoS in the analysis ranged from 2 to over 800 days.
- SRSE has a high burden of illness with significant morbidity, lengthy hospitalizations and significant utilization of ICU and overall hospital resources.
GABA Proof-of-Concept in Essential Tremor (Abstract P4.297)
- Significant reduction of tremor was observed in a randomized, double-blind, placebo-controlled, crossover trial of SAGE-547 in 25 patients with essential tremor.
- This proof-of-concept study using SAGE-547 was designed to evaluate the GABA mechanism as a potential treatment for essential tremor.
- This was a critical first step in developing assessment and statistical methodology for studying GABA-PAM (positive allosteric modulator) compounds in this indication.
- Of the 25 patients enrolled, three patients reported at least one adverse event on blinded SAGE-547, compared to five patients reporting at least one adverse event while on placebo. Of the 17 patients in the open-label, higher dose SAGE-547 portion, eight patients reported at least one adverse event. The only adverse events reported more than once across all SAGE-547 treatment periods were fatigue and dizziness, predominantly at the higher dose of SAGE-547. There was one discontinuation in the higher dose SAGE-547 portion due to hypotension, with recovery following drug discontinuation. There were no reports of serious adverse events.
- Sage intends to develop its next-generation GABAA modulator, SAGE-217, for essential tremor in a Phase 2 trial later this year, subject to successful completion of the ongoing Phase 1 clinical trials.
About SAGE-547
SAGE-547 is an allosteric modulator of both synaptic and extra-synaptic GABAA receptors. SAGE-547 is an intravenous agent in Phase 3 clinical development as an adjunctive therapy for the treatment of super-refractory status epilepticus (SRSE). SAGE-547 has been granted both Fast Track and orphan drug designations by the U.S. Food and Drug Administration
(FDA) for the treatment of SRSE. SAGE-547 is being evaluated as a treatment for patients with SRSE in the global Phase 3 STATUS Trial. For more information about the STATUS Trial, please visit www.statustrial.com.
About Super-Refractory Status Epilepticus
Status epilepticus (SE) is an acute medical emergency of persistent, unremitting seizure lasting greater than five minutes. 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. Physicians typically use anesthetic agents to induce the coma, along with antiepileptic drugs in an attempt to stop the ongoing seizure, in RSE patients. 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.
About Essential Tremor
Essential tremor is a common neurological condition that affects an estimated 10 million Americans and millions more worldwide. Essential tremor causes a rhythmic trembling of the hands, head, voice, legs or trunk. Symptoms generally evolve over time and are both visible and persistent following onset, which commonly occurs either between 15-20 or 50-70 years of age. First-line treatments for essential tremor include the anticonvulsant primidone and the ß-adrenergic blocker propranolol. Current treatments for essential tremor are only moderately effective, reducing, though not resolving, tremor amplitudes in about 50% of patients. In addition, one out of three patients abandons treatment due to side effects or poor efficacy.
About Sage Therapeutics Sage Therapeutics is a clinical-stage biopharmaceutical company committed to developing novel medicines to transform the lives of patients with life-altering central nervous system (CNS) disorders. Sage has a portfolio of novel product candidates targeting critical CNS receptor systems, GABA and NMDA. Sage's lead program, SAGE-547, is in Phase 3 clinical development for super-refractory status epilepticus, a rare and severe seizure disorder. Sage is developing its next generation modulators, including SAGE-217, SAGE-689 and SAGE-718, with a focus on acute and chronic CNS disorders. For more information, please visit www.sagerx.com.
Potential pharmacodynamic biomarker identified for SAGE-547 informs STATUS Trial protocol
Analyses from hospital chargemaster claims data set show significant burden of illness of SRSE in the U.S.
GABA mechanism confirmed as potential target for essential tremor; significant tremor reduction observed in 25-patient trial
CAMBRIDGE, Mass., April 17, 2016 -- Sage Therapeutics, Inc. (NASDAQ:SAGE), a clinical-stage biopharmaceutical company developing novel medicines to treat life-altering central nervous system (CNS) disorders, today announced data from five abstracts to be presented at the 68th American Academy of Neurology (AAN) Annual Meeting, taking place April 15-21, 2016 in Vancouver, BC. Data from the open-label Phase 1/2 trial of SAGE-547 in super-refractory status epilepticus (SRSE) demonstrated that the 77% key efficacy endpoint response rate was not related to age, gender, ethnicity, co-morbid medical condition, or underlying antiepileptic or third line agents. Data suggest that for patients on three third-line agents one additional day of weaning is needed, a change adopted in the ongoing Phase 3 trial. Chargemaster claims data set analyses provided valuable insights into the estimated burden of illness of SRSE in the U.S. In addition, significant reductions in kinetic tremor scores were observed in an exploratory study of SAGE-547 designed to evaluate the GABA mechanism as a potential treatment for essential tremor. Sage intends to study its next-generation GABAA modulator, SAGE-217, for essential tremor in a Phase 2 trial later this year, subject to successful completion of the ongoing Phase 1 clinical trials.
“Sage is taking on SRSE, a condition considered by many to be too challenging for clinical research due to the complexity of the treatment setting, the neurological ICU, and the dire circumstances of the patients. Our team identified creative solutions designed to address these challenges in the drug development pathway, and we applied these learnings when we moved from the Phase 1/2 trial into our ongoing Phase 3 STATUS trial,” said Jeff Jonas, M.D., Chief Executive Officer of Sage. “While the treatment setting is less daunting in essential tremor, the unmet need is significant. We look forward to executing on our plans to advance our GABAA modulator, SAGE-217, into a Phase 2 clinical trial in essential tremor later this year, with the ultimate goal of expanding the options for patients where limited treatments exist.”
"SRSE is a devastating, life-threatening condition that is widely misunderstood, likely underdiagnosed, lacks widely adopted clinical treatment standards, and has an incidence rate and cost of care that have been historically difficult to ascertain. The research underway at Sage, some of which is being presented this year at AAN, helps to provide a more disciplined understanding of the disease as well as highlighting the importance of further development of SAGE-547 for SRSE," said Steve Kanes, M.D., Ph.D., Chief Medical Officer of Sage.
SAGE-547 in Super-Refractory Status Epilepticus (Abstracts P4.210 and P4.197)
- Detailed data regarding effects of underlying disorders, and treatment approaches was presented from the open-label Phase 1/2 study of SAGE-547 in SRSE in a peer-reviewed setting for first time.
- Demonstrated that the 77% (17/22 in evaluable patients) key efficacy endpoint response rate (being successfully weaned off the anesthetic agents while SAGE-547 was being administered at the maintenance dose) was not related to age, gender, ethnicity, co-morbid medical condition, underlying medical condition, or previous antiepileptic or third line agent treatment.
- Subsequent post-hoc analysis involving duration of the weaning period (five days versus six days) showed that 16 of 22 (73%) evaluable subjects were successfully weaned off both anesthetic agents and SAGE-547 within five days of starting the SAGE-547 infusion without the need to reinstate anesthetic agents in the following 24-hour period, while 18 of 22 (82%) evaluable subjects were weaned off both anesthetic agents and SAGE-547 within six days of starting the SAGE-547 infusion without the need to reinstate anesthetic agents in the following 24-hour period, which is the key efficacy endpoint of the Phase 3 clinical trial.
- At baseline, patients were rated to be among the most extremely ill patients in the hospital, with ongoing status epilepticus averaging 9 days (range 3-20 days) before treatment.
- 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. 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.
- An exploratory pharmacodynamic biomarker was identified that was significantly correlated with the plasma concentration of SAGE-547 despite high baseline variability and presence of background medications.
- Sage is currently enrolling the STATUS Trial, a global Phase 3 randomized, double-blind, placebo-controlled clinical trial in SRSE with top-line results expected in the second half of 2016.
Incidence and Cost of Super-Refractory Status Epilepticus (U.S.) (Abstract P4.214)
- Working closely with academic collaborators, Sage estimated the burden of illness of SRSE in the U.S. based on cases classified as SRSE using a treatment algorithm applied to a database of patient-level demographics, resource utilization (diagnostic and therapeutic services, diagnoses, procedures), and hospital data, for 2012.
- Mean length of stay (LoS), based on the cases classified in the study as SRSE using the primary algorithm, was 16.5 days with significant utilization of the ICU (mean LoS 9.3 days). LoS in the analysis ranged from 2 to over 800 days.
- SRSE has a high burden of illness with significant morbidity, lengthy hospitalizations and significant utilization of ICU and overall hospital resources.
GABA Proof-of-Concept in Essential Tremor (Abstract P4.297)
- Significant reduction of tremor was observed in a randomized, double-blind, placebo-controlled, crossover trial of SAGE-547 in 25 patients with essential tremor.
- This proof-of-concept study using SAGE-547 was designed to evaluate the GABA mechanism as a potential treatment for essential tremor.
- This was a critical first step in developing assessment and statistical methodology for studying GABA-PAM (positive allosteric modulator) compounds in this indication.
- Of the 25 patients enrolled, three patients reported at least one adverse event on blinded SAGE-547, compared to five patients reporting at least one adverse event while on placebo. Of the 17 patients in the open-label, higher dose SAGE-547 portion, eight patients reported at least one adverse event. The only adverse events reported more than once across all SAGE-547 treatment periods were fatigue and dizziness, predominantly at the higher dose of SAGE-547. There was one discontinuation in the higher dose SAGE-547 portion due to hypotension, with recovery following drug discontinuation. There were no reports of serious adverse events.
- Sage intends to develop its next-generation GABAA modulator, SAGE-217, for essential tremor in a Phase 2 trial later this year, subject to successful completion of the ongoing Phase 1 clinical trials.
About SAGE-547
SAGE-547 is an allosteric modulator of both synaptic and extra-synaptic GABAA receptors. SAGE-547 is an intravenous agent in Phase 3 clinical development as an adjunctive therapy for the treatment of super-refractory status epilepticus (SRSE). SAGE-547 has been granted both Fast Track and orphan drug designations by the U.S. Food and Drug Administration
(FDA) for the treatment of SRSE. SAGE-547 is being evaluated as a treatment for patients with SRSE in the global Phase 3 STATUS Trial. For more information about the STATUS Trial, please visit www.statustrial.com.
About Super-Refractory Status Epilepticus
Status epilepticus (SE) is an acute medical emergency of persistent, unremitting seizure lasting greater than five minutes. 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. Physicians typically use anesthetic agents to induce the coma, along with antiepileptic drugs in an attempt to stop the ongoing seizure, in RSE patients. 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.
About Essential Tremor
Essential tremor is a common neurological condition that affects an estimated 10 million Americans and millions more worldwide. Essential tremor causes a rhythmic trembling of the hands, head, voice, legs or trunk. Symptoms generally evolve over time and are both visible and persistent following onset, which commonly occurs either between 15-20 or 50-70 years of age. First-line treatments for essential tremor include the anticonvulsant primidone and the ß-adrenergic blocker propranolol. Current treatments for essential tremor are only moderately effective, reducing, though not resolving, tremor amplitudes in about 50% of patients. In addition, one out of three patients abandons treatment due to side effects or poor efficacy.
About Sage Therapeutics Sage Therapeutics is a clinical-stage biopharmaceutical company committed to developing novel medicines to transform the lives of patients with life-altering central nervous system (CNS) disorders. Sage has a portfolio of novel product candidates targeting critical CNS receptor systems, GABA and NMDA. Sage's lead program, SAGE-547, is in Phase 3 clinical development for super-refractory status epilepticus, a rare and severe seizure disorder. Sage is developing its next generation modulators, including SAGE-217, SAGE-689 and SAGE-718, with a focus on acute and chronic CNS disorders. For more information, please visit www.sagerx.com.
