This month’s Innovation that Matters (ITM) features Albert J. Robichaud, Ph.D., chief scientific officer of Cambridge, Mass.-based SAGE Therapeutics, which is developing next-generation medicines for the treatment of rare and life-threatening central nervous system (CNS) disorders.  CNS disorders represent 35 percent of the worldwide disease burden and one of the largest global health care markets, but many available drugs do not address areas of the most urgent need and are often accompanied by side effects.  SAGE Therapeutics’ initial focus is on acute and orphan CNS indications with strong preclinical to clinical translation and accelerated development timelines.

SAGE Therapeutics’ rich chemistry platform fuels a highly differentiated neuroscience pipeline and has attracted considerable attention including a highly successful IPO, fast track designation of the company’s allosteric modulator of GABAA receptors – SAGE-547 – and positive results in a phase 1/2 and exploratory trial of SAGE-547 in super refractory status epilepticus and postpartum depression, respectively.

ITM was able to catch up with the fast-paced CSO:

SAGE Therapeutics has decided to focus on neuroscience, an area that was abandoned by many in recent years. What is differentiating about SAGE Therapeutics’ platform?

Albert: SAGE Therapeutics’ has taken a unique approach to CNS disorders by targeting therapeutic indications which are genetically, molecularly or translationally focused on two key receptor families in the brain – GABA and NMDA. These are well-known systems with potent pharmacological mechanisms, which when imbalanced are implicated in a plethora of CNS disorders. Because these are mechanisms that we understand well, we are able to target new investigational therapeutics to those and bring them rapidly into human clinical testing.


Will the platform address the obstacles faced by prior unsuccessful CNS drug development?

Albert: SAGE Therapeutics has set about doing CNS drug discovery and development somewhat differently from others’ past efforts. We have targeted programs that address well-known mechanisms in the brain and are tractable and translatable from a concise collection of preclinical data. Our initial focus is on acute disorders for which there are few to no targeted treatment options, are defined by molecular or genetic patient populations and possess an objective proof-of-concept pathway. This affords us the ability to rapidly obtain data, with hard and unambiguous endpoints, and clear, rapid and efficient regulatory pathways.


How was SAGE-547 discovered and why is it unique? 

Albert: SAGE-547 is a novel and proprietary formulation of the natural endogenous neuroactive steroid allopregnanolone. Although allopregnanolone has been known for decades, this potent GABAA modulator suffers from druggability issues. At SAGE Therapeutics, our focus has been on optimizing the drug properties of not just allopregnanolone, but on fit-for-purpose, novel, synthetic neuroactive steroids. To that end, we have designed and advanced a large library of proprietary drug candidates that include SAGE-689 and SAGE-217. These two potent, selective second-generation GABAA modulators are optimized for oral and parenteral administration and expand the functionality of this class of molecules beyond allopregnanolone.

What differentiates SAGE-547 and our proprietary family of neuroactive steroids from other potent GABAA modulators, for example benzodiazepines, is the ability to modulate not only the synaptic GABA receptors but also the extrasynaptic GABA receptors.  Defining the utility of this important characteristic of GABA modulation is something that underscores the potential value that the team at SAGE Therapeutics has brought to patients in several highly underserved indications,  such as refractory status epilepticus, a severe condition of chronic seizure, and several orphan genetic epilepsy conditions, such as Dravet and Rett syndrome.


The FDA designated status epilepticus as an orphan indication. The FDA also designated the SAGE-547 program for fast track development. What were the factors leading to that decision and what does it mean for SAGE Therapeutics’ development program?

Albert: The receipt of orphan drug designation for status epilepticus and the fast track designation are both significant regulatory milestones for SAGE-547 and the potential patients who may benefit from it.  Orphan drug designation is intended to facilitate drug development for rare diseases, including diseases with small patient populations for which there are no approved therapies.  Status epilepticus is a life-threatening seizure condition that occurs in approximately 150,000 people in the U.S. each year, of which 30,000 will die.  Currently, there are very limited treatment options for these patients and no approved drugs. SAGE-547’s receipt of orphan drug designation in May 2014 has provided important benefits for the drug’s development, including market exclusivity for the product upon regulatory approval.

Similarly, SAGE-547 was granted fast track designation by the FDA last July. Fast track designation is granted to expedite the review of drug candidates that are intended to treat serious or life-threatening conditions and that demonstrate the potential to address unmet medical needs. This advancement has provided SAGE-547 a rapid path to market, fulfilling our mission to deliver treatment options to patients with SE as quickly as possible.


What are the clinical experiences to date with SAGE-547?

Albert: We have been focused on advancing SAGE-547 as rapidly as possible to bring this NCE to patients in need.  We have reported positive results from our Phase 1/2 trial of SAGE-547 in refractory status epilepticus and plan to initiate the Phase 3 pivotal trial by-mid 2015.  In the Phase 1/2 trial, we observed an unprecedented 77 percent ORR, and SAGE-547 has been well tolerated with no drug-related SAEs.  Further, a number of patients who responded to SAGE-547 have since been able to go home and return to their daily activities. Based on the positive results, we are planning to initiate the Phase 3 STATUS Trial by mid-2015.

In addition, we have been using SAGE-547 to establish proof of principle in exploratory Phase 2a clinical trials for additional CNS disorders, including postpartum depression and essential tremor.  In early June, we announced top-line data from the exploratory clinical trial in postpartum depression that indicated a statistically significant improvement from baseline in depression in four women with the disease within 24 hours after administration of intravenous SAGE-547.  The continued advancement of this important drug candidate serves as the basis of the rapidly evolving library of drug candidates SAGE Therapeutics is developing.


Can you share some insight on SAGE Therapeutics’ other portfolio programs and pipeline? 

Albert: As mentioned at the outset, SAGE Therapeutics’ is focused on discovery and development of compounds focused on two receptor families – GABA and NMDA.  In addition to SAGE-547, our robust pipeline of proprietary second-generation product candidates in the GABA platform is led by SAGE-689 and SAGE-217. SAGE-689 is being developed as a potential follow-on IV product for second-line adjunct status epilepticus targeted for the ER, and SAGE-217 has been designed to be dosed orally, intramuscularly and intravenously, making it suitable as a potential oral, chronic therapy for a broad number of indications.  These products have the ability to provide greater efficacy, selectivity and utility, as well as fewer off-target effects.  Phase 1 trial initiations are anticipated for both SAGE-689 and SAGE-217 in late 2015.

On the NMDA receptor front, we have an advanced discovery platform that has amassed a collection of selective NMDA allosteric modulators with excellent drug-like properties.  Our goal is to rapidly identify and advance clinical candidates with utility for therapeutic indications defined by glutamate deficiency.  Together with our understanding of the GABA pharmacology, the NMDA platform discoveries affords SAGE Therapeutics a leadership position in the CNS arena with the potential to advance NCEs for several key indications of unmet need.