Sage Therapeutics Shifts Gears, Focuses on Rare Form of Epilepsy

Sometimes it takes a little time, and a little luck for a company to find its identity. Of course, when you’re a biotech like Cambridge, MA-based Sage Therapeutics, it doesn’t hurt to have the backing of a life sciences company creation specialist Third Rock Ventures to get there either.

When Xconomy last checked in on Sage upon its formation in October 2011, the company aimed to use its platform of “allosteric receptor modulators” – drugs designed to create an equilibrium among the transmitters in the brain. These drugs were being designed to either positively or negatively tweak specific receptors on brain cells in the hope of effectively treating central nervous system disorders such as schizophrenia. Done right, these drugs could improve the lives of millions of people and create potentially huge market opportunities for drugmakers.

But a funny thing happened on the way. Sage’s SGE-102 exhibited profound results on a single 23-year-old patient with a life-threatening form of epilepsy called status epilepticus. It’s a disease characterized by continuous or repeating seizures.

The patient had been treated with several anticonvulsants and had been placed into a barbiturate-induced coma to suppress his seizures. Sage reported on April 4 that after more than 90 days and eight unsuccessful attempts to take the patient out of the coma without his seizures returning, an intravenous form of SGE-102 was administered over a five-day period. The patient then emerged, seizure-free, has left the hospital and continues to recover, Sage said.

While Sage interim CEO and Third Rock partner Kevin Starr (pictured above) cautions that with one patient, there is always the risk of a false positive, he adds that there is a “huge body of preclinical evidence” showing that administering one of Sage’s compounds later in the seizure cycle “works better than any of the best practices today.”

Benzodiazepines, or benzos, which are GABA modulators that have been around since the 1960s, are the standard of care for patients with SE. But many—about one-third of the 200,000 people who get the disease in the U.S. each year—don’t respond to them, are then placed into comas, and later moved into intensive care units with limited options. This inefficiency is where Sage hopes to capitalize.

As a rare disease, SE is right in Third Rock’s wheelhouse. By going after a small patient population, Sage can design clinical trials are small, and far less costly than trials for a more common disease like schizophrenia. Sage could also apply for a “breakthrough” designation from the FDA, which could speed the path to regulatory approval.

Starr says the plan as of now, while not final, is to begin a small clinical trial before the end of the year to try to replicate the results of the first patient, and to assess safety at escalating doses. Sage will put a second study behind that in 2014 that would combine SGE-102 with benzos. The goal would be for SGE-102 to either replace benzos or, at minimum, be an additive therapy.

The decision to pour its resources into treatment of SE is emblematic of Sage’s identity transformation. Starr explains that when Sage was first formed, it explored developing its drug candidates for not just schizophrenia, but also anxiety, anesthesia, and traumatic brain injury. While Sage is still pursuing some of those uses, it is doing so differently. And SE is now its lead dog.

“It took us about nine months to take that basket and decide how we sort out our resource allocation,” Starr says. “The preclinical data, and then a little bit of serendipity when this patient used our drug, accelerated [SE] to the front of the line.”

Sage’s business plan is now coming together. It starts with three programs it aims to own completely, and one it hopes to split with a partner. That lineup is complemented by a drug discovery platform behind it that it intends to use to snag an alliance with a large pharmaceutical company. Should those partnerships emerge, Starr notes that Sage may avoid any further financing beyond the $35 million Series A Third Rock provided when it started the company 15 months ago.

The plan begins with Sage’s most advanced program behind the SE compound. The drug is a treatment for traumatic brain injury, which can result from a severe blow to the head – typically in car accidents, sports collisions or combat situations. Taking a cue from animal models that show that a pregnant animal is protected from brain trauma because of elevated levels of certain neuroactive steroids designed to protect the fetus, Sage has crafted a drug to mimic that protective mechanism. The drug will enter mid-stage trials this year, Starr says.

Sage is also producing an anesthetic agent designed to get rid of the liabilities associated with propofol (Diprivan)—best known as the drug that caused Michael Jackson’s death. As little as double the usual dose of propofol can immediately shut down a patient’s lungs and heart. Sage’s drug dials in a specific plane of anesthesia – either light, mid or general – and keeps a patient there regardless of dose level. That program will be in the clinic in 2014, according to Starr.

The last program targets Fragile X syndrome, a form of autism in which children are born with the FMR-1 gene—a protein essential for cognitive development – “knocked out,” or unexpressed. There are no approved treatments for Fragile X Syndrome, though Sage hopes to change that. Starr says that Sage’s GABA modulator has shown preclinical evidence of changing the structure of the malformed synapses present in Fragile X Syndrome patients.

Behind those programs, Sage wants to use its NMDA modulators in more broad applications such as postpartum depression, anxiety, post-traumatic stress disorder, and schizophrenia. If everything goes according to plan, Sage would sign a lucrative deal with Big Pharma to tap into that discovery program and find a commercial partner for its anesthesia drug candidate while the company pushes its lead drugs through development.

Starr estimates that it will take between $70 million to $75 million to get the evidence it needs to file an FDA application to start marketing the SE drug, to prove its concept for anesthesia, to get some preliminary data in Fragile X syndrome, and to advance its discovery platform. So far, Sage has used about half of its $35 million Series A round and received $18 million in grants for its Fragile X and traumatic brain injury programs, but that still means it needs to come up with some more money.

“Our goal would be to see where we get to in business development discussions on a big early discovery alliance or on an anesthesia type alliance. If we can do that in the next year, then there’s a chance we don’t need to do any more funding,” Starr says. “But if the clinical data continues to roll and we’re making progress, we may be excited at Third Rock or bring in another syndicate partner to do a B round and keep the ownership up and develop these ourselves.”

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