Sage’s epilepsy drug fails to do better than placebo in key clinical trial

Sage’s epilepsy drug fails to do better than placebo in key clinical trial

Sage Therapeutics’ closely watched drug, brexanolone, did not do much better than a placebo in helping patients with a severe type of epilepsy, data from a phase 3 clinical trial show.

Sage, which is based in Cambridge, Mass. expected brexanolone to lead to its first-ever drug approval. Instead, its shares dropped 25 percent to $66 in pre-market trading.

ChemSpider 2D Image | Allopregnanolone | C21H34O2
The drug was intended to treat a grave form of uncontrollable epilepsy called super-refractory status epilepticus, or SRSE. A continuous infusion of brexanolone over six days weaned 44 percent of SRSE patients from medically induced comas without seizures returning for 24 hours. The comparable response rate for SRSE patients given a placebo was 42 percent. The small difference favoring brexanolone was not statistically significant, failing the primary endpoint of the 140-patient study, Sage said Tuesday.

“This is not what we hoped the study would be,” said Sage CEO Jeff Jonas.

Sage continues to study brexanolone in other neuropsychiatric diseases, including a phase 3 clinical trial of women with severe postpartum depression. Results from that trial are expected later this year.

SRSE is a complicated and relatively understudied condition because the nonstop seizures can be triggered for different reasons — underlying epilepsy, of course, but also traumatic brain injury, drug overdose, stroke, and some autoimmune diseases.

A successful outcome from the SRSE phase 3 clinical trial was never a sure thing, but the placebo-like response rate shown by brexanolone will raise new concerns about the drug’s future.

The brexanolone response rate in earlier SRSE studies was 73 percent but there were no control arms for comparison and just 29 patients were treated. The earlier studies also used a slightly different definition of response from what was used in the phase 3 trial. Looking back now, the robust efficacy signal seen in the prior studies was not to be trusted.

The value of biotech stocks typically plunge when negative phase 3 clinical trial results are announced. Sage’s drop off Tuesday, at least in the early morning trading, is not as severe, which suggests investors are willing to give brexanolone a second chance. The upcoming phase 3 clinical trial in postpartum depression is supported by strong results from placebo-controlled phase 2 study.

Investors will not be as forgiving if brexanolone disappoints in postpartum depression, setting up this next clinical trial catalyst as a must-win for Sage.

Patients’ experience with brexanolone for SRSE varied considerably. One of those who appeared to respond was David Logan, a 56-year-old resident of the Dorchester neighborhood of Boston.

He had such a strong recovery after being given the drug that he had hoped it could help many other patients with the frightening condition.

Logan’s first seizure came on suddenly during a Memorial Day weekend barbecue that he and his wife, Mary, were hosting for friends and family. Hearing a strange banging sound on the upper floor of their house, Mary went looking for the cause and found David convulsing and unresponsive.

“He was on the floor, drooling from both sides of his mouth,” recalled Mary, holding back tears while recalling what she describes as the hardest months of her life. “I didn’t know what was wrong. I have known David since I was 15 but I had never seen this with him before. My son’s friend was with us and he said, ‘I think he’s having a seizure.’”

David was brought to the emergency room at Boston Medical Center. He spent a few days in the hospital while doctors tried to determine a cause for the seizures, without success. Eventually, feeling better, he was sent home with epilepsy medicine. Two days later, Mary found David seizing again. This time, David’s seizures would not stop. He was admitted to Boston Medical Center’s Neurocritical Care Unit, where he was looked after by a medical team led by Dr. Anna Cervantes and Dr. Courtney Takahashi.

Over the next two weeks, Cervantes says David was treated with five different epilepsy medications but none halted the seizures. He was placed in a medically induced coma. Three attempts were made to wean David in the hope that the deep anesthesia would reset his brain’s activity to normal. But each time doctors tried to wake David, monitoring equipment showed his brain still seizing. He was diagnosed with SRSE.

Boston Medical Center was not set up as an investigatory site for Sage’s brexanolone phase 3 clinical trial, but Cervantes, who had recently attended a lecture where the drug and the study were discussed, believed David was a strong candidate. Cervantes contacted Sage, which agreed to provide brexanolone as part of an open-label extension of its trial.

“This was our last chance,” said Cervantes.

The Sage drug was administered to David over six days in the middle of June. This time, when doctors woke him from his coma, David’s brain activity looked normal. After another six weeks of hospitalization and rehabilitation, David walked out of Boston Medical Center. He remains free of seizures.

“I feel great. A little memory loss but I feel great and I’m glad to be alive, thanks to these beautiful people,” said David Logan, referring to his caregivers at Boston Medical Center.

Approximately 37 percent of SRSE patients treated with open-label brexanolone after the end of the double-blind period of the trial achieved treatment response, including Logan.

But Logan’s success story was not replicated enough across the phase 3 clinical trial to demonstrate that brexanolone was the reason for his recovery.

“Though we saw a dramatic effect with the use of brexanolone for David, the results of the randomized trial did not support a benefit to use in all SRSE patients,” said Cervantes. “We know that SRSE is a heterogenous disease — meaning people can have epilepsy from a myriad of causes — some structural, some infectious, some metabolic. Perhaps brexanolone may be beneficial in a subset? Despite the trial findings, I am hopeful that future research will find a way to treat this rare and devastating disease.”

September 12, 2017

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September 13, 2017 / Pharma News