Biotech Values

[Titan V]

Did SAGE Therapeutics Just Break the CNS Curse?

https://www.biospace.com/article/opinion-did-sage-therapeutics-just-break-the-cns-curse-/

Here's hoping for a neuroscience renaissance

Drug development is tough at the best of times, but creating new medicines for central nervous system (CNS) disorders is particularly brutal. Just look at the track record of Alzheimer's drugs, or the many failed trials in diseases ranging from Parkinson's to Lou Gehrig's disease.

In fact, one of the last truly groundbreaking innovations in neuropharmacology--the development of Prozac, the first of the SSRIs--happened 30 years ago. A lot has happened since, of course, from the development of many other SSRIs to the related SNRIs to innovations in schizophrenia and elsewhere. But CNS drugs have a dismal rate of success and, not coincidentally, the field has seen a slowdown in new research. Many major drug companies, including AstraZeneca, GlaxoSmithKline, Merck, Novartis, Pfizer and Sanofi, have winnowed or entirely shuttered their neuroscience programs.

Around half of patients with depression or anxiety aren't adequately addressed by existing drugs. This is just one of the reason why the World Health Organization has labeled lack of neuroscience innovation as a "crisis."

All of that is a backdrop to recent news from SAGE Therapeutics. The company has had quite a year, reporting in November that its drug brexanolone was effective in rapidly relieving the symptoms of post-partum depression in the majority of new mothers who were treated. And just this month, there was potentially more important news: SAGE-217 quickly put 64% of patients who took it into remission from major depression disorder. And both drugs work with an entirely different mechanisms than existing antidepressants.

This is obviously great news for SAGE, its investors, and patients who may ultimately be helped by these drugs. But it could also open up a new area of research and, with luck, bring about a small renaissance in neuroscience.

When No One Else Was Looking…

In some respects, SAGE is a beneficiary if the industry's growing disenchantment with CNS research. The hints that both brexanolone and SAGE-217 had the potential to address depression have been around for years, but few companies were interested in pursuing that path.

That's because both of these drugs work by modulating GABA and the GABA-glutamate balance in the brain. They aren't unique in this regard; the benzodiazapines (Xanax, etc.) also work through a GABAergic mechanism. But it is exactly because benzos don't work in depression that many researchers have dropped this line of inquiry.

A notable exception is Bernhard Luscher from Pennsylvania State University, who got some attention last year for a study showing that increasing GABA production appeared to improve symptoms of depression in mice. His work follows on older research (including his own) indicating that other GABAergic or glutamate-blocking drugs may have antidepressant effects. That includes Lamictal (lamotrigine), which was originally approved as an anticonvulsant in 1994 but got a label for bipolar disorder in 2003 and has since become a first-line treatment. It also, intriguingly, includes Rilutek (riluzole). This glutamate blocker is only approved for amyotrophic lateral sclerosis, but has been studied in depression with some promising results. (You may notice the common link of these drugs working in both convulsions and mood disorders--which is part of the reason SAGE is also pursuing its drugs in epilepsy, Parkinson's, and tremor). But at least one theory is that SSRIs work by indirectly affecting the GABA-glutamate balance, explaining why it takes so long for them to work. SAGE-217, in contrast, took effect very quickly.

Certainly SAGE's drug isn't perfect--its effects appeared to lessen over time, and many patients reported some of the sleepiness associated with benzodiapines. There's little information on whether it may also have some of the habit-forming effects associated with those drugs. These offer areas for potential improvement that may now attract a good deal more research. The bottom line is that SAGE may have a long headstart in a promising area because everyone else was looking the other way. You can bet that more companies will start to pay attention to the GABA literature now.

2017 has been about bright new things in bioscience--gene therapy, CRISPR, RNAi, CAR-T, and more. But one of the most exciting new frontiers in CNS research over the coming years may turn out to be something old.