On the second day of the J.P. Morgan Healthcare Conference, Alto Neuroscience announced positive Phase IIa safety and efficacy for ALTO-100, its targeted drug candidate. This is the most advanced trial data Alto has presented since launching in 2021, providing key validation to the company’s platform approach in precision psychiatry.

The data show that patients with major depressive disorder (MDD) and a unique cognitive profile saw greater symptom improvement as measured by validated depression scales and clear clinical benefit whether given ALTO-100 by itself or with existing antidepressants. The study leveraged Alto’s Precision Psychiatry Platform™ to identify people with MDD and a unique cognitive profile with distinguished biomarkers. Alto developed ALTO-100 to target brain plasticity for patients with this biomarker profile specifically, a drastically different approach than using a molecular biomarker target for patient selection.

“We are on the cusp of some really exciting clear evidence supporting the use of a precision approach in psychiatry,” Amit Etkin, CEO at Alto Neuroscience, told GEN Edge. “We have two really exciting novel elements just within ALTO-100: the first objective test to guide drug prescription in psychiatry and the first new target since the NMDA receptor and the work of ketamine 20 years ago.”

A Paradigm shift For psychiatry

Many of today’s neuropsychiatric treatments have been developed through a combination of serendipity to initially find a drug and then iteration on essentially what that mechanism is. “There’s a lot of untapped potential across the board in psychiatry and in things from pharma and biotech that are sitting on the shelf with no idea of how to develop them,” said Etkin. “There has been no shortage of really interesting molecules created.”

The trouble, according to Etkin, is a huge shortage of knowing how actually to deploy these molecules and that a lot of work doesn’t add anything new to psychiatry.

“We have a lot of drugs, and they’re very similar to each other,” said Etkin. “We use trial and error in the clinic to choose which to prescribe. It’s incredibly frustrating to patients and costly in terms of both health and economics. It’s not a way to develop knowledge and new drugs. The problem is that the way we’re doing things now, we don’t know why something works or fails, and that’s a worst-case scenario—you’re left throwing random darts and hoping to hit the target.”

What Etkin had been doing earlier in the lab at Stanford, which he is extending at Alto, is understanding how to segment populations beyond the clinical definition and into measurable biology that defines subgroups with different profiles. For Etkin, this all points to the biology of brain circuit function.

Psychiatric disorders and certain neurological disorders have dysfunction in brain circuits for cognition, emotion, social interaction, sleep, and circadian rhythms. Etkin says that all of these are measurable, either directly with tools like electroencephalography (EEG), behavioral tests of cognition and emotion, and wearables to look at sleep and activity. Over the years, Etkin developed the ability to analyze and understand data that segmented populations, which is what ultimately led him to leave his tenured professorship at Stanford to start Alto.

At the core of Alto is the marriage between their biomarker platform and a drug pipeline specifically constructed for subgroups that are identifiable using biomarkers.

“There’s a co-evolution of the way we define people with biomarkers and the interventions we are developing,” said “Etkin. “They’re all intended to be first in or best in class drugs and all have really interesting properties to them. But our approach is also meant to be scalable and applicable across neuropsychiatry. There’s no reason you can’t segment in schizophrenia, autism, Parkinson’s, or Alzheimer’s. We’re just beginning precision approaches for the brain, taking a page out of oncology, which has been doing this forever.”

ALTO-100 is the first of several drugs that the company is developing for various indications, all with an understanding of biomarkers to define subgroups that are either responsive or non-responsive.

“Of course, it’s important that we have a convincing, strong clinical outcome for the people who are positive for a biomarker and equally that the people who are negative, that they don’t get the drug,” said Etkin. “Part of this is figuring out how to develop this drug, but from a clinical perspective, it’s knowing it’s really the right drug for the right person. They need to have a clear clinical response. That’s what we see in our data.”

Alto will present data highlights at the 41st Annual J.P. Morgan Healthcare Conference at 5:00 p.m. PT on January 11, 2023.

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