By Melane Sampson
Alto Neuroscience (NYSE: ANRO) is aiming to redefine the way neuropsychiatric conditions are treated through a biology-driven pipeline designed to deliver more effective treatment options. Drawing on expertise in central nervous system (CNS) drug development and commercialization, the company is seeking to move psychiatry beyond its traditional trial-and-error approach.
“Precision medicine has enabled massive advances in therapeutic areas like oncology and genetic medicine, but if you look at the history of psychiatric diagnoses and treatments, we have a huge gap in linking disease biology to treatment and in some area we have no therapeutic options at all,” Amit Etkin, MD, PhD, founder, president, and CEO of Alto, says in an interview with BioTuesdays.
“The way the field has looked at our drugs and patient populations historically is without any understanding of which therapeutic option may be best suited to an individual. That stands in sharp contrast to the vast majority of medicine, where precision has progressively increased over time,” he adds.
Dr. Etkin explains that until now psychiatry has relied on clinical observation to prescribe medicines, neglecting to consider the underlying biological differences among patients. “This leads to variability in response to treatment, with most patients cycling through multiple treatments before finding one that works for them, if they even do.”
Alto combines neuroscience research, extensive clinical and biological datasets, and machine-learning technologies to match drug candidates with biologically defined patient populations. Its precision psychiatry approach seeks to improve both development and treatment outcomes by identifying which patients are most likely to benefit from a particular therapy.
Dr. Etkin points out that the need for innovation is significant as mental health disorders are a leading cause of disability globally. In the U.S. alone, one in five people live with a mental health disorder. “An estimated $280 billion is spent on mental health services annually in the U.S.,” he says. “Despite the enormous need, the current standard of care consists of treatments that are ineffective for many patients.”
Founded in 2019, Alto was built around the concept that biological differences between patients should guide psychiatric treatment selection. The company’s Precision Psychiatry Platform uses biomarkers to identify the patients most likely to respond to a given treatment. Rather than relying solely on symptom-based diagnoses, Alto incorporates EEG recordings, cognitive assessments, wearable technologies, and machine-learning analyses to characterize underlying biological differences among patients.
“The core concept is measuring the biology of individual patients,” Dr. Etkin says. “Ultimately, we need to know what a drug does and who the right people are to give it to. We believe that is the only way to truly get better outcomes in this field.”
The company’s platform generates biological and clinical insights that Alto believes are not often obtained through traditional CNS drug development approaches. These insights are then used to guide candidate selection, clinical trial design, patient classification, and program advancement.
Dr. Etkin’s interest in precision psychiatry stems from more than a decade of research conducted at Stanford University before founding Alto. “I ran a lab at Stanford for a decade, and what we were trying to understand was which measures of brain biology and processes enable us to advance precision mental health treatment,” he indicates.
Today, the company’s pipeline is focused primarily on affective disorders, including treatment resistant depression (TRD), major depressive disorder (MDD), and bipolar depression.
Alto’s lead asset, ALTO-207, is a fixed-dose combination of pramipexole and ondansetron being developed for patients with TRD.
Pramipexole, a dopamine D3-preferring agonist, has demonstrated antidepressant activity across multiple published randomized clinical studies. However, its use in depression has historically been limited by dose-dependent nausea and vomiting.
“The challenge with pramipexole has always been tolerability,” Dr. Etkin says. “If you dose more aggressively, you see high rates of nausea and vomiting.”
To address that issue, ALTO-207 combines pramipexole with ondansetron, a 5-HT3 receptor antagonist commonly used to prevent nausea.
“It has been demonstrated that by pairing pramipexole with ondansetron, the nausea and vomiting can be mitigated so you can dose much higher and faster,” Dr. Etkin notes. “That’s really the unlock here—to be able to use this mechanism.”
He emphasizes that the scientific rationale is compelling. Dopamine plays a critical role in reward, motivation, and other pathways disrupted in depression. According to Dr. Etkin, directly stimulating dopamine receptors may offer advantages over current adjunctive approaches that primarily rely on antipsychotic medications.
“There have been multiple pramipexole clinical trials, and the antidepressant effects have been very clear across independent studies,” he contends.
In a previously completed Phase 2a study, ALTO-207 demonstrated significant improvements in depression scores compared with placebo while maintaining a favorable tolerability profile. The program is currently being evaluated in a Phase 2b trial involving approximately 178 patients with TRD.
Dr. Etkin says the study is designed to assess ALTO-207 as an adjunctive therapy added to stable antidepressant treatment and is expected to generate data that could support future registrational development.
“We are at a very exciting point,” Dr. Etkin says. “We launched a Phase 2 study earlier this year that is potentially registration supportive. We are anticipating starting a Phase 3 study by early 2027 following FDA alignment discussions.”
He adds that the company is funded through the execution of the planned Phase 3 program and potential NDA submission activities.
Beyond ALTO-207, Alto is advancing several additional clinical-stage programs that apply the same precision psychiatry framework.
ALTO-300 is being developed as an adjunctive treatment for patients with MDD who have demonstrated inadequate response to standard antidepressants. The compound, known internationally as agomelatine, is approved in Europe and Australia but has not been approved in the U.S.
Unlike traditional antidepressants, ALTO-300 combines melatonergic agonism with serotonergic antagonism, producing downstream effects on dopamine and norepinephrine pathways while maintaining a favorable tolerability profile.
Alto’s development strategy for ALTO-300 centers on a machine-learning-derived EEG biomarker that appears to identify patients most likely to respond to treatment.
“About half of the patients we evaluated carried the EEG biomarker associated with response,” Dr. Etkin says. “What was particularly encouraging was that the biomarker also appeared to relate directly to the mechanism of action of ALTO-300.”
The company is currently evaluating ALTO-300 in an ongoing Phase 2b trial.
Another key program is ALTO-100 being developed for bipolar depression, an area where treatment options are limited and largely dominated by antipsychotic medications.
ALTO-100 is a first-in-class oral small molecule designed to enhance neuroplasticity within the hippocampus, a brain region associated with learning, memory, and mood regulation.
“We believe a subset of patients with bipolar depression are characterized by impairments in neuroplasticity,” Dr. Etkin explains. “ALTO-100 is designed specifically to address that biology.”
Patients in the ongoing Phase 2b study are selected using cognitive biomarkers intended to identify individuals most likely to benefit from the therapy. The trial is supported in part by an $11.7 million funding award from the Wellcome Trust. “This grant is a clear recognition of the huge unmet need in bipolar depression,” Dr. Etkin suggests.
With multiple late-stage clinical programs underway and several key data readouts expected over the next two years, Alto believes it is positioned to bring precision medicine to a field that has historically lagged behind other therapeutic areas.
“Any innovation in neuropsychiatry would be welcomed because the unmet need for new classes of treatments is very high,” Dr. Etkin concludes. “The question is whether we can identify with greater certainty which individuals will respond and deliver treatments that are more effective than what is available today. That’s the challenge we’re trying to solve.”
• • • •
To connect with Alto Neuroscience or any other companies featured on BioTuesdays, send us an email at editor@biotuesdays.com.
