Phase 1 Study Findings Support Efficacy of ALTO-101 for the Treatment of Cognitive Impairment in Schizophrenia

CONFERENCE REPORTER

What are the pro-cognitive pharmacodynamic effects of ALTO-101 on cognition in conditions such as schizophrenia? Adam Savitz, MD, PhD, and colleagues shared the results from a recent phase 1 study of ALTO-101 for the treatment of cognitive impairment in central nervous system disorders, such as schizophrenia, in a poster presentation at the 2024 American Society of Clinical Psychopharmacology (ASCP) Annual Meeting. Savitz is chief medical officer at Alto Neuroscience.

According to the investigators, enhancing cyclic adenosine monophosphate (cAMP)/protein kinase A (PKA) signaling in the brain has shown potential in previous animal models and early clinical trials exploring treatments for cognitive impairment in conditions such as schizophrenia. ALTO-101, a selective inhibitor of phosphodiesterase-4 (PDE4), increases cAMP levels in critical brain regions, suggesting that it could be a novel treatment for cognitive deficits.¹

In order to explore this possibility, the investigators launched a randomized, double-blind, placebo-controlled phase 1 trial including 40 healthy adults aged 40 to 64 years. Participants received a single oral dose of placebo, 0.5 mg ALTO-101, and 1.5 mg ALTO-101 in a 3-way crossover design, with a 7-day washout period between doses. Neurocognitive tests and electroencephalography (EEG) were used to assess the drug’s acute effects.¹

The results indicated significant differences between the ALTO-101 and placebo conditions. The investigators observed increased amplitude of the mismatch negativity potential (0.5 mg: d = 0.38, p = 0.07; 1.5 mg: d = 0.53, p = 0.02); enhanced gamma band phase locking response to auditory stimuli (0.5 mg: d = 0.35, p = 0.08; 1.5 mg: d = 0.68, p = 0.003); decreased relative theta power in resting-state EEG (0.5 mg: d = 0.51, p = 0.02; 1.5 mg: d = 0.88, p = 0.0003); and improved processing speed (0.5 mg: d = 0.32, p = 0.16; 1.5 mg: d = 0.63, p = 0.006).¹

According to the investigators, this study is notable for its robust design, involving 40 participants in a cross-over format, which provides more reliable data compared with typical phase 1 trials with smaller sample sizes. They concluded that the positive results highlight the drug’s potential and support its continued development as a therapeutic option for cognitive impairment in CNS disorders.¹

“These findings demonstrate strong pharmacodynamic effects of ALTO-101 in driving key brain processes important for cognition as measured by EEG, along with behavioral evidence of cognitive improvement,” the investigators stated. “Since these measures index schizophrenia-related deficits in cognition and cognitive processing, these data support further development of ALTO-101 for the treatment of cognitive impairment associated with schizophrenia.”

Research shows that an estimated 70% to 80% of individuals with chronic schizophrenia experience cognitive impairment.² Explore the following and more expert discussions on cognitive impairment and other issues associated with schizophrenia in Psychiatric Times®:

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Follow the Psychiatric Times coverage of the 2024 ASCP Annual Meeting, and stay up-to-date on news related to research on promising new interventions and developments in the treatment of a wide variety of psychiatric disorders, at psychiatrictimes.com.

References

1. Ravidran A, Sundar G, Goncalves S, et al. Pro-cognitive pharmacodynamic effects of ALTO-101: results from brain and behavioral outcomes in a randomized, double-blind phase 1 study. Poster presentation. 2024 American Society of Clinical Psychopharmacology Annual Meeting. May 30, 2024.

2. Stainton A, Chisholm K, Griffiths SL, et al. Prevalence of cognitive impairments and strengths in the early course of psychosis and depression. Psychol Med. 2023;53(13):5945-5957.