ALTO NEUROSCIENCE, INC.

• Alto Neuroscience's ALTO-300, a novel biomarker-based antidepressant, advances in Phase 2b trial for Major Depressive Disorder with topline results expected by mid-2026. • The company's robust pipeline includes ALTO-203 for anhedonia, ALTO-101 for cognitive impairment in schizophrenia, and ALTO-100 for bipolar depression, with multiple data readouts expected in 2025-2026. • Previous open-label Phase 2a data demonstrated ALTO-300's superior efficacy in biomarker-positive patients, showing a 17-point MADRS improvement compared to 12.3 points in biomarker-negative patients.

Alto Neuroscience reports positive interim results from its Phase 2b trial of ALTO-300 as an adjunctive treatment for major depressive disorder (MDD).

• AbbVie's emraclidine failed to demonstrate statistically significant improvement in schizophrenia symptoms in Phase II trials, a setback for the muscarinic pathway approach. • Bristol Myers Squibb's Cobenfy (KarXT), a muscarinic agonist, now stands as the frontrunner in schizophrenia treatment after AbbVie's trial failures. • Neurocrine Biosciences is advancing NBI-1117568, an oral muscarinic M4 selective agonist, with Phase III trials planned for early 2025, showing a potential path forward. • Other companies like Neumora Therapeutics and Reviva Pharmaceuticals are also exploring novel mechanisms for schizophrenia treatment, indicating a dynamic therapeutic landscape.

• Investment in neuroscience is increasing, driven by emerging treatments and unmet needs in CNS disorders, despite high risks and failure rates. • A major challenge is the high cost and poor translation of animal models in Phase III trials, making patient selection and biomarker identification crucial. • Advances in technology, such as AI and blood-based diagnostics, are improving early patient identification and streamlining clinical trial processes. • The potential of psychedelics for treating PTSD, depression, and anxiety is growing, but requires large-scale, robust trials due to a lack of biomarkers.

• Investment in neuroscience is increasing, driven by emerging treatments and the potential of psychedelics for conditions like PTSD and depression. • A major challenge in neuroscience is the high cost and failure rate of Phase III trials, coupled with the poor translation of animal models to CNS disorders. • Advances in technology, such as AI and blood-based biomarkers, are crucial for improving diagnostic efficiency and enabling targeted treatment approaches. • Identifying the right patient population and improving diagnostic methods are key to tackling neurodegenerative diseases like Alzheimer's.

• Alto Neuroscience's ALTO-100, designed to upregulate BDNF, did not meet the primary endpoint in a Phase 2b trial for major depressive disorder. • The trial, involving 301 participants, assessed the change in Montgomery-Åsberg Depression Rating Scale (MADRS) compared to placebo, but ALTO-100 showed no significant improvement. • Despite the disappointing results, Alto Neuroscience will analyze the data and continue developing other depression treatments like ALTO-203, ALTO-300 and ALTO-202. • ALTO-100 is still being tested for bipolar depression and PTSD, offering potential for success in different patient populations.

Alto Neuroscience's ALTO-100 failed to meet its primary endpoint in a Phase 2b trial for major depressive disorder (MDD), as measured by the MADRS scale.