A Phase 2b Study of the Efficacy of a Novel Pro-Neurogenesis/Pro-Plasticity Drug for Bipolar Depression Using a Precision Psychiatry Approach

Bipolar disorder is a severe, life-long psychiatric condition associated with a high burden of disability and risk of suicide. The only approved treatments for its depressive phase (BD-D) are antipsychotic medications, which carry many side effects. As BD-D is defined by clinical phenomenology rather than by biology, successful development of new treatment options will most likely come by targeting biologically defined patient subgroups characterized by relevant pathophysiology (i.e. a precision psychiatry approach). Extensive data show neuroplasticity-related abnormalities in the brains of BD-D patients that can be clinically identified as deficits in memory, commonly seen in BD-D. A drug that enhances hippocampal neuroplasticity therefore holds promise specifically for memory-impaired BD-D patients. ALTO-100 is an orally active small molecule with a novel pro-neurogenesis/neuroplasticity mechanism of action. We have shown that MDD or PTSD patients with poor memory respond better to ALTO-100 than those with intact cognition. Here, we propose taking a precision psychiatry approach through a poor memory-stratified Phase 2b trial of ALTO-100 in BD-D, following closely the already FDA-tested design of a recently launched MDD Phase 2b. A successful outcome would accelerate this drug into Phase 3, potentially providing a groundbreaking new option for a highly underserved clinical population.