IND-enabling development and first-in-human safety exposure of MW073 - dementia is an increasing global health challenge

The National Institute on Aging, part of the Department of Health and Human Services, awarded a cooperative agreement to Northwestern University on September 1, 2026, totaling $2,083,260 under the Aging Research program (CFDA 93.866) to support IND-enabling development and first-in-human safety exposure of MW073, a selective serotonin 5-HT2B receptor antagonist candidate for treating cognitive impairment and neuropsychiatric syndromes in Alzheimer's disease and related conditions.

MW073 is designed as a first-in-class, orally bioavailable small molecule that selectively inhibits 5-HT2B receptor signaling and arrestin recruitment while avoiding off-target liabilities associated with cardiovascular and psychiatric side effects. The compound has demonstrated high tolerability and dual attenuation of synaptic and behavioral dysfunction in preclinical Alzheimer's disease models. The award funds advancement of MW073 toward human clinical trials, addressing a gap in safe, effective dual-action therapies targeting both cognitive loss and neuropsychiatric syndromes, which collectively drive the major public health and economic burden of dementia.

Performance occurs in Chicago, Illinois. The period of performance runs through August 31, 2031. Northwestern University's Sponsored Research Division is the recipient.

Alzheimer's disease (ad) is the predominant form of dementia. While cognitive impairment is the primary clinical hallmark of ad, IT is the collective impact of cognitive impairment and neuropsychiatric syndromes (NPS) that generate societal manifestations, profound difficulties for families and friends, and the major public health and economic impact. However, there is a lack of safe, effective dual-action therapies for cognition and NPS. Ad pathologies coincident with cognitive and neuropsychiatric symptom progression include loss of serotonin (5-hydroxytryptamine; 5-HT) neurons in the raphe nucleus and appearance of neurofibrillary tangles in the dorsal raphe nucleus (DRN) that is rich in 5-HT neurons. In addition, human HTR2B gene variants are directly implicated in neuropsychiatric syndromes. We have shown that brain 5-HT2BR levels are increased in ad, like findings for ALS and brain injury morbidity. A body of clinical and basic science evidence supports the hypothesis that selective 5-HT2BR antagonists offer a new potential therapeutic intervention to attenuate cognitive loss and NPS in ad and other disorders. Regrettably, clean 5-HT2BR antagonists as therapeutics has been neglected. We directly addressed the challenge with development of MW073, a first-in-class and uniquely selective inhibitor of serotonin 5- HT2B receptor (5-HT2BR) activation and arrestin recruitment. MW073 is an orally bioavailable candidate with high tolerability in preclinical studies and exhibits a novel dual attenuation of synaptic and behavior dysfunction in preclinical ad models. MW073 was specifically designed to avoid key off-target liabilities, particularly 5-HT2BR agonist activity and dopaminergic receptor engagements that limited therapeutic development due to concerns about cardiovascular and psychiatric side effects. MW073 selectively inhibits 5-HT2BR signaling via the GQ-PLCΒ2 pathway and Β-arrestin recruitment in both human and mouse receptor systems, a mechanism associated with downstream lipidomic end points in neurodegenerative and neuropsychiatric disorders. We propose to meet the technical and regulatory requirements for entry into future phase 2 trials in cognitively impaired ad patients. Specifically, we propose to: 1) produce GMP clinical drug and reference standard required for a first-in-human phase 1A (SAD) evaluation of safety, tolerability, and exposure; 2) perform required GLP toxicology studies in rats and dogs with recovery phase and toxicokinetics; 3) perform a first-in-human phase 1A (SAD) evaluation of safety, tolerability, and exposure; 4) identify and qualify translatable lipidome-based endpoints for future clinical trials. Overall, the outcomes will allow US to proceed immediately to a future planned phase 2 clinical study of ad patients. MW073 provides a potentially novel precision pharmacological pathway for treating alzheimer's disease and neuropsychiatric syndromes. Long term success will be transformative due to the common pathophysiology theme and availability of a precision intervention therapeutic.