Our lead program is in a clinical Phase 2/3 study on agitation in Alzheimer's disease dementia
Lead program
Exciva's lead program is now advanced into a clinical Phase 2/3 study on agitation in Alzheimer's disease dementia patients - the SERENADA study (Serenity in Alzheimer’'s Disease Agitation).
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Our lead project is built upon two innovative drug development approaches targeting the symptomatic management of Alzheimer’s disease dementia that have recently emerged after decades of preclinical and clinical research .
Exciva combines dextromethorphan, an NMDA receptor channel blocker, with EXV-801, a triple-acting agent that is a CYP2D6 inhibitor and a 5-HT2A/2C receptor inverse agonist.
When combined, these two novel modes of action (NMDA receptor antagonism and 5-HT2A/2C receptor inverse agonism) will deliver a broad and synergistic treatment targeting various domains of neuropsychiatric symptoms associated with dementia, including hallucinations, delusions, aggression, agitation, depression, apathy, and insomnia.
This pharmacological approach offers the opportunity treat such symptoms without affecting the dopaminergic system, hence avoid an acceleration of cognitive decline, and increased risk for morbidity and mortality.
Neuropsychiatric symptoms of dementia
Neuropsychiatric symptoms of dementia (NPS) are the leading cause of institutionalization of people with Alzheimer’s disease and other dementias and constitute the major source of caregiver distress.
The term NPS covers a range of symptoms including agitation/aggression, anxiety, depression, apathy, irritability, disinhibition, delusions/hallucinations, etc. These symptoms are distinct in clinical presentation and are often considered mutually exclusive. Indeed, patients rarely display all of the symptoms simultaneously. Conversely, clinical experience indicates that there is rarely a patient with just one specific symptom. For instance, a frequently observed cluster of symptoms in AD could be aggression, agitation, wandering, repetitiveness, and anxiety.
Neurodegenerative diseases like AD are characterized by progressive neuronal cell death resulting in overall brain atrophy. This does not only result in accentuated neuronal loss in certain brain areas initially, but also leads to the pathology spreading to other brain regions as the diseases progress. As different brain areas are responsible for different functional roles, this explains why more advanced stages of the disease, with more widespread and generalized brain atrophy, are accompanied by a wider spectrum of symptoms.
Key publications:
1. Effect of Dextromethorphan-Quinidine on Agitation in Patients With Alzheimer Disease Dementia – open access
A seminal 2015 publication by Jeff Cummings, Constantine Lyketsos and colleagues that spurred interest in development of dextromethorphan-based therapies for treatment of neuropsychiatric symptoms in dementia
2. Evaluation of the Safety, Tolerability, and Efficacy of Pimavanserin Versus Placebo in Patients with Alzheimer's Disease Psychosis – paywalled access
A 2018 proof-of-concept study by Clive Ballard and colleagues on pimavanserin, a drug mechanistically similar to EXV-801
3. A Descriptive Statistical Analysis of Neuropsychiatric Symptom Pair Prevalence - paywalled access
Publication by the Exciva team providing detailed quantitative analysis of co-occurrence of neuropsychiatric symptoms.
4. Progress in Pharmacologic Management of Neuropsychiatric Syndromes in Neurodegenerative Disorders – open access
A 2024 review by Jeff Cummings, Krista Lanctôt and colleagues on clinical consensus definition of neuropsychiatric symptoms as well as current and emerging therapies.