VU319 / Acadia Pharma - LARVOL DELTA

Application of Deuterium in an M1 Positive Allosteric Modulator Back-Up Program: The Discovery of VU6045422. (PubMed, ACS Chem Neurosci) - "In both rat and dog in vivo, low doses proved to mirror the in vitro profile; however, at higher doses in 14-day exploratory toxicology studies, the amount of the same undesired metabolite derived from VU6045422 was equivalent to that produced from VU0467319. This unexpected IVIVC result, coupled with less than dose-proportional increases in exposure and no improvement in solubility, led to discontinuation of VU0467319/VU6045422 development."

Journal

Discovery of VU0467319: an M1 Positive Allosteric Modulator Candidate That Advanced into Clinical Trials. (PubMed, ACS Chem Neurosci) - P1 | "Moreover, signals of target engagement were seen at the highest dose tested. Thus, VU319 demonstrated the feasibility of achieving selective targeting of central M1 muscarinic receptors without eliciting cholinergic AEs that have plagued other drugs targeting CNS cholinergic neurotransmission."

Journal • Metastases

Discovery of VU6007496: Challenges in the Development of an M1 Positive Allosteric Modulator Backup Candidate. (PubMed, ACS Chem Neurosci) - "Herein we report progress toward a backup clinical candidate to the M1 positive allosteric modulator (PAM) VU319/ACP-319...However, VU6007496 proved to be a highly selective and CNS penetrant M1 PAM, with minimal agonism, that displayed excellent multispecies IV/PO pharmacokinetics (PK), CNS penetration, no induction of long-term depression (or cholinergic toxicity) and robust efficacy in novel object recognition (minimum effective dose = 3 mg/kg p.o.). Thus, VU6007496 can serve as another valuable in vivo tool compound in rats and nonhuman primates, but not mouse, to study selective M1 activation."

Journal • CNS Disorders • Depression • Epilepsy • Psychiatry

Acadia Pharmaceuticals Inc (ACAD) Q2 2021 Earnings Call Transcript (The Motley Fool) - “…a brief summary of our ACP-319 M1 PAM program for the potential treatment of schizophrenia and cognitive impairment in Alzheimer's disease. As part of our transition, we are completing some additional nonclinical work and we'll be progressing our Phase I program with the initiation of a multiple-ascending dose study in the fourth quarter of this year.”

New P1 trial • Alzheimer's Disease • CNS Disorders • Cognitive Disorders • Schizophrenia

Multiple Ascending Dose Putative Cognitive Enhancer VU319 (clinicaltrials.gov) - P1; N=0; Withdrawn; Sponsor: Vanderbilt University Medical Center; N=24 ➔ 0; Trial completion date: Dec 2020 ➔ May 2021; Not yet recruiting ➔ Withdrawn; Trial primary completion date: Dec 2020 ➔ May 2021

Enrollment change • Trial completion date • Trial primary completion date • Trial withdrawal • Alzheimer's Disease • Cognitive Disorders

[VIRTUAL] Safety And Pharmacokinetics of The Muscarinic Positive Allosteric Modulator VU319: A Phase 1 Single Dose Study (AAIC 2020) - "Single dose VU319 across five ascending cohorts appeared to have a favorable safety profile and a PK profile consistent with once daily dosing. Administration of VU319 with food increased absorption and was associated with improvements in performance measures. These results provide a strong foundation for the planned multiple ascending dose study and a Phase 2a POC study in MCI."

Clinical • P1 data • PK/PD data

[VIRTUAL] Cognitive Performance Effects Following a Single Dose Of The M1 Muscarinic Positive Allosteric Modulator VU319 (AAIC 2020) - "We conclude that these results demonstrate likely enhancement of the cholinergic system functioning in healthy adults following a single oral dose of VU319. These results provide an indication of the potential measures that are sensitive to cognitive activity by M1 allosteric modulators and provide a framework to examine the cognitive impact of multiple doses of VU319 in AD patients."

Alzheimer's Disease • CNS Disorders • Cognitive Disorders

Vanderbilt University partners with ACADIA Pharmaceuticals to develop novel treatments for central nervous system disorders (Vanderbilt University Medical Center) - "Vanderbilt University’s Warren Center for Neuroscience Drug Discovery has entered into an exclusive worldwide licensing and collaboration agreement with San Diego-based ACADIA Pharmaceuticals Inc., which will seek to develop and commercialize treatments for central nervous system disorders, such as Alzheimer’s disease and schizophrenia....This collaboration will focus on positive allosteric modulators (PAMs) of the M1 receptor...A lead compound—VU319, which recently began Phase 1 clinical trials—was discovered by Vanderbilt researchers at the Warren Center and could help slow memory loss accompanying serious brain disorders."

Licensing / partnership • Alzheimer's Disease • CNS Disorders

Putative Cognitive Enhancer VU319 (clinicaltrials.gov) - P1; N=52; Completed; Sponsor: Vanderbilt University; Recruiting ➔ Completed

Trial completion

Multiple Ascending Dose Putative Cognitive Enhancer VU319 (clinicaltrials.gov) - P1; N=24; Not yet recruiting; Sponsor: Vanderbilt University Medical Center; Initiation date: Dec 2019 ➔ Dec 2020

Trial initiation date

FUNCTIONAL ACTIVITY OF THE MUSCARINIC POSITIVE ALLOSTERIC MODULATOR VU319 DURING A PHASE 1 SINGLE ASCENDING DOSE STUDY. (CTAD 2019) - "We conclude that these results demonstrate potential enhancement of the cholinergic system functioning in healthy adults following a single dose of VU319. These results provide an indication of the potential measures that are sensitive to cognitive activity by VU319 and therefore provide a potential framework to examine the cognitive impact of multiple doses of VU319 in AD patients."

P1 data

Phase 1 Single Ascending Dose Study Of The Muscarinic Positive Allosteric Modulator VU319 (CTAD 2019) - "Single dose VU319 across ve ascending cohorts appeared to have a favorable safety pro le, had a PK pro le consistent with once daily dosing, and appeared to alter cognitive performance and brain activity at doses that do not appear to produce peripheral muscarinic side e ects. Planned further studies include a multiple ascending dose study, and a Phase 2a POC study to assess VU319 e ects on cognition and modulation of the functional integrity of cortical networks in MCI by assessing resting and task-based connectivity of the default mode and cognitive control networks. This will help in selecting measures for larger Phase 2 and 3 trials."

P1 data

Multiple Ascending Dose Putative Cognitive Enhancer VU319 (clinicaltrials.gov) - P1; N=24; Not yet recruiting; Sponsor: Vanderbilt University Medical Center; Initiation date: Aug 2019 ➔ Dec 2019

Trial initiation date

Multiple Ascending Dose Putative Cognitive Enhancer VU319 (clinicaltrials.gov) - P1; N=24; Not yet recruiting; Sponsor: Vanderbilt University Medical Center

New P1 trial

Optimization of novel M1 PAMs for clinical development with enhanced efficacy while avoiding adverse effect liability for the treatment of Alzheimer’s disease (AAIC 2019) - "In addition, highly potent M1 agonist-PAMs, such as MK-7622, PF-06764427, and PF-06827443, can engender excessive activation of M1, leading to agonist actions in the prefrontal cortex that impair cognitive function, induce behavioral convulsions, and result in other classic cholinergic adverse events. The VCNDD has developed highly potent, selective M1 PAMs with enhanced physiochemical and pharmacokinetic properties and clean safety profile, providing an unprecedented opportunity to evaluate the potential of selective potentiation of M1 as a novel treatment of symptoms associated with AD. As opposed to direct activation of M1, PAMs dramatically potentiate the response of the receptor to its endogenous ligand acetylcholine, offering high selectivity while maintaining normal spatiotemporal signaling patterns and avoiding adverse effects of overstimulation. Phase I clinical trials are currently being conducted with the M1 PAM clinical candidate VU319 under the direction of..."

Adverse events • Clinical

Development of the Muscarinic Cholinergic PAM VU319 for Cognitive Enhancement: Phase 1 Tests of Safety and Target Engagement (AAIC 2019) - "Acute VU319 in the dose range tested do not show significant adverse effects, show a PK profile consistent with once daily dosing, and can alter cognitive performance and brain activity at doses that do not produce typical muscarinic side effects. Planned further studies include a multiple ascending dose study, and a Phase 2a POC study to assess VU319 effects on cognition and modulation of the functional integrity of cortical networks in MCI by assessing resting and task-based connectivity of the default mode and cognitive control networks. This will help in selecting measures for larger Phase 2 and 3 trials."

Clinical • P1 data

Cognitive and Electrophysiological Measures of a Phase 1 Single Ascending Dose Study of the Muscarinic Positive Allosteric Modulator VU319 (AAIC 2019) - "We conclude that these preliminary results suggest potential enhancement of the cholinergic system in healthy adults following a single dose of VU319. These early results indicate potential measures that are sensitive to target engagement by VU319 and support the examination of multiple doses of VU319 in healthy volunteers or patients."

P1 data

Putative Cognitive Enhancer VU319 (clinicaltrials.gov) - P1; N=52; Recruiting; Sponsor: Vanderbilt University; Trial completion date: Oct 2018 ➔ Oct 2019; Trial primary completion date: Oct 2018 ➔ Oct 2019

Trial completion date • Trial primary completion date