mevidalen (LY3154207) / Eli Lilly - LARVOL DELTA

Multiple Allosteric Sites Allow for Synergistic Enhancement of GPCR Signaling. (PubMed, bioRxiv) - "When combined with LY3154207, this cooperative architecture enhances dopamine potency by more than 1,000-fold. These findings elucidate the first structural blueprint for multi-site GPCR cooperativity, unlocking transformative therapeutic strategies inaccessible to orthosteric and single- site allosteric drugs."

Journal

A Study of Mevidalen (LY3154207) in Participants With Alzheimer's Disease (clinicaltrials.gov) - P2 | N=300 | Recruiting | Sponsor: Eli Lilly and Company | Not yet recruiting ➔ Recruiting

Enrollment open • Alzheimer's Disease • CNS Disorders

A Study of Mevidalen (LY3154207) in Participants With Alzheimer's Disease (clinicaltrials.gov) - P2 | N=300 | Not yet recruiting | Sponsor: Eli Lilly and Company

New P2 trial • Alzheimer's Disease • CNS Disorders

Computational insights into diverse binding modes of the allosteric modulator and their regulation on dopamine D1 receptor. (PubMed, Comput Biol Med) - "The dopamine D1 receptor (DRD1), a member of Class A GPCRs, is critical for treating psychiatric disorders, and LY3154207 serves as its promising positive allosteric modulator (PAM)...It should result from its induced weaker correlation between the allosteric site and the orthosteric site, and between the orthosteric site and the transducer binding site than the other three binding modes, as well as its weakened interaction between a crucial activation-related residue (S2025.46) and the orthosteric ligand (dopamine). Overall, the work offers atomic-level information to advance our understanding of the complex allosteric regulation on GPCRs, which is beneficial to the allosteric modulator design and development."

Journal • CNS Disorders • Mental Retardation • Psychiatry

Cognitive Impairment in Parkinson's Disease: An Updated Overview Focusing on Emerging Pharmaceutical Treatment Approaches. (PubMed, Medicina (Kaunas)) - "Accumulating preclinical and clinical evidence shows that several agents may provide beneficial effects on patients with PD and cognitive impairment, including ceftriaxone, ambroxol, intranasal insulin, nilotinib, atomoxetine, mevidalen, blarcamesine, prasinezumab, SYN120, ENT-01, NYX-458, GRF6021, fosgonimeton, INT-777, Neuropeptide S, silibinin, osmotin, cordycepin, huperzine A, fibroblast growth factor 21, Poloxamer 188, ginsenoside Rb1, thioredoxin-1, tangeretin, istradefylline and Eugenia uniflora. In this updated overview, we aim to cover the clinical aspects of the spectrum of PD-related cognitive impairment and discuss recent evidence on emerging treatment approaches that are under investigation at a preclinical and clinical level. Finally, we aim to provide additional insights and propose new ideas for investigation that may be feasible and effective for the spectrum of PD-related cognitive impairment."

Journal • Review • Alzheimer's Disease • CNS Disorders • Cognitive Disorders • Dementia • Inflammation • Movement Disorders • Parkinson's Disease • FGF21

The Molecular Mechanism of Positive Allosteric Modulation at the Dopamine D1 Receptor. (PubMed, Int J Mol Sci) - "Additionally, we identified an allosteric pathway likely responsible for the positive allosteric effect of LY3154207 in enhancing Gs protein coupling. This mechanistic understanding of LY3154207's allosteric action at the D1R paves the way for the rational design of more potent and effective allosteric modulators."

Journal • CNS Disorders • Mental Retardation • Psychiatry • IL2

Using Clinical Scales and Digital Measures to Explore Falls in Patients with Lewy Body Dementia. (PubMed, Digit Biomark) - "The association of falls with worse baseline disease severity and higher BMI and overall trend toward improvements on cognitive and motor scales suggest that falls in PRESENCE may be related to increased activity in mevidalen-treated participants at greater risk for falling. Future studies to confirm this hypothesis using fall diaries and digital assessments are necessary."

Journal • Alzheimer's Disease • CNS Disorders • Dementia • Lewy Body Disease • Movement Disorders • Parkinson's Disease

Molecular mechanism of positive allosteric modulation at the dopamine D1 receptor (ACS-Fall 2023) - "The allosteric pathway we identified is likely associated with the positive allosteric effect of LY3154207 to enhance Gs protein coupling. Taken together, we propose an allosteric mechanism of LY3154207 at the D1R that may facilitate rational design of more effective allosteric modulators."

Alzheimer's Disease • CNS Disorders • Mental Retardation • Movement Disorders • Parkinson's Disease • Psychiatry • Schizophrenia • IL2

Clinical trials for cognition in Parkinson's disease: Where are we and how can we do better? (PubMed, Parkinsonism Relat Disord) - "Amongst a large number of trials for cognition in PD, only a small proportion were completed. Few showed significant improvement, with no proven long-lasting effects. Trial design, lack of enrichment for at-risk groups, short follow-up duration, insensitive outcome measures likely contribute to lack of detectable benefit and should be considered in future trials."

Journal • Review • Alzheimer's Disease • CNS Disorders • Cognitive Disorders • Movement Disorders • Parkinson's Disease

Wrist-worn sensor-based measurements for drug effect detection with small samples in people with Lewy Body Dementia. (PubMed, Parkinsonism Relat Disord) - P2 | "Digital measurements detected treatment effects in a smaller cohort over a shorter period than conventional clinical assessments."

Journal • Alzheimer's Disease • CNS Disorders • Dementia • Lewy Body Disease • Movement Disorders • Parkinson's Disease

Evaluation of Actigraphy-Based Circadian Rhythm and Motor Function Measures for Monitoring Treatment of Lewy Body Dementia in PRESENCE Study (MDS Congress 2022) - "Background: PRESENCE (NCT:03305809) was a phase 2 clinical trial assessing mevidalen (LY3154207), a D1 receptor positive allosteric modulator, to treat symptoms of LBD [1]... The results demonstrate promising application of passively collected actigraphy data using a low burden device to obtain clinically meaningful insight in circadian rhythm, bradykinesia, and tremor from patients with LBD."

Alzheimer's Disease • CNS Disorders • Dementia • Lewy Body Disease • Parkinson's Disease

Route selection and process development for Mevidalen (ACS-Fall 2022) - "Optimization of the final steps to eliminate a protecting group and improve efficiency will be disclosed. The development process resulted in an improved regulatory starting material strategy and shortened the route significantly, which gave the benefits of reduced lead time, cost, and environmental burden."

Alzheimer's Disease • CNS Disorders • Dementia • Lewy Body Disease

Discovery of mevidalen, a novel dopamine D1 positive allosteric modulator for the treatment of neurodegenerative disorders (ACS-Fall 2022) - "At Lilly, a series of tetrahydroisoquinoline-based D1 PAMs has been developed that significantly increase the affinity of dopamine for the D1 receptor (high alpha-shift) and provide excellent D1 subtype selectivity. Multi-parameter optimization of molecules in this series resulted in the identification of mevidalen (LY3154207), a potent and selective D1 PAM currently in clinical development for the treatment of symptomatic Lewy body dementia."

Alzheimer's Disease • CNS Disorders • Dementia • Lewy Body Disease • Mood Disorders • Movement Disorders • Parkinson's Disease • Psychiatry • Schizophrenia • Sleep Disorder

Evaluating the Use of Digital Biomarkers to Test Treatment Effects on Cognition and Movement in Patients with Lewy Body Dementia. (PubMed, J Parkinsons Dis) - "Devices used in the LBD population achieved adequate compliance and digital metrics detected statistically significant treatment effects."

Biomarker • Journal • Alzheimer's Disease • CNS Disorders • Dementia • Lewy Body Disease • Movement Disorders • Parkinson's Disease

Ligand recognition and biased agonism of the D1 dopamine receptor. (PubMed, Nat Commun) - "Here, we report three cryo-electron microscopy structures of the D1 dopamine receptor (D1R)-Gs complex bound to two agonists, fenoldopam and tavapadon, and a positive allosteric modulator LY3154207. Moreover, LY3154207 stabilizes the second intracellular loop of D1R in an alpha helical conformation to efficiently engage the G protein. Through a combination of biochemical, biophysical and cellular assays, we further show that the broad conformation stabilized by two fenoldopam molecules and interaction between TM5 and the agonist are important for biased signaling of D1R."

Journal • CNS Disorders • Psychiatry

A Modular Approach for Diversity-Oriented Synthesis of 1,3-trans-Disubstituted Tetrahydroisoquinolines: Seven-Step Asymmetric Synthesis of Michellamines B and C. (PubMed, Angew Chem Int Ed Engl) - "With widely available simple aryl iodides, aziridines and (triisopropyl)acetylene as the building blocks, this method paves a practical way for the diversity-oriented synthesis of 1,3- trans -disubstituted THIQs. Based on this new method, concise syntheses of an analogue of the new drug mevidalen and four naphthylisoquinoline alkaloids have been accomplished, demonstrating the broad synthetic utility of this approach."

Journal

A Study to Evaluate LY3154207 on the Brain of Healthy Participants (clinicaltrials.gov) - P1 | N=16 | Completed | Sponsor: Eli Lilly and Company | Recruiting ➔ Completed

MRI • Trial completion

Synthesis and Preclinical Characterization of LY3154885, a Human Dopamine D1 Receptor Positive Allosteric Modulator with an Improved Nonclinical Drug-Drug Interaction Risk Profile. (PubMed, J Med Chem) - "Results from recently completed clinical studies suggest the dopamine D1 receptor positive allosteric modulator (PAM) mevidalen (1) could offer unique value for lewy body dementia (LBD) patients. While attempts to introduce additional metabolic pathways mediated by other CYP isoforms failed to provide molecules with an acceptable profile, we discovered that the relative contribution of CYP-mediated oxidation and UGT-mediated conjugation could be tuned to reduce the CYP3A4-mediated victim DDI risk. We have identified LY3154885 (5), a D1 PAM that possesses similar in vitro and in vivo pharmacologic properties as 1, but is metabolized mainly by UGT, predicting it could potentially offer lower victim DDI risk in clinic."

Journal • Preclinical • Alzheimer's Disease • CNS Disorders • Dementia • Lewy Body Disease

A Study to Evaluate LY3154207 on the Brain of Healthy Participants (clinicaltrials.gov) - P1; N=15; Recruiting; Sponsor: Eli Lilly and Company; N=34 ➔ 15

Clinical • Enrollment change

The dopamine D1 receptor positive allosteric modulator mevidalen (LY3154207) enhances wakefulness in the humanized D1 mouse and in sleep deprived healthy volunteers. (PubMed, J Pharmacol Exp Ther) - "In both the human and mouse, drug exposure was correlated to sleep latency supporting the use of sleep-wake activity as a translational central biomarker for the mechanism. Overall, the wake promoting effects of D1PAMs including mevidalen may offer therapeutic opportunities in several conditions including sleep disorders and excessive daytime sleepiness related to neurodegenerative disorders."

Journal • Preclinical • CNS Disorders • Excessive Daytime Sleepiness • Sleep Disorder

Safety and Efficacy of Mevidalen in Lewy Body Dementia: A Phase 2, Randomized, Placebo-Controlled Trial. (PubMed, Mov Disord) - "Mevidalen harnesses a novel mechanism of action that improves motor symptoms associated with LBD on top of standard of care while improving or not worsening non-motor symptoms associated with traditional dopaminergic therapy."

Clinical • Journal • P2 data • Alzheimer's Disease • Cardiovascular • CNS Disorders • Dementia • Lewy Body Disease • Movement Disorders • Parkinson's Disease

Safety, Tolerability, and Pharmacokinetics of Mevidalen (LY3154207), a Centrally Acting Dopamine D1 Receptor-Positive Allosteric Modulator, in Patients With Parkinson Disease. (PubMed, Clin Pharmacol Drug Dev) - "In the Movement Disorder Society-United Parkinson's Disease Rating Scale, all patients taking mevidalen showed a better motor examination sub-score on day 6 compared to only some patients in the placebo group. These data support examining mevidalen for symptomatic treatment of patients with Parkinson disease and Lewy body dementia."

Clinical • Journal • PK/PD data • Alzheimer's Disease • CNS Disorders • Dementia • Lewy Body Disease • Movement Disorders • Parkinson's Disease

[VIRTUAL] Utilizing digital biomarkers to explore risk factors for falls in patients with Lewy Body Dementia (MDS Congress 2021) - "The association of falls with baseline disease severity and BMI, and overall improvements of activity and daytime sleep suggest that falls in PRESENCE may be related to increased activity in mevidalen-treated participants at the greatest risk for falling. Future trials of mevidalen using fall diaries and digital assessments are necessary to confirm this hypothesis."

Biomarker • Clinical • Alzheimer's Disease • CNS Disorders • Dementia • Lewy Body Disease

[VIRTUAL] Evaluating the Use of Digital Biomarkers to Test Treatment Effects on Cognition and Motor in Patients with Lewy Body Dementia (MDS Congress 2021) - "Objective: To evaluate if frequent cognitive and motor tests using an iPad app and a wrist-worn actigraphy watch to track activity and sleep can detect mevidalen (LY3154207) effects in patients with Lewy Body Dementia (LBD)... The results demonstrated that devices used in the LBD population achieved adequate compliance and derived digital metrics detected statistically significant treatment effects."

Biomarker • Clinical • Alzheimer's Disease • CNS Disorders • Dementia • Lewy Body Disease

[VIRTUAL] Motor and non-motor effects of mevidalen in Lewy Body Dementia as measured by the Movement Disorder Society's Unified Parkinson's Disease Rating Scale (MDS-UPDRS) (MDS Congress 2021) - "Mevidalen, which harnesses a novel mechanism of action, resulted in symptomatic improvement of motor and select non-motor symptoms of parkinsonism associated with LBD, and avoided worsening of non-motor symptoms associated with traditional dopaminergic therapy."

Alzheimer's Disease • CNS Disorders • Dementia • Lewy Body Disease • Parkinson's Disease