Therapeutics

Mevidalen

Overview

Name: Mevidalen
Synonyms: LY3154207, Mevidalen hydroxybenzoate
Chemical Name: 2-(2,6-dichlorophenyl)-1-[(1S,3R)-3,4- dihydro-3-(hydroxymethyl)-5-(3-hydroxy-3-methylbutyl)-1-methyl-2(1H)- isoquinolinyl]ethanone
Therapy Type: Small Molecule (timeline)
Target Type: Other Neurotransmitters (timeline)
Condition(s): Parkinson's Disease Dementia, Dementia with Lewy Bodies
U.S. FDA Status: Parkinson's Disease Dementia (Phase 2), Dementia with Lewy Bodies (Phase 2)
Company: Eli Lilly & Co.

Background

LY3154207 is a small-molecule, positive allosteric modulator of the dopamine receptor D1 (D1 PAM). The drug increases affinity of the D1 receptor for dopamine, and is thought to improve dementia symptoms by amplifying the effect of endogenous dopamine. LY3154207 is being developed for the treatment of Parkinson's disease dementia and dementia with Lewy bodies. It is taken in tablet form.

Preclinical work suggests D1 PAMs may be useful in multiple disorders, including Alzheimer's disease, cognitive impairment in schizophrenia, major depressive disorder, and narcolepsy or excessive daytime sleepiness (Svensson et al., 2019). As an allosteric modulator, LY3154207 potentially avoids some negative aspects of currently used D1 agonists, which have a narrow therapeutic range and can lose activity with repeated dosing (Hao et al., 2019).

Findings

Between February 2015 and March 2017, Lilly completed two Phase 1 studies in healthy adults. The first tested single ascending doses in 64 volunteers, using a placebo-controlled crossover design that included CSF collection from some participants, and a cohort to assess interaction with the anti-fungal itraconazole. The second enrolled 80 healthy participants, who received drug or placebo daily for two weeks. For both trials, the primary outcome was the number of people with drug-related serious adverse events; secondary was pharmacokinetics. In the single-dose study, LY3154207's tolerability was acceptable up to 200 mg, though doses above 75 mg caused acute increases in blood pressure and pulse rate. In the repeat-dosing study, 14 days of 15, 30, 75, or 150 mg daily in 48 healthy Japanese and non-Japanese volunteers produced no serious adverse events. Common side effects were mostly mild and included insomnia, dizziness, nausea, nervousness, and palpitations. Dose-related increases in blood pressure and pulse rate were seen on the first day of treatment, but abated after two weeks of dosing (Wilbraham et al., 2020).

Lilly completed three additional Phase 1 studies between 2015 and 2019. One assessed Mevidalen’s effect on sleep in 16 healthy men, one studied tissue distribution and metabolism in eight healthy men dosed with 14C-LY3154207; the third compared capsule and tablet formulations, and interaction with fluconazole, in 36 healthy adults who took the drug for up to 11 weeks. In that trial, the primary outcome was drug-related serious adverse events; secondary outcomes included changes in blood pressure, pulse rate, and plasma PK. No results have been published for these studies.

In November 2017, a Phase 2 study called PRESENCE began to evaluate Mevidalen's effect on cognition in people with Parkinson’s disease or dementia with Lewy bodies. It enrolled 344 participants with mild to moderate dementia to receive 10, 30, or 75 mg LY3154207 or placebo for three months. The primary outcome was change from baseline in the continuity of attention composite score of the Cognitive Drug Research Computerized Cognition Battery (CDR-CCB-CoA). A long list of secondary outcomes included clinical, cognitive, sleep, and motor function measures, plus blood pressure, pulse rate, and pharmacokinetics. Conducted at 77 centers in the U.S., Canada, and Puerto Rico, the trial ended in July 2020.

As presented in March 2021 at AAT-AD/PD, Mevidalen at any dose failed to change the primary endpoint of cognition. Among secondary measures, the Clinical Global Impression of Change, the Unified Parkinson's Disease Rating Scale, and daytime sleepiness were improved, with the 75 mg dose being most effective. Adverse events increased with dose; the most common being dizziness, nausea, hallucinations, headache, insomnia. The 75 mg dose was discontinued mid-study after four serious cardiovascular adverse events in that group. As in Phase 1, Mevidalen caused a temporary increase in blood pressure and pulse in the 10 and 30 mg groups. The increase in blood pressure persisted in people taking 75 mg.

Lilly registered a new Phase 1 trial in 2020. Starting in September, the study planned to enroll 34 healthy adults to take a single dose of Mevidalen or placebo, followed by a functional MRI scan. The sole outcome is change from baseline in intrinsic functional connectivity in the brain's resting-state networks. After a delay, the study began recruiting in January 2021, with completion expected in November 2021.

For details on trials, see clinicaltrials.gov.

Last Updated: 20 Apr 2021

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References

Paper Citations

  1. . Safety, Tolerability, and Pharmacokinetics of Mevidalen (LY3154207), a Centrally Acting Dopamine D1 Receptor-Positive Allosteric Modulator (D1PAM), in Healthy Subjects. Clin Pharmacol Drug Dev. 2020 Oct 7; PubMed.
  2. . Positive allosteric modulators of the dopamine D1 receptor: A new mechanism for the treatment of neuropsychiatric disorders. Adv Pharmacol. 2019;86:273-305. Epub 2019 Jul 13 PubMed.
  3. . Synthesis and Pharmacological Characterization of 2-(2,6-Dichlorophenyl)-1-((1S,3R)-5-(3-hydroxy-3-methylbutyl)-3-(hydroxymethyl)-1-methyl-3,4-dihydroisoquinolin-2(1H)-yl)ethan-1-one (LY3154207), a Potent, Subtype Selective, and Orally Available Positive . J Med Chem. 2019 Oct 10;62(19):8711-8732. Epub 2019 Sep 30 PubMed.

External Citations

  1. clinicaltrials.gov

Further Reading

Papers

  1. . Preclinical profile of a dopamine D1 potentiator suggests therapeutic utility in neurological and psychiatric disorders. Neuropharmacology. 2018 Jan;128:351-365. Epub 2017 Oct 26 PubMed.