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).

High-resolution structures of the D1 receptor with LY3154207 bound in an allosteric pocket have been reported (see Sibley et al., 2021). This has enabled a better understanding of allosteric modulation (Chen et al., 2024; Goldberg et al., 2023).

Findings

Between February 2015 and March 2017, Lilly completed two Phase 1 studies. 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 48 healthy participants and 25 people with Parkinson’s disease, 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). Fewer side effects were reported in Parkinson’s patients. All treated patients improved on the UPDRS motor score, compared to half of those on placebo (Wilbraham et al., 2022).

Lilly completed three additional Phase 1 studies between 2015 and 2019. One assessed Mevidalen’s effect on sleep in 16 healthy men, and results were published (McCarthy et al., 2022). Mevidalen at 15, 30, or 75 mg promoted wakefulness, delaying the onset of sleep in sleep-deprived men. Another study assessed 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 the latter two studies.

In November 2017, a Phase 2 study called PRESENCE began to evaluate Mevidalen's effect on cognition in people with Lewy body dementia due to 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. Trial results were published after peer review (Biglan et al., 2022). Sub studies evaluated the use of wrist-worn activity sensors and digital cognitive testing. These detected significant effects on daytime sleep and activity, and spatial working memory in treated patients (Wang et al., 2022). Treatment-related changes in activity and cognition could be ascertained in smaller numbers of patients over shorter times using digital means compared to clinical measures (Chen et al., 2023). A trend toward more falls was observed in people taking drug, and was attributed to increased activity (Battioui et al., 2023).

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.

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 was change from baseline in intrinsic functional connectivity in the brain's resting-state networks. After a delay, the study began recruiting in January 2021. It finished in January 2022 after enrolling 16 participants.

Lilly published on a second generation D1 PAM, LY3154885, which was designed to have similar pharmacologic activity to Mevidalen, but less risk of drug-drug interactions (Hao et al., 2022). In August 2019, LY3154885 began Phase 1 testing. The study was terminated in February 2020 for business reasons. Results are posted on clinicaltrials.gov.

As of May 2024, Mevidalen is still in Lilly’s pipeline, but no active trials are registered.

For details on Mevidalen trials, see clinicaltrials.gov.