Movement Disorder: How does the new drug Mevidalen treat dementia with Lewy bodies?

Lewy body dementia, including Parkinson's disease dementia (PDD) and Lewy body dementia (DLB), is the second most common neurodegenerative dementia after Alzheimer's disease (AD)
.

Lewy body inclusions throughout subcortical and cortical brain regions, mainly containing misfolded and aggregated α-synuclein, are a histopathological hallmark of LBD

Although once thought to be two separate entities, the combination of supporting pathological, clinical, imaging, and neurochemical data suggest that PDD and DLB belong to the same general class of disorders
.

They share common neuroimaging features with overlapping patterns of atrophy, glucose utilization, and neurotransmitter changes (cortical cholinergic disorders and striatal/cortical dopaminergic disorders)

LBD is a multifaceted disorder with core motor and non-motor features that often leads to the use of multiple drugs in a situation that balances symptomatic efficacy and drug side effects
.

The use of standard dopaminergic therapy is limited by non-motor complications that often lead to undertreatment of motor symptoms, and rivastigmine remains the only drug approved in the United States to treat cognitive impairment in PDD

Mevidalen (LY3154207) represents a novel mechanism as a selective positive neoplastic modulator (PAM) of the dopamine D1 receptor subtype (D1PAM)
.

It works by increasing the tone of D1 receptors and their affinity for dopamine, thereby amplifying the response to dopamine at the time and location of dopamine release

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Conversely, Mevidalen, by enhancing the response to residual brain dopamine (or administered levodopa), will be under normal feedback control with a lower tendency to overstimulate
.

Melvidaren has the potential to improve cognitive performance by enhancing frontal dopaminergic neurotransmitters, activating cortical neurons, enhancing synaptic plasticity, and D1-mediated enhanced acetylcholine release

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Here, Kevin Biglan et al.
, Indianapolis - Eli Lilly and Company, utilized a (PRESENCE; NCT03305809) clinical trial to evaluate the safety and efficacy of mevidalen compared with placebo in patients with mild to moderate IBD (PDD or DLB)
.

The primary objective was to test the hypothesis that treatment with mevidalen at 10, 30 or 75 mg daily for 12 weeks would result in significant improvements in cognitive performance

PRESENCE is a 12-week Phase 2 study that randomly assigned (1:1:1:1) patients with LBD (N = 344) to daily doses of mevidalen (10, 30 or 75 mg) or placebo
.

The primary outcome measure was the change from baseline in the Cognitive Medicine Study Continuity of Attention (CoA) composite score
.

Secondary outcomes included Alzheimer's Disease Assessment Scale-Cognitive Subscale 13 (ADAS-cog13), Movement Disorders Association-Unified Parkinson's Disease Rating Scale (MDS-UPDRS), and Alzheimer's Disease Collaborative Study-Clinical Global Change Impressions (ADCS-CGIC)

What they found: Mevidalen failed to meet primary or secondary cognitive endpoints
.

Mevidalen resulted in a significant, dose-dependent improvement in the total MDS-UPDRS score (P<0.

Compared with placebo, the 30 mg and 75 mg mevidalen doses significantly improved ADCS-CGIC scores (minimal or better improvement: 30 mg P<0.
01, 75 mg P<0.
01; moderate or better improvement: 30 mg P < 0.
05, 75 mg P < 0.
001)
.

30 mg and 75 mg mevidalen doses significantly improved ADCS-CGIC scores 30 mg and 75 mg mevidalen doses significantly improved ADCS-CGIC scores

Increases in blood pressure, adverse events, and serious cardiovascular adverse events were most pronounced at the 75 mg dose
.

Blood vessel

The significance of this study is the discovery that: Mevidalen utilizes a novel mechanism of action to improve LBD-related motor symptoms in addition to standard of care , while improving or not exacerbating non-motor symptoms associated with traditional dopaminergic therapy
.

Mevidalen utilizes a novel mechanism of action to improve motor symptoms associated with LBD on top of standard care

Original source:
Biglan K, Munsie L, Svensson KA, et al.
Safety and Efficacy of Mevidalen in Lewy Body Dementia: A Phase 2, Randomized, Placebo‐Controlled Trial.
Mov Disord.
Published online December 2, 2021:mds.
28879.
doi: 10.
1002/mds.
28879

Safety and Efficacy of Mevidalen in Lewy Body Dementia: A Phase 2, Randomized, Placebo‐Controlled Trial.
Mov Disord.

 

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