The results of the Phase 2 trial: Mevidalen improves motor symptoms

The results of the Phase 2 safety/efficacy, randomized, placebo-controlled trial of Mevidalen (selective PAM of dopamine D1 receptor) in Lewy Body Dementia; N = 344 randomly assigned (1:1:1:1) to daily doses of 10, 30, or 75 mg; Improves motor symptoms.

"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."

movementdisorders.onlinelib...

[park_bear]

Thanks for bringing this to our attention. This appears to be a new type of dopamine agonist. They did get substantial improvement in the UPDRS but they also got adverse effects:

"Reports from four participants with vascular-related SAEs, occurring in close temporal proximity to initiation of the 75 mg mevidalen dose, led the IAC to recommend discontinuing the 75 mg mevidalen group. The SAEs reported by these participants included congestive heart failure, hypertension, stroke, and hypertensive encephalopathy. A total of 214 participants (62.2%) in PRESENCE had at least one treatment-emergent adverse event (TEAE) across all groups with a significant number of these occurring in the treatment groups (P < 0.05), and 74.7% of the 75 mg mevidalen group experiencing a TEAE (P < 0.01). The most common TEAE was falls, occurring in 10.2% of the total participants, with the highest proportion of these occurring in the 10 mg and 75 mg mevidalen groups (14.0% and 13.8%, respectively). There was an overall statistically significant incidence of fatigue (P < 0.05), headache (P < 0.05), and vomiting (P < 0.05) in treatment groups versus placebo, while incidence of headache also increased in the 30 mg mevidalen group (P < 0.05) in comparison to other treatment groups."

[Bolt_Upright]

It's good that it helped motor symptoms, but...

Objective

To assess the safety and efficacy of mevidalen for treatment of cognition in patients with Lewy body dementia (LBD).

Results

Mevidalen failed to meet primary or secondary cognition endpoints. Mevidalen resulted in significant, dose-dependent improvements of MDS-UPDRS total score (sum of Parts I−III, 10 mg P < 0.05, 30 mg P < 0.05, 75 mg P < 0.01, compared to placebo). The 30 mg and 75 mg mevidalen doses significantly improved ADCS-CGIC scores compared to placebo (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). Increases in blood pressure, adverse events, and cardiovascular serious adverse events were most pronounced at the 75 mg dose.

Conclusions

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.