Dementia with Lewy bodies (DLB) is a devastating neurodegenerative dementia characterized by diverse symptoms including cognitive, motor, and behavioral alterations. It is the second most prevalent type of degenerative dementia after Alzheimer’s disease (AD) and accounts for approximately 5% of all dementia cases. DLB is frequently misdiagnosed because it resembles other forms of dementia. It has many clinical and pathological similarities with Parkinson's disease dementia (PDD). DLB has a worse prognosis and is related to high healthcare expenses, a higher caregiver burden, and worsening quality of life .
Where do we stand?
Management of DLB patients is difficult due to the wide range of symptoms, the lack of effective treatments, and the patient’s high sensitivity to drug-induced side effects. The current pharmacological therapeutic strategies for DLB make use of drugs that are approved for other indications and work to alleviate symptoms.
There is no disease-modifying therapy for DLB and while symptomatic treatments may reduce the progression of the disease, they cannot modify the disease pathology. As a result, DLB patients need both disease-modifying and symptomatic therapy that can help to alleviate the most troublesome symptoms without causing significant adverse effects .
Dopamine D1 receptor: what is it?
Dopamine is a catecholamine neurotransmitter that is crucial for maintaining consciousness, mood, and other central processes like cognition and motor function. Dopamine works by binding to G-protein-coupled receptors. The most prevalent dopamine receptor subtypes are the D1 and D2 receptors, which are expressed at least ten times higher than the D3, D4, and D5 receptors. The D1 receptor subtype is more important for maintaining cognitive abilities including working memory, attention, and executive function than the other dopamine receptor subtypes. For many diseases, including schizophrenia and neurodegenerative conditions like Parkinson’s and Alzheimer’s disease, impaired performance of these cognitive areas continues to be an unmet medical need.
Under these circumstances, stimulation of the brain dopamine D1 receptor has received more attention in the development of improved therapies for diseases like DLB. Dopaminergic therapies are existing for several conditions like dopamine agonists for PD, dopamine reuptake inhibitors for depression, dopamine releasers for attention deficit hyperactivity disorders and narcolepsy, and dopamine receptor antagonists for schizophrenia and bipolar disorders .
Do we need LY3154207?
Eli Lilly is now investigating the effects of LY3154207, a selective positive allosteric modulator of the dopamine D1 receptor subtype, on participants with DLB or PDD. Cognitive function, motor impairments, behavioral symptoms, and daytime sleepiness are all linked to dopamine and D1 receptors in particular are crucial for motor activity, cognition, wakefulness, and reward/motivation.
According to the postulated mechanism, LY3154207 enhances the affinity of dopamine for the D1 receptor, which intensify the tone of the D1 receptor at the location of dopamine release and improve the response to endogenous dopamine. Patients with insufficient physiological dopamine, such as those with DLB, may benefit from this. LY3154207 may increase D1 activity without these restrictions while direct D1 receptor agonists may accelerate the development of tolerance by excessive stimulation of the D1 receptor .
Is there any clinical evidence?
LY3154207 is now in phase 2 clinical trials for the treatment of cognition in patients with mild to moderate dementia associated with DLB or PDD (Identifier: NCT03305809). The primary outcome measure was an improvement in the capacity to focus for an extended length of time without making mistakes. Improvements in cognitive ability, attention, parkinsonism, daytime sleepiness, and neuropsychiatric symptoms were assessed as secondary outcomes .
The way forward with LY3154207?
The preclinical and clinical findings support the use of LY3154207 against a variety of DLB symptoms. This provides a foundation for the clinical evaluation of LY3154207 in neurodegenerative diseases, like DLB. Further research into LY3154207 as a potential treatment for DLB is necessary due to the varied characteristics of the disease and the various constellations of symptoms. Many features of DLB care require further research and the lack of information from high-quality, extensive clinical studies on these patients is a significant unmet challenge. There is a need to expand the understanding of the underlying molecular pathways driving the disease and recognize new targets like LY3154207 for therapeutic intervention.
G. Lee, J. Cummings, B. Decourt, J. B. Leverenz, and M. N. Sabbagh, “Clinical drug development for dementia with Lewy bodies: past and present,” Expert Opin Investig Drugs, vol. 28, no. 11, pp. 951–965, Nov. 2019, doi: 10.1080/13543784.2019.1681398.
D. Wilbraham, K. M. Biglan, K. A. Svensson, M. Tsai, and W. Kielbasa, “Safety, Tolerability, and Pharmacokinetics of Mevidalen (LY3154207), a Centrally Acting Dopamine D1 Receptor-Positive Allosteric Modulator (D1PAM), in Healthy Subjects,” Clin Pharmacol Drug Dev, vol. 10, no. 4, pp. 393–403, Apr. 2021, doi: 10.1002/cpdd.874.
Eli Lilly and Company, “Effect of LY3154207 on Cognition in Mild-to-Moderate Dementia Due to Lewy Body Dementia (LBD) Associated With Idiopathic Parkinson’s Disease (PD) or Dementia With Lewy Bodies (DLB),” clinicaltrials.gov, Clinical trial registration NCT03305809, Jul. 2021. Accessed: Jan. 10, 2023. [https://clinicaltrials.gov/ct2/show/NCT03305809]. Available: https://clinicaltrials.gov/ct2/show/NCT03305809