Study review highlights limits of levodopa effectiveness
Inbrain study points to need for continuous delivery system
Note: This story was updated Sept. 16, 2024, to correct that A-dopamine is a form of dopamine.
Levodopa, a mainstay in treating Parkinson’s disease, isn’t always well absorbed by the brain or digestive tract, doesn’t last long in the body, and often loses effectiveness with age and disease progression, leading to inconsistent control of symptoms, according to a study by Inbrain Pharma, which is developing a form of dopamine that’s delivered directly to the brain.
Continuous delivery of levodopa aims to address some of these limitations but still falls short of full control of symptoms. That points to a need for options that more closely mimic the brain’s natural production of dopamine, the chemical messenger that becomes depleted in Parkinson’s.
The study “highlights the significant gap between these treatments and the ideal of continuous dopaminergic stimulation,” Caroline Moreau, MD, PhD, Inbrain’s clinical scientific adviser and co-founder and a neurologist at Lille University Hospital in France, said in a company press release. “Medical needs in the management of Parkinson’s disease remain very great.”
The study, “Effectiveness of Continuous Dopaminergic Therapies in Parkinson’s Disease: A Review of L-DOPA Pharmacokinetics/Pharmacodynamics,” was published in the Journal of Parkinson’s Disease. It was led by David Devos, MD, PhD, also an Inbrain cofounder and adviser and a neurologist and pharmacologist at Lille.
Parkinson’s is caused by the loss of dopaminergic neurons, the nerve cells in the brain that produce the dopamine needed to control movement. Depletion of dopamine causes motor symptoms, such as tremors, stiffness, slowness of movement, and impaired balance. Because dopamine cannot cross into the brain or digestive tract, its precursor, levodopa or L-DOPA, remains the mainstay of treatment. However, as Parkinson’s progresses, patients need higher doses, more often. This leads to periods when symptoms are poorly controlled, called off episodes, and side effects such as dyskinesia or involuntary movements.
Continuous delivery as boost for levodopa effectiveness
To better understand the limitations of levodopa and how current treatments that provide continuous delivery help, researchers reviewed 75 articles, narrowing them down to 10 for detailed analysis of levodopa’s pharmacokinetics (how a compound moves into, through, and out of the body) and pharmacodynamics (how it works in the body).
The analysis revealed that limitations associated with levodopa treatment include poor absorption in the brain and digestive tract, unnecessary distribution in other parts of the body, and a short half-life, a measure of how quickly levodopa leaves the body. With age and disease progression, the body begins to loose its capacity to convert levodopa into dopamine.
“These new data help to highlight that many of L-DOPA’s pharmacokinetic and pharmacodynamic constraints are not resolved by existing subcutaneous [under-the-skin] or enteral [into-the-intestine] continuous dopaminergic stimulation,” the researchers wrote.
These constraints do not appear to be resolved by current options for continuous delivery of levodopa. According to the researchers, while these treatment approaches improve the time that symptoms are controlled, patients still experience dyskinesia.
“It is against this backdrop that we have developed pharmacological neuromodulation by continuous personalized delivery of the deficient neurotransmitter … to treat people with advanced Parkinson’s disease with severe late complications refractory to L-DOPA,” said Moreau.
Unlike levodopa, which is usually taken by mouth, A-dopamine is delivered by a pump via a surgically implanted catheter directly into the brain, where it’s actually needed. The pump can provide a steady supply of A-dopamine in the absence of oxygen, which is thought to make it less effective.
Preclinical studies have found that A-dopamine could ease Parkinson’s symptoms without the side effects usually associated with levodopa, even when delivered at high doses.
Early results from a completed Phase 1/2 clinical trial, called DIVE-I (NCT04332276), showed that A-dopamine was safe and effective at controlling severe symptoms, while allowing for reduced dosage of oral levodopa in patients, ages 45 to 75. Full results will be shared later this month at an international meeting in Philadelphia.
“A-dopamine treatment considerably reduced the periods during which patients suffered from dopamine-dependent tremors, slowness, pain and difficulty walking and communicating, as well as L-DOPA-induced abnormal symptoms (involuntary movements, agitation) limiting their autonomy and quality of life,” Devos said.
Most current levodopa “formulations and delivery strategies retain the many [pharmacokinetic/pharmacodynamic] limitations,” the researchers concluded. “This should encourage researchers and manufacturers to develop new dopaminergic stimulation strategies without L-DOPA, such as dopamine administration,” they wrote.
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