The search for a pill that stops Parkinson’s disease progressing has taken a significant step forward, as scientists released the first clinical results for an oral drug targeting an enzyme that plays a key role in the degenerative brain disorder.
Researchers from Denali Therapeutics, a Californian biotech company, and academic colleagues showed that the experimental drug — called DNL201 — worked safely in animals and 150 human volunteers. It reduced levels of the LRRK2 enzyme implicated in Parkinson’s.
Although the trial, published in Science Translational Medicine, was not designed to assess the effect of DNL201 on Parkinson’s symptoms, experts on neurodegenerative diseases welcomed the demonstration that it crossed the blood-brain barrier efficiently and had the desired biochemical effect on volunteers.
“To date there are no drugs that slow, halt or reverse the progression of Parkinson’s disease,” said Professor Patrick Lewis, an expert on the condition at London’s Royal Veterinary College, who was not involved in the study. “The paper presents an important advance along the drug development pathway for a target that has long been a priority for the Parkinson’s disease research community.”
Denali is evaluating two “small molecule” drugs that can be taken by mouth as Parkinson’s treatments: DNL201 and a related compound DNL151 whose details have not yet been published in a peer-reviewed journal. Both work by suppressing excessive levels of the LRRK2 enzyme, which can damage microscopic bodies called lysosomes in the patient’s brain.
“Lysosomes perform a garbage disposal and recycling role for cells,” explained Carole Ho, Denali’s chief medical officer. “If they are not working properly, toxic proteins build up and interfere with the proper functioning of cells in the brain. Dopamine-producing cells, which die off in Parkinson’s disease, seem to be particularly sensitive to lysosomal activity.”
David Dexter, associate director of research at the charity Parkinson’s UK, pointed out that Denali initially developed DNL201 for a genetic form of the disease caused by a mutation in the gene for LRRK2.
“Since the build-up of toxic proteins is also a feature of sporadic [non-inherited] Parkinson’s, this drug may also be beneficial for the wider Parkinson’s community,” said Dexter, adding that the results paved the way for large clinical studies in people living with the disease. “These early-phase clinical trials in small groups of people with and without Parkinson’s have demonstrated that the drug is safe and free from respiratory side effects, which was a potential concern identified in animal studies.”
Denali is pressing ahead with a larger trial of its companion drug DNL151 in collaboration with Biogen, the Massachusetts-based biotech company. They plan to compare the safety and efficacy of DNL151 in 640 people with early Parkinson’s disease.
Although DNL201 remains in Denali’s drug repertoire, the company chose to go ahead with DNL151 first for “pharmacokinetic” reasons, Ho said. In particular DNL151 can be taken as a single daily dose while DNL201 requires two doses.
“It is a very exciting time for Parkinson’s research as we have now reached the point of clinically testing novel treatments that have been developed based on a better understanding of the underlying biology,” said Simon Stott, deputy research director at Cure Parkinson’s. His charity’s 2022 Parkinson’s drug development pipeline report identified 56 disease-modifying treatments in clinical trials.