Parkinson’s drug DNL201 passes large phase 1 clinical safety study

There are currently no FDA-approved drugs to prevent or cure Parkinson’s, a disease that affects more than 10 million adults worldwide and is expected to rise to 1.2 million by 2030. Patients usually show symptoms around the age of 50 and are prescribed the drug L-Dopa to relieve some symptoms, such as tremors or involuntary body movements. Unfortunately, it does not slow or stop the progression of Parkinson’s disease.

We may have a better form of treatment on the way soon. In a study published in the journal on Wednesday Science Translational MedicineResearchers at Denali Therapeutics of San Francisco have developed a drug called DNL201 that targets LRRK2, a protein that is commonly mutated in Parkinson’s disease and ends up killing brain cells. DNL201 eliminated the presence of the rogue protein in laboratory mice suffering from Parkinson’s disease and was also shown to be safe in a 150-person phase 1 clinical trial (which included both healthy subjects and subjects with Parkinson’s disease). Should future clinical trials also prove successful, this new drug could be a powerful new intervention to address a growing public health crisis.

Parkinson’s results from the destruction of neurons that produce dopamine, best known as the “feel good” chemical, which is associated with pleasure and reward but is also crucial for motor function. Scientists estimate that 85 percent or more of all cases are caused by complex interactions between environmental and common genetic risk factors.

One of the genes that seems to play a role regulates the production of LRRK2. Mutated versions of the gene promote inflammation that kills dopamine-producing neurons.

Early genetic and animal studies conducted in the mid-2010s by scientists in Germany, the UK and biotechnology company Genetech showed a way to target LRRK2 with small molecule drugs that can more easily enter our cells.

Enter: DNL201. In previous studies on lab rats and macaques, the drug helped lower LRRK2 levels in the brain safely. Denali Therapeutics conducted two human studies and administered DNL201 as a pill. Just like in the animal studies, the drug significantly reduced blood levels of LRRK without causing any side effects.

Specifically, in the second study, DNL201 was administered to 28 patients with mild to moderate Parkinson’s disease, some of whom carried the LRRK2 gene mutation. Again, DNL201 lowered LRRK2 levels with no significant side effects except for those receiving the higher dose of the drug (although the most severe complaint for these participants was headaches).

Although these early results are a promising start, the researchers warn that the study’s results are insufficient to guarantee that DNL201 can treat Parkinson’s disease. It boils down to whether the drop in LRRK2 correlates with the rescue of dopamine-producing neurons from chemical destruction in humans, as it did in the cell studies. To test that, DNL201 needs to be closely monitored in much larger studies and for periods longer than just one year, the researchers point out.

In the meantime, Denali Therapeutics is focusing on another LRRK2 blocker being developed in parallel with DNL201, called DNL151. This drug has also been shown to be fairly effective at reducing LRRK2 and may be more convenient for patients since they only need to take it once a day, Laura Hansen, a spokeswoman for Denali Therapeutics, told The Daily Beast in an email. A clinical trial is currently underway testing DNL151 in people with early-stage Parkinson’s disease. Another clinical trial for Parkinson’s patients who are carriers of the LRRK2 mutation is expected later this year. Parkinson’s drug DNL201 passes large phase 1 clinical safety study


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