DNL201 and LRRK2 Inhibition in Parkinson Disease: Phase 1b Trial Results

In this podcast, Joohi Jimenez-Shahed, MD, discusses the findings of the study, “Safety, Tolerability, and Pharmacodynamic Profile of DNL201 at dose levels demonstrating LRRK2 inhibition in Parkinson's Disease Patients with and without LRRK2 mutations,” which was presented at the International Parkinson and Movement Disorder Society Virtual Congress. Dr Jimenez-Shahed did not take part in this study.

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Joohi Jimenez-Shahed, MD, is an Associate Professor of Neurology and Medical Director of Movement Disorders Neuromodulation and Brain Circuit Therapeutics at Mount Sinai Hospital in New York.


Christina Vogt: Hello everyone, and welcome back to another podcast. I’m Christina Vogt, managing editor of Neurology Learning Network. Today, I’m joined by Dr Joohi Jimenez-Shahed. We will be discussing the study, “Safety, Tolerability, and Pharmacodynamic Profile of DNL201 at dose levels demonstrating LRRK2 inhibition in Parkinson's Disease Patients with and without LRRK2 mutations,” which was presented at the MDS Virtual Congress. Thank you for joining me today, Dr Jimenez-Shahed. First, could you discuss the study and its findings?

Joohi-Jimenez-Shahed, MD: So, this study is sponsored by Denali Therapeutics, and is an investigation of a novel therapeutic for Parkinson's disease. We know that for certain patients with Parkinson's disease, they have it for a genetic reason. And one of the most common mutations actually is the LRRK-2 mutation. LRRK-2 is a kinase, and when you have mutations of this enzyme, then that can increase kinase activity which leads to excessive phosphorylation, lysosomal dysfunction, and eventually excessive accumulation of α-synuclein. So, LRRK-2 inhibitors can prevent this cascade and can restore normal lysosomal function in patients with Parkinson's disease, and DNL201, which is the compound that was studied in this investigation, is a first-in-class LRRK-2 kinase inhibitor.

So, the study was to assess the safety and tolerability and the target pathway engagement of this molecule, and patients with mild to moderate Parkinson's disease who had the LRRK-2 mutation and those who did not have the mutation were enrolled and received either placebo, low-dose, or high-dose DNL201.

And so, what they found in the study is that it was pretty well-tolerated, and the most common adverse events that patients experienced were headache and nausea. And through a variety of blood and CSF tests and other biomarkers, they were able to show evidence of target engagement, pathway engagement, and reduction in lysosomal function, all of which really points to a positive signal in terms of being able to use this medication to manage patients with Parkinson's disease who have the LRRK-2 mutation.

Christina Vogt: What is the proposed mechanism for this drug in PD?

Dr Jimenez-Shahed: LRRK-2 carriers, as we mentioned, have the mutation in this enzyme that can downstream lead to lysosomal dysfunction. And so really, the proposed mechanism would be that correcting the lysosomal dysfunction could eventually improve the likelihood or the cascade of cell death and also reduce the accumulation of α-synuclein in the brains of patients with this mutation.

Christina Vogt: What areas of future research are still needed for this therapy?

Dr Jimenez-Shahed: So, this was an early phase 1b study, and it was really focused on looking at safety tolerability, and target pathway engagement. So, we don't yet know how this treatment will affect α-synuclein aggregation in actual patients with Parkinson's disease. We also don't know yet how it affects Parkinson's symptoms or the progression of the disease, but certainly, based on the results of this study, DNL201 will progress to the next phase of clinical development to assess all these different aspects of its therapeutic efficacy.

Christina Vogt: What key takeaways about this topic do you hope to leave with neurologists center all the providers?

Dr Jimenez-Shahed: So, I think the study provides promising evidence that LRRK-2 kinase inhibition is safe and well-tolerated in Parkinson's patients who have this mutation and also in those who don't.

And further studies will be able to be conducted now based on these preliminary results to develop this treatment further. I think it's also an important step toward personalized treatments in patients with Parkinson's disease who meet a specific genetic profile. And as we uncover more and more about the genetic abnormalities contributing to Parkinson's disease and the associated molecular pathways that go along with those genetic mutations, we're likely to see similar approaches in the future.

Christina Vogt: Thanks again for joining me today, Dr. Jimenez-Shahed. For more podcasts like this, visit neurologylearningnetwork.com.

Jennings D, LeWitt P, Kern D, et al. Safety, tolerability, and pharmacodynamic profile of DNL201 at dose levels demonstrating LRRK2 inhibition in Parkinson’s disease patients with and without LRRK2 mutations. Paper presented at: International Parkinson and Movement Disorder Society Virtual Congress; September 12-16, 2020. Accessed November 12, 2020. https://www.mdsabstracts.org/abstract/safety-tolerability-and-pharmacodynamic-profile-of-dnl201-at-dose-levels-demonstrating-lrrk2-inhibition-in-parkinsons-disease-patients-with-and-without-lrrk2-mutations/