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First Parkinson’s Patient Dosed in Early Trial of DNL151, Potential LRRK2 Inhibitor

DNL151 early trial

A Phase 1b clinical trial exploring the oral LRRK2 inhibitor DNL151 has started dosing Parkinson’s patients, the therapy’s developer Denali Therapeutics announced.

The 28-day, multicenter, and double-blind study (NCT04056689) is testing two doses of DNL151 against placebo in people with mild to moderate Parkinson’s disease, and with or without LRRK2 mutations, the most common genetic cause of the disease.

Twenty-four patients, ages 30 to 75, are expected to take part in the trial, and enrollment is ongoing at the Centre for Human Drug Research, in Leiden, the Netherlands. More information and contacts can be found here.

The company also announced the launch of its Engage Parkinsons website, where patients, caregivers, healthcare professionals, and advocates can find information about the disease and its link with genetics, overall advancements in Parkinson’s research, and Denali’s clinical trials. Registrants will also be informed about future studies sponsored by Denali.

“We are encouraged by the progress with our LRRK2 clinical program,” Ryan Watts, PhD, Denali’s CEO, said in a press release. “The launch of our Engage Parkinson’s website is intended to strengthen our engagement and interactions with the Parkinson’s disease patient community.”

“This is an important part of our efforts to connect with patients who may be eligible for our current and future clinical trials.”

DNL151 is a small molecule inhibitor of LRRK2, a protein that regulates the activity of cellular structures called lysosomes — tiny vesicle were a cell’s waste is broken down and recycled. High levels of LRRK2 impair lysosomal function, and may result in the formation of toxic protein clumps called Lewy bodies in brain cells. Lewy bodies are associated with neurodegeneration.

By selectively suppressing LRRK2, DNL151 aims to restore lysosomal function, which, according to Denali, may slow Parkinson’s progression in all patients.

The Phase 1b trial will primarily assess the safety, tolerability, pharmacokinetics — a compound’s absorption, distribution, metabolism, and excretion — and overall impact on the body of a high and low dose of DNL151. Biomarkers of target binding and exploratory clinical endpoints (goals) will also be evaluated.

Participants will be randomly assigned to either dose of DNL151, or a placebo. Study completion is expected by February 2020.

“Based on data generated from our prior study in healthy volunteer subjects, we are excited to evaluate DNL151 in Parkinson’s disease patients,” said Carole Ho, MD, Denali’s chief medical officer. “We believe that this study will provide additional important safety and biomarker data in patients to inform the choice between either DNL151 or DNL201 for potential registrational trials.”

These future trials are expected to form the basis of requests for regulatory approval of either therapy.

DNL201 is the company’s lead candidate for Parkinson’s disease, and is also an oral LRRK2 inhibitor able to reach the brain. A Phase 1 trial (NCT03710707) has a similar design to DNL151’s Phase 1 study, but is taking place at sites across the U.S. It is expected to conclude shortly.

Preclinical work supports the potential therapy’s ability to substantially inhibit LRKK2 activity even when administrated at lower dose.

Reported results of a prior Phase 1 study showed that DNL201 was safe and well-tolerated in healthy volunteers, and it demonstrated an ability to effectively suppress LRRK2 effects, as measured by blood biomarkers.

The post First Parkinson’s Patient Dosed in Early Trial of DNL151, Potential LRRK2 Inhibitor appeared first on Parkinson’s News Today.

CENTOGENE, Denali Partnering to Recruit LRRK2 Parkinson’s Patients for Clinical Trials

CENTOGENE, Denali collaboration

CENTOGENE and Denali Therapeutics are teaming up to identify and recruit Parkinson’s disease patients who carry mutations in the LRRK2 gene for future clinical trials, the companies announced.

CENTOGENE will carry out a targeted global recruitment campaign to identify and characterize Parkinson’s patients with LRRK2 mutations  and sequence the LRRK2 gene in this population, using its proprietary CentoCard, a dried blood spot collection kit.

CENTOGENE-recruited patients will participate in clinical trials supporting Denali’s LRRK2 inhibitor therapy program.

Mutations in the LRRK2 gene are one of the most commonly known genetic causes of Parkinson’s disease and usually result in the malfunctioning of lysosomes — special compartments within cells that digest and recycle different types of molecules.

Lysosomal dysfunction is involved in the formation of Lewy body protein aggregates and, therefore, neurodegeneration. LRKK2 regulates the formation and function of lysosomes, which are impaired in Parkinson’s disease and may eventually be restored by inhibiting LRRK2 activity, both in patients with a genetic LRRK2 mutation as well as in those with sporadic Parkinson’s disease.

“Our exclusive collaboration underscores CENTOGENE’s CEO and founder of CENTOGENE, said in a press release. “We believe we can contribute to Denali’s development of disease modifying medicines for patients with Parkinson’s disease. CENTOGENE will help Denali speed up the enrollment of patients in clinical studies for its LRRK2 program.”

CENTOGENE’s dried blood spot collection kit contains a validated procedure to extract high-quality DNA, enzymes, and biomarkers from patients’ blood samples. The technology has several advantages, including ease of handling — the samples are stable once they are dry and can be sent to CENTOGENE by regular mail — no sensitivity over time or to temperature, and cost-effectiveness.

This aids in the delivery of biological samples and makes genetic, enzymatic, and biomarker testing available worldwide.

After the identification of LRRK2 Parkinson’s patients, data will be sent to Denali to potentially recruit patients for its clinical trials testing LRRK2 inhibitor therapies.

Denali’s Parkinson’s pipeline includes two investigational LRRK2 inhibitors currently in the early phase of development, DNL201 and DNL151.

The company’s latest results revealed that DNL201 was safe and well-tolerated by healthy individuals in a Phase 1 clinical trial. The investigational therapy is currently being tested in a dose-escalation Phase 1 study in healthy volunteers in the Netherlands.

“Denali is the first company to conduct clinical trials with LRRK2 inhibitors for the treatment of Parkinson’s disease. This partnership with CENTOGENE is a central part of our global efforts to identify and recruit PD [Parkinson’s disease] patients with a mutation in the LRRK2 gene into our planned clinical studies,” said Carole Ho, MD, chief medical officer and head of development at Denali. “We are impressed with CENTOGENE’s approach and technology and believe that our joint efforts will accelerate the enrollment of PD patients and the completion of our clinical trials.”

The post CENTOGENE, Denali Partnering to Recruit LRRK2 Parkinson’s Patients for Clinical Trials appeared first on Parkinson’s News Today.