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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.

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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.”

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Potential Parkinson’s Treatment, DNS201, Safe and Well-Tolerated in Phase 1 Study, Denali Says

DNL201 Phase 1 results

Denali Therapeutics’ reports that its investigational compound for Parkinson’s disease, DNL201, was found to be safe and well-tolerated by healthy individuals in a Phase 1 clinical trial. The company is planning to advance the compound into a Phase 1b study in patients, a press release states.

DNL201 is an inhibitor of leucine-rich repeat kinase 2 (LRRK2). Mutations in the LRRK2 gene are the most frequent genetic cause of Parkinson’s and are usually associated with problems in the working of lysosomes, a structure within cells that breaks down molecules and provides the cell with the simpler nutrients it requires.

Lysosomal dysfunction contributes to the formation of Lewy body protein aggregates, and consequently, neurodegeneration. LRRK2 is known to regulate 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.

The randomized, double-blind, placebo-controlled Phase 1 study investigated the safety, pharmacokinetic and pharmacodynamic of  DNL201 in more than 100 healthy individuals. Pharmacokinetics refers to a drug’s absorption, bioavailability, distribution, metabolism, and excretion in the body; pharmacodynamics refers to the relationship between a medicine’s concentration at the site of action and the resulting effect, including the time course and intensity of therapeutic and adverse effects.

Participants took single or multiple ascending doses of DNL201 or placebo, the company reports, adding that all were generally well-tolerated, with no serious side effects.

Treatment was also well-tolerated at elevated doses that achieved high levels of cerebrospinal fluid (CSF) exposure. LRRK2 inhibition was effective, as measured by two blood biomarkers and effects on lysosomal function — the main mechanism affected by LRRK2 mutations.

“We conclude from this clinical trial that DNL201 was able to achieve the targeted levels of LKKR inhibition at doses that were safe and well-tolerated,” Carole Ho, MD and chief medical officer of Denali Therapeutics, said in the release.

“We are pleased that the trial was a success in all these key measures. The trial data give us confidence to proceed with further clinical testing in Parkinson’s patients and provide a solid basis for selection of the optimal dose for future clinical trials in patients,” Ho added.

Preclinical studies demonstrated DNL201’s capacity to stop an average 90 percent of LRKK2 activity at its highest concentration and 50 percent when the compound’s levels dropped to a lower concentration, showing its potential as a Parkinson’s therapy. The release did not specify what dose levels were used, and a trial document was not available on clinicaltrials.gov website.

Details of the Phase 1 study will be presented at a future medical conference, Denali said.

“We are leading the way in testing LRRK2 inhibitors in humans with the goal of bringing a disease modifying therapeutic to patients suffering from Parkinson’s disease,” said Ryan Watts, PhD and chief executive officer of Denali. “We are also encouraged to see mounting evidence supporting a role of LRRK2 inhibition in the broader sporadic Parkinson’s disease population, in addition to Parkinson’s disease genetically associated with a LRRK2 mutation.”

Denali is developing a second inhibitor of LRRK2, called DNL151, that is now testing in a dose-escalation Phase 1 study in healthy volunteers in the Netherlands.

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Source: Parkinson's News Today