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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UCB Launches Phase 1b Trial Testing UCB0599 for Parkinson’s Disease Treatment

UCB0599 Phase 1b trial

UCB has announced the start of a Phase 1b clinical trial to evaluate the efficacy and safety of its therapeutic candidate UCB0599 for the treatment of Parkinson’s disease.

This multicenter clinical trial will take place across the United States.

Current treatments for Parkinson’s, which include levodopa and dopamine agonists, can help manage early motor symptoms associated with the disease. However, as the disease progresses and neurons continue to degenerate, these therapies ultimately become less effective at treating the symptoms.

Many neurodegenerative diseases, including Parkinson’s, occur due to the accumulation of toxic protein aggregates known as prions.

In the case of Parkinson’s, misfolding and the subsequent aggregation of a protein known as alpha-synuclein results in the formation of Lewy bodies, which are toxic and lead to disease symptoms and progression.

By preventing alpha-synuclein from clumping into Lewy bodies, clearing them out, or stopping their spread from cell to cell, researchers believe they can prevent or slow Parkinson’s progression.

Developed as part of a collaboration between Neuropore Therapies and UCB, UCB0599 is designed to inhibit alpha-synuclein misfolding.

UCB0599 is a small molecule compound that is taken orally and can penetrate the blood-brain barrier, which is a semipermeable membrane that separates the blood from the cerebrospinal fluid and protects the brain from the outside environment. This membrane is an obstacle for the efficient delivery of therapies that need to reach the brain.

“We are pleased to reach the milestone of advancing into Parkinson’s patients for the first time with UCB0599, a therapeutic candidate arising from our collaboration with UCB,” Errol De Souza, president and CEO of Neuropore Therapies, said in a press release. “We believe that inhibition of alpha-synuclein misfolding and oligomerization with an orally active, brain penetrant, small molecule represents a potential advantage over antibody therapeutics that are currently in development.”

In January 2015, Neuropore Therapies granted UCB a license to develop and commercialize therapies that target alpha-synuclein in all indications around the world. It is thought that alpha-synuclein aggregation also plays a role in other neurodegenerative diseases.

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Voyager’s Gene Therapy Shows Positive Interim Results in Phase 1b Trial

Gene therapy

An investigational gene therapy being developed for the treatment of Parkinson’s disease was well-  tolerated and eased patients’ motor fluctuations in a dose-dependent manner after a one-time administration, according to interim results.

The study, “Magnetic Resonance Imaging-Guided Phase 1 Trial of Putaminal AADC Gene Therapy for Parkinson’s Disease,” was published in Annals of Neurology.

VY-AADC01 is a gene therapy being developed by Neurocrine Biosciences and Voyager Therapeutics. It uses a viral vector (AAV) to deliver the AADC gene — which codes for an enzyme called L-amino acid decarboxylase (AADC) and mediates the conversion of levodopa into dopamine — directly into a specific brain area called the putamen, a large structure filled with dopamine receptors.

Death of dopaminergic neurons and a reduction in AADC enzyme levels are two fundamental mechanisms underlying Parkinson’s disease. By delivering the AADC enzyme into brain cells, researchers aim to restore the conversion of levodopa and increase dopamine production.

The open-label, Phase 1b study (NCT01973543) enrolled 15 people (13 men and two women, mean age 57.7 years) with moderately advanced Parkinson’s disease and fluctuating responses to levodopa. Subjects were divided into three groups and treated with ascending doses of VY-AADC01 (7.5 × 1011vector genomes (vg); 1.5 × 1012vg; 4.7 × 1012vg).

The therapy was administered in a single-dose infusion using magnetic resonance imaging (MRI) to guide its delivery. Group 1 (lower dose) was followed for up to three years, group 2 through two years, and group 3 (higher dose) for up to 1.5 years. During the study, patients kept taking their antiparkinsonian medications, including levodopa.

The trial’s primary goals were the safety, tolerability, and distribution of ascending doses of VY-AADC01. Secondary objectives included AADC activity changes in response to levodopa, clinical outcomes over a year, and the durability of those changes after 12 months.

Results showed that large-volume administrations of VY-AADC01 were well-tolerated. At six months post-treatment, the MRI-guided delivery approach increased the coverage area reached by the gene therapy: coverage of 21% in group 1, 34% in group 2 and 42% in group 3. This was found to be closely correlated with increases in AADC activity: 13%, 56%, and 79%, respectively. The increase in putaminal coverage was also related to reductions in the patients’ medication regimen: 15% less in group 1, 33% less in group 2 and 42% less in group 3.

A year after treatment, investigators observed VY‐AADC01 dose-dependent improvements in motor fluctuations, motor scores on the Unified Parkinson’s Disease Rating Scale (UPDRS part III) and patients’ quality of life, despite reductions in antiparkinsonian medications.

Patients reported increases in their “on” periods (when medication does not wear off and motor symptoms are controlled) without experiencing troublesome abnormal involuntary movements (dyskinesia).

“The interim results from this Phase 1b trial demonstrated that administration of [VY-AADC01] to the putamen using a novel technique, which included intraoperative monitoring with magnetic resonance imaging guidance, facilitated targeted delivery of the investigational gene therapy,” Chad Christine, MD, professor of neurology, University of California, San Francisco and investigator in this trial, said in a news release.

“Additionally, administration of [VY-AADC01] resulted in dose-dependent increases in AADC enzyme expression and improvements in clinical measures and has been well-tolerated to date,” he said.

Based on these open-label results, researchers have initiated the RESTORE-1 Phase 2 trial (NCT03562494) to evaluate the safety and efficacy of VY-AADC01 and understand “its efficacy relative to optimal medical management alone,” they said.

The trial, which is recruiting, will randomize patients with advanced Parkinson’s disease who have not responded adequately to oral therapy to either optimized medical management plus VY-AADC01 or continued optimized medical management — including levodopa — plus placebo-surgery. Researchers plan to enroll 42 participants.

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FDA Grants Regenerative Medicine Advanced Therapy Designation to VY-AADC for Parkinson’s

VY-AADC gene therapy

The U.S. Food and Drug Administration granted Voyager Therapeutics’ gene therapy candidate VY-AADC regenerative medicine advanced therapy (RMAT) designation for the treatment of therapy-resistant motor fluctuations in Parkinson’s patients.

The RMAT designation, recently created by the FDA, is given to regenerative medicine products intended to treat, modify, reverse, or cure a serious or life-threatening disease or condition, and that have early clinical evidence supporting their effectiveness.

This designation enables early interactions with the FDA to discuss intermediate evidence to support accelerated approval and meet post-approval requirements.

“The RMAT designation was based on our Phase 1b clinical data with VY-AADC and represents an important milestone for the program and recognition of this gene therapy as a potential treatment for Parkinson’s,” Robert Pietrusko, senior vice president of regulatory affairs and quality assurance at Voyager, said in a press release.

Parkinson’s is characterized by the loss of dopamine-producing neurons in the substantia nigra, a brain region key in controlling movement. Neurons in the substantia nigra release dopamine into an area of the brain called putamen, which contains dopamine receptors.

Although effective in the early stages of Parkinson’s, the effectiveness of levodopa — a standard Parkinson’s treatment — gradually decreases with disease progression. As a result, patients experience longer periods of reduced mobility and stiffness, where medication is not effective — called off periods — and shorter episodes where motor symptoms are controlled with medication, or on periods. This is referred to as motor fluctuations.

An enzyme called 1-amino acid decarboxylase (AADC) regulates the generation of dopamine from levodopa. Because AADC levels are reduced in the putamen of Parkinson’s patients, the conversion of oral levodopa to dopamine is limited.

VY-AADC, which consists of a modified, harmless adeno-associated virus, is intended to deliver the DDC gene — which contains the instructions for making AADC — directly into the putamen.

According to Voyager, VY-AADC has the potential to increase the generation of dopamine in a durable manner, and provide clinically meaningful improvements by restoring motor function and improving symptoms.

Voyager’s ongoing Phase 1b clinical trial in Parkinson’s patients showed that a one-time administration of VY-AADC led to robust and sustained improvements in motor function, as well as marked reductions in the use of levodopa and other medications.

The investigational treatment was well-tolerated, and has not caused any serious adverse events to date.

Besides Parkinson’s, Voyager is collaborating with pharmaceutical companies and academic institutions to develop its gene therapy approach for patients with amyotrophic lateral sclerosis (ALS) due to mutations in the SOD1 gene, Huntington’s, Friedreich’s ataxia, Alzheimer’s, and severe, chronic pain.

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Source: Parkinson's News Today