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Phase 2 Trial of Gene Therapy VY-AADC to Include More Parkinson’s Patients

VY-AADC

The ongoing Phase 2 study of the gene therapy VY-AADC will enroll more Parkinson’s disease patients than originally planned, Voyager Therapeutics announced.

The company’s revised trial protocol will include more patients — up from 75 to 100 — in the RESTORE-1 Phase 2 clinical trial (NCT03562494). Voyager also is planning to conduct a parallel Phase 3 study named RESTORE-2, with similar size and design to RESTORE-1.

These updates result from a type B meeting the company had with the U.S. Food and Drug Administration (FDA) in December 2018 and from the written feedback Voyager got from the agency.

“Our recent meeting with the FDA was informative and helps to clarify the expected regulatory pathway for VY-AADC,” Andre Turenne, Voyager’s president and CEO, said in a press release. “We look forward to continuing to engage with the FDA and other regulators as we advance our clinical development program and our work to bring VY-AADC to patients in need,” he said.

Parkinson’s is characterized by progressive loss of dopamine-producing neurons in a brain area called substantia nigra, which is key in controlling movement. This leads to lower levels of dopamine in the putamen, a connected brain region that contains dopamine receptors.

In Parkinson’s patients, the putamen also has markedly reduced levels of the enzyme AADC, which is required to convert levodopa — the gold standard treatment — into dopamine.

Voyager’s VY-AADC consists of a modified and harmless adeno-associated virus to deliver the DDC gene, thereby providing the instructions for making the AADC enzyme directly in the putamen.

RESTORE-1 is currently enrolling individuals diagnosed with Parkinson’s for four years or more and who are not responding well to oral medications. Eligible patients also need to have at least three hours of daily “off” periods — characterized by the return of motor and non-motor symptoms when levodopa’s effects wear off — as assessed by a self-reported patient diary.

Enrolled participants are then randomized to either one-time administration of VY-AADC or placebo surgery.

The double-blind trial’s primary efficacy endpoint, or goal, is on time without troublesome dyskinesia (involuntary, jerky movements), or good “on” time, as measured by a self-reported patient diary at 12 months. The scientists will continue following the patients beyond this timepoint to collect further safety data and to assess how long the therapy’s potential benefits last.

Secondary goals include assessing changes in response to levodopa and in activities of daily living assessed with the United Parkinson’s Disease Rating Scale (UPDRS-II), quality of life with the Parkinson’s Disease Questionnaire, and global function through the proportion of patients with improved Clinical Global Impression score.

The trial also will assess the treatment’s safety, as well as changes in non-motor symptoms with the Non-Motor Symptom Scale. As for biomarkers, the investigators will measure the extension of VY-AADC coverage of the putamen , and AADC enzyme expression and activity in this brain region. Changes in patients’ levodopa dose per day and related medications also will be analyzed.

The company anticipates that RESTORE-1 will take about 15 to 21 months to fully enroll. Recruitment for RESTORE-2 is planned in both active Phase 2 sites and other global locations in the first half of 2020. If positive, results from the Phase 2 and Phase 3 trials could be the basis for the submission of a biologics license application to the FDA covering VY-AADC, according to Voyager.

In June 2018, the FDA granted VY-AADC regenerative medicine advanced therapy (RMAT) designation for the treatment of therapy-resistant motor fluctuations in Parkinson’s patients.

This designation was based on the positive results of a Phase 1b trial (NCT03065192) in 15 Parkinson’s patients, which revealed improvements in motor function and marked reductions in daily use of levodopa and other medications upon treatment with VY-AADC.

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First Patient Dosed with VY-AADC Gene Therapy in Parkinson’s Phase 2 Trial

RESTORE-1 Voyager VY-AADC

Voyager Therapeutics has begun patient dosing in a Phase 2 trial testing its investigational VY-AADC gene therapy in Parkinson’s patients whose motor symptoms are not responding adequately to oral medication.

The trial, called RESTORE-1 (NCT03562494), is recruiting participants across seven sites in the United States.

VY-AADC is a therapy that delivers the DDC gene, which provides instructions for making the AADC enzyme, directly to brain cells in the putamen region. The enzyme converts the standard-of-care Parkinson’s treatment levodopa into dopamine, the signaling molecule that is lacking in Parkinson’s disease.

The approach is expected to bypass the effects of degenerating dopamine neurons in the substantia nigra, a part of the midbrain, by increasing dopamine levels in the putamen.

In an ongoing Phase 1b trial (NCT01973543), a single administration of the therapy induced robust and durable improvements in patients’ motor function up to three years after treatment.

The treatment also effectively increased AADC enzyme activity, allowing patients to reduce their doses of oral levodopa. Also, patients reported significant improvement in quality of life.

The newly begun Phase 2 trial aims to determine whether VY-AADC is better than a placebo at reducing motor fluctuations in Parkinson’s patients whose symptoms are not effectively controlled with levodopa or related treatments.

The trial is expected to enroll approximately 42 patients who have been diagnosed with Parkinson’s disease for at least four years and are not responding adequately to oral medications. To be eligible, participants must be experiencing at least three hours of OFF time during the day, as measured by a validated, self-reported patient diary.

Participants will be randomized to receive either a single infusion of VY-AADC or a placebo into the brain via surgery. They will be followed for 12 months to determine their changes in motor fluctuations, changes in the ability to perform daily activities, and quality of life.

During the new Phase 2 trial, researchers will also determine the efficacy of treatment delivery by assessing AADC enzyme levels and activity in the putamen through positron emission tomography (PET). Changes in patients’ daily doses of oral levodopa and related medications will also be evaluated.

More information about RESTORE-1, including recruitment details, can be found here.

“Patients with Parkinson’s disease need new therapeutic options, especially as the disease progresses and there is less AADC enzyme in parts of the brain where it is needed to convert levodopa to dopamine,” Mark Richardson, MD, PhD, associate professor, director of Epilepsy and Movement Disorders Surgery at the University of Pittsburgh Medical Center and principal investigator in the RESTORE-1 trial, said in a press release.

The U.S. Food and Drug Administration granted regenerative medicine advanced therapy (RMAT) designation to VY-AADC for therapy-resistant motor fluctuations in Parkinson’s patients.

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Parkinson’s Gene Therapy Now in Phase 2 Trial, VY-AADC, Continues to Show Motor Benefits, Voyager Says

VY-AADC clinical trial

Voyager Therapeutics announced likely plans to request approval of VY-AADC as a Parkinson’s gene therapy, based on feedback it received from the U.S. Food and Drug Administration (FDA) and eventual outcomes of a newly opened Phase 2 trial.

The company also reported that its Phase 1 trial of VY-AADC showed improvements in patients’ motor function and reduced use of medications, among other benefits, further supporting a future biologics license application (BLA).

Progressive loss of dopamine-producing neurons in the substantia nigra – a brain area controlling movement – is a hallmark of Parkinson’s. Normally, the neurotransmitter dopamine is released into a brain region called the putamen, which contains dopamine receptors.

But in Parkinson’s, this process is impaired. And while levodopa — a precursor of dopamine — is effective in treating Parkinson’s, patients require the enzyme AADC to make this conversion. This enzyme, however, is markedly reduced in the putamen.

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

As a result of a requested type C meeting, the FDA indicated that successful completion of the ongoing Phase 2 trial (NCT03562494) may be sufficient to accept the BLA’s submission for review.

This single-site study is assessing the distribution, efficacy, and safety of VY-AADC02 in Parkinson’s patients with motor fluctuations. Its primary goal is to analyze whether one-time administration of the gene therapy candidate reduces patient-rated motor fluctuations compared to placebo one year after surgical infusion into the brain.

Patient enrollment – an estimated 42 participants – is currently ongoing at the University of Pittsburgh Medical Center. For information on contacts, click here.

The FDA, in a written response, also said that if Phase 2 trial results failed to show significant benefit in easing motor fluctuations but still supported the use of VY-AADC02, Voyager may use results from a Phase 3 study in approximately 120 patients, depending on its efficacy and safety data. The Phase 2 trial, which opened in June, is expected to conclude in December 2020.

Voyager also announced in a press release early findings from a Phase 1 trial evaluating a one-time infusion of VY-AADC into the back of the head. Besides a positive tolerability profile, results showed increased coverage of the putamen in all eight patients, reduced surgical times by two to three hours, and improvements in patients’ motor function at six months.

Investigators also reported that VY-AADC increased the activity of AADC in the putamen, suggestive of an increased capacity to convert levodopa to dopamine.

Motor improvements were observed in the four patients who completed assessments at six months, and matched those seen at the same time point in Voyager’s Phase 1b trial (NCT03065192). This study enrolled 15 patients and assessed VY-AADC infusion through the top of the head.

Participants in both studies were, on average, 57 years old and diagnosed with Parkinson’s for an average of nine years. Both trials showed marked reductions in daily use of oral levodopa and other Parkinson’s medications upon treatment with VY-AADC. Voyager plans to present full data from the Phase 1 trial at future conferences.

Given these findings, the company determined that infusions through the back of the head will continue to be preferred and that, moving forward, the VY-AADC dose will be between the two higher doses in the Phase 1b trial, 1.5 x 1012 and 4.7x 1012.

“We are very pleased with feedback from the FDA regarding our pivotal program for VY-AADC that includes the potential to file a BLA based on the safety and efficacy results from the Phase 2 trial, or if needed, from the Phase 3 trial,” Robert Pietrusko, senior vice president of regulatory affairs and quality assurance at Voyager, said in the release. “We look forward to continuing to work closely with the agency to expedite the development of this potentially important treatment for patients with Parkinson’s,” he added.

Based on results from the Phase 1b trial, the FDA recently designated VY-AADC a regenerative medicine advanced therapy as a potential treatment of therapy-resistant motor fluctuations in Parkinson’s patients.

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Source: Parkinson's News Today

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

Voyager’s Gene Therapy to Enter Phase 2/3 Trial Program for Advanced Parkinson’s Disease

VY-AADC trial

Voyager Therapeutics will soon initiate a global Phase 2/3 clinical trial program to evaluate its VY-AADC gene therapy for the treatment of advanced Parkinson’s disease.

The trial follows approval by the U.S. Food and Drug Administration of the company’s investigational new drug (IND) application for VY-AADC.

“Following institutional review board approval and patient screening at clinical referral and surgical sites, we continue to plan to dose the first patient in our pivotal program during the second quarter of this year, representing a very important milestone for both the program and the company,” Bernard Ravina, chief medical officer at Voyager Therapeutics, said in a press release.

The IND application included information demonstrating that Voyager’s baculovirus/Sf9 therapy manufacturing process is comparable, and not inferior, to the standard production system based on mammalian cells. The new baculovirus manufacturing process uses insect-derived cells, which allows for the production of greater amounts of VY-AADC with a reduced risk of introducing mammalian cell-derived impurities.

“Our baculovirus manufacturing process is designed for production of AAV [adeno-associated virus] vectors at clinical and commercial scale, with the potential for increased yields and efficient scalability compared with mammalian-based systems,” Ravina said. “We are pleased to initiate our pivotal program and begin dosing patients with the baculovirus-produced vector.”

VY-AADC is a therapy designed to deliver the AADC gene directly to brain cells in the putamen region. This enzyme is responsible for converting the standard of care treatment levodopa into dopamine, the signaling molecule that is missing in Parkinson’s patients.

The approach is expected to bypass the effects of degenerating dopamine neurons in the substantia nigra, a part of the midbrain, by increasing dopamine levels in the putamen.

VY-AADC is currently being evaluated in a new Phase 1 trial (NCT03065192) and an earlier Phase 1b trial (NCT01973543) in patients with Parkinson’s disease.

Preliminary data have shown that after a single administration, the therapy induced a durable, dose-dependent, and time-dependent response across multiple measures of motor function. The treatment also effectively increased AADC enzyme activity and enhanced the response of levodopa. To date, no serious adverse events have been reported due to VY-AADC.

Voyager is recruiting participants for the Phase 1 trial, which will be testing a new VY-AADC delivery method, and expects to provide an update from these studies during the first quarter of 2018.

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Source: Parkinson's News Today