Posts

#AANAM — Investigational VY-AADC01 Gene Therapy Provides Benefits for Parkinson’s Patients, Phase 1 Data Show

VY-AADC01 Phase 1 trial

A single-dose infusion of VY-AADC01, an investigational gene therapy, improves motor function and reduces the need for antiparkinsonian medications in advanced Parkinson’s disease patients, results from the Phase 1 PD-1102 clinical trial show.

Trial findings were presented in a scientific poster, titled “PD-1102: A Phase 1 study of VY-AADC01 Administered Using a Posterior Approach in Patients with Parkinson’s Disease and Motor Fluctuations,” during the 2019 American Academy of Neurology (AAN) annual meeting, taking place through May 10 in Philadelphia.

VY-AADC01, a gene therapy being developed by Neurocrine Biosciences and Voyager Therapeutics, delivers the AADC gene directly into a specific brain area called the putamen, a large structure filled with dopamine receptors. This gene carries the information for the production of the L-amino acid decarboxylase (AADC) enzyme that mediates the conversion of levodopa into dopamine.

Death of dopaminergic neurons and a reduction in AADC enzyme levels are two key underlying features of Parkinson’s. The strategy of delivering the AADC enzyme into brain cells is aimed at restoring the conversion of levodopa and increasing dopamine production.

PD-1102 (NCT03065192) is an ongoing open-label Phase 1 trial evaluating the safety and efficacy of a single dose of VY-AADC01 — 9.4 × 1012 vg — injected directly into the striatum using a surgical approach in which the gene therapy is delivered through the back of the patient’s head (posterior surgical approach).

Another ongoing Phase 1b trial, called PD-1101 (NCT01973543), is evaluating the safety and efficacy of ascending doses of VY-AADC01 — 7.5 × 1011 vector genomes (vg), 1.5 and 4.7 × 1012 vg — whereby the gene therapy is injected directly into the striatum of 15 Parkinson’s patients via a surgical procedure through the top of the head (frontal surgical approach). The surgical intervention is aided by real-time magnetic resonance imaging (MRI) to monitor the gene therapy’s delivery.

Interim results of this trial reported dose-dependent improvements in motor function, patients’ quality of life, and reduction of antiparkinsonian medications.

The new neurosurgical strategy employed in the PD-1102 trial is thought to decrease the infusion time while enhancing the gene therapy’s coverage of its targeted brain area.

PD-1102’s main objectives include safety and measures of efficacy, such as coverage of the putamen brain area, AADC activity, changes in motor function and in dyskinesia (the abnormal involuntary movements that characterize advanced Parkinson’s), use of antiparkinsonian medications, and patients’ reported on and off times.

Off periods in Parkinson’s are characterized by the reappearance or worsening of symptoms — such as tremors and dyskinesia — due to a gradual decline in levodopa’s therapeutic effectiveness. These symptoms become more frequent and severe as the disease progresses.

The trial enrolled eight patients, at a mean age of 56.8 years, with advanced Parkinson’s (mean disease duration of 9.2 years) and with similar characteristics to those enrolled in the PD-1101 study. 

At the start of the trial, patients’ mean off time was 6.8 hours, while the mean on time (the period when levopoda is working) was 9.1 hours.

Administration of a single dose of VY-AADC was able to cover 54% of the putamen brain area. Moreover, infusion of the gene therapy took 3.1 hours, two hours less than the time of infusion in the PD-1101 trial (5.2 hours).

Treatment with VY-AADC increased AADC enzyme activity in the putamen area by 85%, which reflects the ability of neurons to convert levodopa to dopamine.

Compared with the beginning of the study, the gene therapy improved patients’ motor function at 12 months and improved patients’ good on time (on time without troublesome dyskinesia) by 1.7 hours and reduced off time by 2.2 hours after 12 months.

The treatment also lowered patients’ use of antiparkinsonian medications by 28% six and 12 months after infusion.

Exploratory analyses in four patients with low or no dyskinesia or absence of impulse control disorder at the start of the trial showed that a single infusion of VY-AADC in this group led to greater improvements, with good on time increased by 3.2 hours and off time reduced by 3.2 hours after 12 months.

Infusions of VY-AADC were well-tolerated with no serious adverse events.

VY-AADC also improved patients’ quality of life, as measured by the 39-item Parkinson’s Disease Questionnaire, a self-administered questionnaire that addresses aspects of functioning and well-being. Patients’ mean scores decreased — or improved — by 7.6 points after 12 months.

“The results from this Phase I trial in patients with Parkinson’s disease provide further evidence that VY-AADC administration can allow neurons in the brain to convert levodopa to dopamine and improve motor function,” Eiry W. Roberts, MD, chief medical officer of Neurocrine, said in a press release.

“[These results] confirm previous data from a separate, ongoing Phase I study demonstrating that increased coverage of the putamen with VY-AADC leads to an increase in AADC enzyme activity and improvements in motor function and quality of life in patients with Parkinson’s disease — with less need for oral levodopa medication,” he added.

Based on the positive results from both the PD-1101 and PD-1102 trials, researchers have launched the RESTORE-1 Phase 2 trial (NCT03562494). The trial, currently recruiting participants, will randomize patients with advanced Parkinson’s disease who have failed to respond properly to oral therapy to either optimized medical management plus VY-AADC01 or continued optimized medical management — including levodopa — plus placebo-surgery.

The post #AANAM — Investigational VY-AADC01 Gene Therapy Provides Benefits for Parkinson’s Patients, Phase 1 Data Show appeared first on Parkinson’s News Today.

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.

The post Voyager’s Gene Therapy Shows Positive Interim Results in Phase 1b Trial appeared first on Parkinson’s News Today.

AbbVie, Voyager Team Up to Develop Antibodies for Parkinson’s, Other Diseases

antibodies

AbbVie and Voyager Therapeutics have extended their collaboration to co-develop and commercialize antibodies that target the toxic forms of alpha-synuclein to treat Parkinson’s disease and other synucleinopathies.

The collaboration will combine AbbVie’s expertise in monoclonal antibodies with Voyager’s gene therapy platform to deliver antibodies across the blood-brain barrier using a one-time injection into the blood. The blood-brain barrier is a semipermeable membrane that protects the brain against the external environment, and is a major barrier for the efficient delivery of certain therapeutics that need to reach the brain and central nervous system.

Researchers will use a modified and harmless adeno-associated virus (AAV) with a high capacity to penetrate the blood-brain barrier to deliver genes that carry the information for producing therapeutic antibodies against toxic forms of alpha-synuclein.

“The expansion of AbbVie’s partnership with Voyager represents the potential we see in the ability of its vectorized antibody platform to surpass the blood-brain barrier and more effectively deliver biologic therapies,” Jim Summers, PhD, vice president, discovery neuroscience research, AbbVie said in a press release. “We are hopeful that Voyager’s technology will enable further development of transformative treatments for patients with neurodegenerative diseases,” Summers said.

Parkinson’s disease belongs to a class of neurodegenerative disorders called synucleinopathies, characterized by the accumulation of misfolded alpha-synuclein aggregates. These abnormal protein aggregates are toxic and trigger the death of dopamine producing-nerve cells — those responsible for releasing the neurotransmitter dopamine, a critical neurotransmitter that regulates brain cell activity and function.

Given the key role of alpha-synuclein in the development and progression of Parkinson’s disease, many efforts have been made to find ways to effectively prevent its toxicity, such as using antibodies targeting the toxic forms of alpha-synuclein.

However, delivering antibodies to the brain is not an easy task. This is because the central nervous system (CNS) — comprised by the brain and spinal cord — is protected from the circulatory blood system by the very selective blood-brain barrier.

Current delivery of antibodies to the brain requires frequent injections and large amounts of antibodies. This new approach is expected to result in higher therapeutic antibody levels in the brain.

“Our scientific platform allows us to develop unique AAV gene therapies that are designed to knock down disease-causing gene expression, increase the expression of missing proteins, or enable the expression of therapeutic antibodies through vectorization,” said Andre Turenne, president and CEO of Voyager Therapeutics.

“We are excited to expand our efforts towards pathological species of alpha-synuclein given its role in the progression of disease, and AbbVie is the ideal partner to advance this new target and therapeutic modality,” Turenne added.

The post AbbVie, Voyager Team Up to Develop Antibodies for Parkinson’s, Other Diseases appeared first on Parkinson’s News Today.

Neurocrine, Voyager Team Up to Develop VY-AADC for Parkinson’s Disease

Neurocrine Biosciences

Neurocrine Biosciences and Voyager Therapeutics have joined efforts in a new strategic collaboration to further develop and market Voyager’s gene therapies VY-AADC for Parkinson’s disease and VY-FXN01 for Friedreich’s ataxia.

With this partnership, Neurocrine Biosciences will apply its expertise in neuroscience, drug development, and commercialization to help expedite the development of Voyager’s gene therapy programs.

“We are excited to collaborate with Voyager to advance our shared mission to discover and develop medicines that can benefit the lives of people with serious neurological disorders,” Kevin Gorman, PhD, CEO of Neurocrine, said in a press release.

Neurocrine will have the opportunity to expand its “clinical development pipeline addressing neurological disorders, leverage Voyager’s expertise in [central nervous system]-focused gene therapy, and develop potential treatments for diseases,” he said.

Based on the terms of the agreement, Neurocrine is going to finance the Phase 2-3 pivotal program for VY-AADC for Parkinson’s disease. After the completion of the Phase 2 RESTORE-1 trial (NCT03562494), in which the therapy is currently being evaluated, Voyager will have the option to decide whether it will share commercialization responsibilities or give Neurocrine full rights to the therapy in the U.S. in return for milestone payments and royalties.

A similar plan was established for the future of VY-FXN01 for Friedreich’s ataxia. In addition, Neurocrine also agreed to fund two additional gene therapies programs yet to be determined.

“This is a transformational collaboration for Voyager that greatly enhances our efforts towards becoming the leading, fully-integrated gene therapy company focused on severe neurological diseases while allowing us to continue to invest in our additional pipeline programs and platform,” said Andre Turenne, president and CEO of Voyager.

VY-AADC is an investigational gene therapy that uses a modified and harmless adeno-associated virus to deliver the ADDC gene directly into the putamen brain region, which is involved in movement control.

This gene provides instructions for making an enzyme, called 1-amino acid decarboxylase (AADC), that converts levodopa (the gold standard treatment for Parkinson’s) to dopamine — a signaling molecule that acts as a messenger between brain cells and is present at lower levels in Parkinson’s patients.

Researchers believe that with a single administration of VY-AADC, it may be possible to achieve the sustainable conversion of levodopa to dopamine, enhancing its clinical effects and significantly restoring the motor function of Parkinson’s patients.

The ongoing RESTORE-1 trial is currently recruiting individuals who have been 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.

The study will evaluate the impact of VY-AADC on patients’ motor symptom fluctuations, measured by a self-reported patient diary and response to levopoda treatment. Researchers will also evaluate changes in quality of life and global function, as well as changes in non-motor symptoms, upon treatment with VY-AADC compared to placebo.

VY-AADC received the regenerative medicine advanced therapy designation from the U.S. Food and Drug Administration in June 2018 for the treatment of therapy-resistant motor fluctuations in Parkinson’s patients.

The FDA’s decision was supported by positive results of a Phase 1b trial (NCT01973543) in 15 Parkinson’s patients, in which a single administration of the therapy induced robust and durable improvements in patients’ motor function up to three years after treatment.

VY-AADC treatment also effectively increased AADC enzyme activity, allowing patients to reduce their doses of oral levodopa and improving their quality of life.

The post Neurocrine, Voyager Team Up to Develop VY-AADC for Parkinson’s Disease appeared first on Parkinson’s News Today.

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.

The post Phase 2 Trial of Gene Therapy VY-AADC to Include More Parkinson’s Patients appeared first on Parkinson’s News Today.

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.

The post First Patient Dosed with VY-AADC Gene Therapy in Parkinson’s Phase 2 Trial appeared first on Parkinson’s News Today.

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.

The post Parkinson’s Gene Therapy Now in Phase 2 Trial, VY-AADC, Continues to Show Motor Benefits, Voyager Says appeared first on Parkinson’s News Today.

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.

The post FDA Grants Regenerative Medicine Advanced Therapy Designation to VY-AADC for Parkinson’s appeared first on Parkinson’s News Today.

Source: Parkinson's News Today

Voyager’s Gene Therapy Improves Parkinson’s Patients’ Movement Over Long Term, Trial Shows

Long-term Parkinson's trial

A single administration of Voyager Therapeutics gene therapy improves advanced Parkinson’s patients’ movement up to three years later, a Phase 1b trial indicates.

Voyager designed VY-AADC01 to deliver the aromatic L-amino acid decarboxylase (AADC) gene to a specific brain region, the putamen. The gene provides instructions for the production of the AADC enzyme. The enzyme is responsible for converting the treatment levodopa into dopamine, the signaling molecule that is missing in Parkinson’s patients.

In advanced Parkinson’s disease, AADC expression is lowered. This leads to the death of nerve cells that produce dopamine in the substantia nigra — a midbrain region. The neuron deaths prevent the substantia nigra from being able to convert oral levodopa to dopamine.

Voyager’s gene therapy is aimed at increasing dopamine production in the putamen, bypassing the effects of the dying dopamine neurons. The goal is for the treatment to improve motor function while reducing the requirement for levodopa or other dopaminergic medications.

VY-AADC01 is being evaluated in both the Phase 1b (NCT01973543) trial and a Phase 1 study (NCT03065192) in patients with advanced Parkinson’s.

Previous data had shown that a single treatment triggers a dose-dependent and time-dependent response across multiple measures of motor function. It also increased AADC enzyme activity and enhanced levodopa’s response.

The Phase 1b trial data that Voyager just announced showed that the therapy continues to yield robust and durable improvements in patients’ motor function from a year to three years later. It also allowed patients to make substantial reductions in their use of daily oral levodopa and other Parkinson’s medications.

The trial includes 15 patients with advanced Parkinson’s disease who have disabling motor fluctuations despite treatment with optimal anti-Parkinson’s medications. Patients are 58 years of age on average and have had a Parkinson’s diagnosis for 10 years.

Key trial objectives are to assess the efficacy of three increasing doses of VY-AADC01 given in a single administration, and to see if the treatment is safe and tolerable.

Among the three groups of patients, those who received the second-highest dose have achieved the best results. They experienced the highest improvement in daily levodopa on-time without any impairment of voluntary movement.

During the trial, patients were instructed to reduce their daily doses of oral levodopa and related medications­­ — called levodopa equivalent doses — to achieve optimal motor control after treatment with VY-AADC01.

All three patient groups were able to reduce their intake of levodopa equivalent doses within six months of treatment. The mean decrease was 15% for the lowest gene therapy dose, 33% for the middle one, and 42% for the highest one.

“Given the improvements in motor function and wider spectrum to titrate oral levodopa with our Cohort 2 dose, we are excited to consider this as our likely dose in the pivotal program while still planning to review the six-month results from the Phase 1 posterior trajectory trial next quarter,” Bernard Ravina, the chief medical officer of Voyager Therapeutics, said in a news release.

VY-AADC01 also generated durable improvements in other measurements of motor function, including reductions in daily on-time with troublesome dyskinesia, or involuntary muscle movements.

In patient group 1, the improvement in on-time without troublesome dyskinesia was 2.1 hours at three years after treatment. In group 2 it was 3.5 hours at 18 months. And in group 3 it was 1.5 hours at 12 months.

Quality of life also improved in a dose-dependent manner, measured by patients’ scores on the Unified Parkinson’s Disease Rating Scale (UPDRS) and on the 39-item Parkinson’s Disease Questionnaire (PDQ-39).

Infusions of VY-AADC01 were well-tolerated in all patients, with no serious adverse events, supporting previous safety findings.

“We continue to be pleased with the duration and magnitude of effect of VY-AADC on multiple measures of patients’ motor function and quality of life, which is consistent with the mechanism of action of VY-AADC suggesting a greater capacity for patients to make more dopamine and improve their motor function with less need for oral levodopa,” Ravina said.

Voyager expects to use data from the Phase 1 and Phase 1b trials to design a Phase 2-3 pivotal trial program, which is expected to start mid-2018.

“We look forward to reviewing these results from the Phase 1b with the FDA,” Ravina said. “And we continue to expect to dose the first patient in the pivotal Phase 2-3 program in mid-2018.”

The post Voyager’s Gene Therapy Improves Parkinson’s Patients’ Movement Over Long Term, Trial Shows appeared first on Parkinson’s News Today.

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.

The post Voyager’s Gene Therapy to Enter Phase 2/3 Trial Program for Advanced Parkinson’s Disease appeared first on Parkinson’s News Today.

Source: Parkinson's News Today