#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.

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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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AXO-Lenti-PD Gene Therapy Shows Benefits in 2 Advanced Parkinson’s Patients in Phase 1/2 Trial


One-time treatment with the gene therapy candidate AXO-Lenti-PD led to improved motor function and was well-tolerated after three months in two patients with advanced Parkinson’s disease, according to early results of an ongoing Phase 1/2 clinical trial.

These findings are from the open-label, dose-escalation portion of the SUNRISE-PD study (NCT03720418), in which the patients received the lowest dose (4.2×106 TU) of Axovant’s AXO-Lenti-PD. The goal is to test the safety, tolerability, and efficacy of the potential treatment.

“These findings are highly encouraging, and we look forward to advancing to higher dose cohorts where we will explore the full clinical potential of AXO-Lenti-PD in patients with Parkinson’s,” Gavin Corcoran, Axovant’s executive vice president of research and development, said in a press release.

Patient enrollment is ongoing in the U.K. (yet to open in France) for a total of about 30 participants ages 48–70 who have been diagnosed with idiopathic Parkinson’s for at least five years. More information on contacts and trial locations is available here.

AXO-Lenti-PD uses a harmless virus-based system to deliver three genes that generate key enzymes — tyrosine hydroxylase, cyclohydrolase 1, and aromatic L-amino acid decarboxylase — for the production of dopamine, the neurotransmitter found at reduced levels in Parkinson’s patients. The gene therapy — delivered surgically directly into the brain — is aimed at restoring dopamine levels in the brain to provide long-lasting benefits with a single administration.

As measured with the physician-rated Unified Parkinson’s Disease Rating Scale (UPDRS) part III off score — assessed after levodopa washout to not throw off the results — the two patients experienced a 25-point improvement in motor function, which represents an average 42% change from the beginning of the study. Off time is when medication — namely levodopa — is not working optimally, and Parkinson’s motor and non-motor symptoms return.

The benefits were observed across all subparts of the UPDRS scale, with an overall improvement of 54.5 points, or 55% from before treatment. In UPDRS part II, which refers to activities of daily living, average improvements were 22 points, and in part IV, dealing with complications of therapy, the patients showed a seven-point improvement.

Data further showed a mean 18% improvement in dyskinesia — involuntary, jerky movements — determined with the Rush Dyskinesia Rating Scale on score, which measures functional disability during activities of daily living while on treatment with levodopa.

According to a patient-recorded diary, both patients had an improvement in on time with dyskinesia and troublesome dyskinesia, with average decreases from before treatment of 3.5 hours (or 57%) and 1.3 hours (85%), respectively.

Treatment with AXO-Lenti-PD was also associated with an average reduction of 208 mg (19%) in levodopa equivalent daily dose — the amount of levodopa with a similar effect as the medication taken — at three months. No serious adverse events were reported.

Results of a Phase 1/2 trial (NCT00627588) of ProSavin, the predecessor to AXO-Lenti-PD, had shown favorable safety and tolerability, as well as significant improvement in motor function, at four years of treatment in most patients.

Compared with ProSavin, preclinical data of AXO-Lenti-PD showed higher production of the crucial enzymes and a minimum fivefold greater potency in improving behavior and movement in an animal model of Parkinson’s disease.

“These early data support the safety of the lowest dose of AXO-Lenti-PD, similar to what was observed with the earlier generation construct, ProSavin, and also suggest substantially greater biological activity than the highest dose of ProSavin previously tested,” Corcoran said.

Roger Barker, one of the principal investigators in SUNRISE-PD, said the results suggest that AXO-Lenti-PD “has the potential to significantly improve motor function in patients with advancing Parkinson’s.”

He also said that given the mechanism of action of AXO-Lenti-PD and the experience with ProSavin, the scientists expected the main benefit to be in relieving the off state — “and the results so far are very encouraging in this regard.”

Axovant is now planning to proceed to the second dose group (1.4×107) after receiving positive feedback from the trial’s data monitoring committee. Dosing of the first patient in this second group is expected in the second quarter of this year.

“I am hopeful that this development program will translate into a significant new therapeutic option for patients with Parkinson’s,” said Baker, a professor of clinical neuroscience and honorary consultant in neurology at the University of Cambridge and Addenbrooke’s Hospital.

Axovant recently gave a presentation at the Cowen and Company 39th Annual Health Care Conference in Boston. A copy of the slides and link to a webcast can be found here.

In June 2018, Axovant obtained exclusive worldwide rights to AXO-Lenti-PD from Oxford BioMedica, which originally developed the gene therapy.

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Gene Therapy Preserves Nerve Fibers in Mouse Model of Severe Neurodegeneration

Gene therapy

An investigational gene therapy was able to preserve nerve axons — long projections that connect nerve cells and transport information — in a mouse model of severe axonal degeneration.

Because axon degeneration precedes the death of neurons in several neurodegenerative diseases, including Parkinson’s disease and amyotrophic lateral sclerosis (ALS), the findings support this therapy’s potential as an effective treatment.

The study, “Gene therapy targeting SARM1 blocks pathological axon degeneration in mice,” was published in the Journal of Experimental Medicine.

Axons, or nerve fibers, are the long projections of a nerve cell, which conduct electrical impulses away from the cell body to other nerve cells, muscles, and glands. There is currently no treatment that effectively inhibits axon degeneration.

When an axon is injured, a protein called SARM1 becomes activated and triggers axons to self-destruct. In healthy nerve cells, this protein is switched off. Deleting the gene that codes for this protein, the SARM1 gene, has been shown to have a protective effect against axonal degeneration after injury in both a fruit fly model and a mouse model.

SARM1 acts as an enzyme that destroys metabolic factors needed for axons to work properly. It works by rapidly degrading a metabolite, called NAD+, causing a metabolic failure in neurons that trigger axonal degeneration. When this protein is mutated, it prevents rapid energy loss and subsequent destruction of axons.

SARM1’s multiple components must bind together for the protein to work properly. If one of these components is changed, the protein’s assemblage is faulty and unable to function. As such, scientists only have to alter or mutate a part of the protein to inhibit its function.

Researchers at St. Louis’ Washington University School of Medicine have developed a gene therapy to block the activity of SARM1.

The team introduced single mutations, affecting only one nucleotide — the building blocks of DNA — in the SARM1 gene, which resulted in the production of a faulty SARM1 protein. Similar to neurons without the SARM1 gene, when this gene therapy was inserted into nerve cells grown in the laboratory, no axonal degeneration was observed.

Accordingly, in injured neurons with a normal SARM1 protein, NAD+ levels were reduced. However, upon treatment with the gene therapy, they remained constant.

Researchers then treated neurons with vincristine, a chemotherapy agent, to simulate nerve cell damage. Two days later, the treatment resulted in axonal fragmentation. However, neurons that received the gene therapy remained intact and had normal metabolic activity — proof of how the therapy was able to inhibit SARM1 function.

To test the gene therapy in living organisms, the team used an inactive virus — adeno-associated virus (AAV) — as a vehicle to deliver the therapy into nerve cells of a mouse model of severe axonal degeneration. Researchers had induced a severe nerve injury in the sciatic nerve to trigger axonal degeneration.

Within five weeks, the viral vector containing the altered SARM1 gene was present in several of the affected nerves, including peripheral nerves and spinal cord nerve cells.

In animals treated with the gene therapy, their axons remained intact up to 10 days after nerve injury, and neurons preserved their normal conformation, architecture and myelin — a protective coating around nerve fibers — thickness.

In control (untreated) mice, there was almost a complete (99%) loss of axons at sites of nerve injury.

“With our viral gene therapy, we delivered a mutated form of SARM1 that is not only inactive itself but also blocks normal SARM1 proteins that have become activated in mice with nerve injuries,” senior author Jeffrey D. Milbrandt, MD, PhD, said in a university news release. “For a long time, viral gene therapy was a pipe dream, but there are now a number of ongoing clinical trials in other disorders that suggest we are on a promising track.”

“This has the potential to be transformative because it cuts across so many diseases,” said co-senior author Aaron DiAntonio, MD, PhD. “Rather than addressing a single disease, it is potentially a treatment for a disease process that is shared among many different neurodegenerative disorders.”

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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.

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Sirion and Denali Collaborating to Develop Gene Therapies for Neurodegenerative Diseases

gene therapies, Denali, Sirion

Sirion Biotech and Denali Therapeutics have agreed to partner on the development of gene therapies for Parkinson’s disease and other neurodegenerative disorders.

According to the license and collaboration agreement, the two companies will pursue the development of harmless, next-generation adeno-associated viral vectors (AAV) able to cross the blood-brain barrier — a semipermeable membrane that protects the brain against the external environment.

Besides Parkinson’s, these potential gene therapies will also target Alzheimer’s, amyotrophic lateral sclerosis, and other diseases of the central nervous system — brain and spinal cord.

“This ground-breaking collaboration will help Denali Therapeutics to increase the availability of protein therapeutics in the brain, and to quickly enter clinical trials with efficient, safe and scalable therapeutic candidates,” Christian Thirion, PhD, Sirion’s founder and CEO, said in a press release.

According to Sabine Ott, PhD, Sirion’s vice president of business development and licensing, the company believes that through its partnership with Denali, AAV-based gene therapies can reach the market “in the fastest possible way, providing novel treatment options to many millions of patients.”

Specifically, the aim is to create new and modified AAV capsids (the protein shell of a virus) that are safe and have greater specificity and high efficiency to deliver therapeutic levels of medicines to the brain. AAV vectors are regarded as the most promising gene delivery system for therapies.

Sirion’s collaboration with Dirk Grimm, PhD, a professor of viral vector technologies at Heidelberg University Hospital in Germany, will play a key part in the research.

“By contributing and harnessing our unique and proprietary expertise in the engineering and high-throughput in vivo screening of AAV capsid libraries, we will significantly accelerate this joint endeavour and increase our chances to realize its pivotal aims,” Grimm said.

The main terms of the agreement between Germany-based Sirion and San Francisco-based Denali include development expenses, milestone payments to Sirion, and royalties from future products or therapies.

According to Alexander Schuth, Denali’s chief operating officer, the company is “excited to partner with Sirion” and combine its “expertise around the blood-brain barrier and neurodegenerative diseases with Sirion’s leading expertise on viral vectors for gene therapy to enable new treatments for diseases of the brain,” further saying that the partnership will add a new therapeutic modality to the company’s portfolio and is complementary to other programs from Denali.

In October 2018, Denali and Centogene announced a collaboration to identify and recruit Parkinson’s patients carrying mutations in the LRRK2 gene for future clinical trials. Mutations in LRRK2 are a well-known genetic cause of Parkinson’s. These patients will participate in trials of Denali’s LRRK2 inhibitor therapy program, which includes DNL201 and DNL151.

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


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


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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Investigational Gene Therapy AXO-Lenti-PD Tested in Phase 1/2 Clinical Trial in Parkinson’s Patients


The first patient has been dosed in Axovant’s Phase 1/2 clinical trial testing the investigational gene therapy AXO-Lenti-PD for the treatment of Parkinson’s disease.

The patient reported no complications associated with surgery or administration of the therapy and was discharged as planned in the initial trial design. Preliminary data from the first group of patients treated in the trial are expected to be announced during the first half of 2019.

Currently recruiting participants, the trial (NCT03720418) is expected to enroll about 30 patients ages 48-70 who have had bilateral idiopathic (of unknown cause) Parkinson’s disease for at least 5 years.

The study, being conducted in the United Kingdom and France, consists of two parts. In part A, researchers will evaluate the safety and tolerability of increasing doses of the investigational gene therapy, and select the optimal dose to be used in further testing.

Part B is a randomized, double-blind phase in which patients will receive either the designated dose from Part A or an imitation surgical procedure (ISP). Patients will be followed for about 6 months to assess AXO-Lenti-PD’s safety and potential to enhance motor function and improve movement control.

AXO-Lenti-PD, also known as OXB-102, is a gene therapy that uses a harmless virus-based system to deliver three genes that encode critical enzymes involved the synthesis of dopamine — the signaling molecule, or neurotransmitter, produced at low levels in Parkinson’s patients.

This treatment is expected to provide significant and long-lasting clinical benefits to patients with Parkinson’s disease upon a single administration.

The gene therapy was initially designed by Oxford BioMedica, which in June 2018 granted the exclusive worldwide rights over AXO-Lenti-PD’s development and marketing to Axovant Sciences.

“We are very excited to bring AXO-Lenti-PD into clinical development and believe it will be an important new therapy for patients with Parkinson’s disease who suffer from motor fluctuations on the current standard of care,” Pavan Cheruvu, MD, the CEO of Axovant, said in a press release. “This marks the first of our gene therapy programs to enter the clinic, and our focus now is on rapid execution of the clinical study.”

A recently completed Phase 1/2 trial of ProSavin (NCT00627588), AXO-Lenti-PD’s predecessor, demonstrated favorable safety and tolerability and a significant improvement of motor function at 6 and 12 months in Parkinson’s patients. This benefit was sustained for up to six years.

Compared with ProSavin, preclinical studies of AXO-Lenti-PD showed increased production of the key enzymes, as well as at least a fivefold greater potency in improving behavior and movement in an animal model of the disease.

“Building upon the evidence of safety and durable improvements in motor symptoms seen up to six years in the prior clinical study of ProSavin, we feel a sense of urgent responsibility to accelerate the development of AXO-Lenti-PD,” Cheruvu said.

“Mid- to late-stage Parkinson’s disease remains a challenge to treat, with current therapies leading to debilitating adverse events and unpredictable therapeutic effects over time,” said Stéphane Palfi, MD, PhD, coordinating investigator of the AXO-Lenti-PD trial.

“We are pleased to advance AXO-Lenti-PD in the clinic and are eager to see the trial expand upon the long-term safety and efficacy results we observed in the Phase 1/2 clinical trial of ProSavin,” he said.

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New Method Captures Images of All Brain Areas Following Gene Therapy

gene therapy

A new method that allows imaging of all brain areas can help researchers monitor the success of gene therapy in the treatment of neurological diseases such as Parkinson’s.

The study, “A Novel Positron Emission Tomography Reporter Gene/Reporter Probe for the Central Nervous System,” was presented recently during the SNMMI 2018 Annual Meeting in Philadelphia, and published in the Journal of Nuclear Medicine.

Gene therapy is a therapeutic approach that has the potential, by replacing a defective gene copy with a healthy one, to be a one-time treatment that fixes, rather than treats, disease.

In neurological diseases – such as Parkinson’s disease or Alzheimer’s disease – gene therapy is often limited by the lack of an adequate imaging technique that can successfully help monitor the delivery and expression of the therapeutic gene directly into the brain.

While many reporter gene systems — a construct that tags genes with fluorescent probes and allows tracking within the body— have been developed for imaging gene therapies, current systems do not allow imaging all areas of the brain.

It is challenging to find a reporter gene and imaging agent that can be used in all areas of the brain with a high signal-to-background ratio,” Thomas Haywood, PhD, department of radiology at Stanford University, said in a press release.

Researchers now have developed a new positron emission tomography (PET) reporter gene system that allows for monitoring of gene expression (the process by which information in a gene is synthesized to create a working product, like a protein) in all areas of the brain.

PET imaging uses small amounts of radioactive materials, called radiotracers, along with a special camera and computer to help evaluate organ and tissue functions.

The newly developed system allows researchers to monitor the level and location of gene expression in all areas of the brain in a non-invasive manner, helping physicians determine the likelihood of treatment success.

To test their new method, researchers infected mice brain cells with a viral vector containing the PKM2 gene. PKM2 was considered an ideal choice for a reporter gene because the protein it produces, pyruvate kinase M2, is not expressed at very high levels in the healthy brain. As such, it can be specifically monitored and traced in an experimental setting.

Animals then were imaged with the 18F-DASA-23 radiotracer over a period of two months to observe the increase in PKM2 expression over time. Importantly, this radiotracer is able to cross the blood brain barrier (BBB), a semi-permeable membrane that protects the brain from outside circulating blood.

18F-DASA-23 is a novel radiotracer, or reporter probe, developed in the Gambhir lab at Stanford that is capable of crossing the blood–brain barrier and targeting the pyruvate kinase M2 protein in the central nervous system with minimal endogenous [normal] expression in the brain,” Haywood explained. “This allows us to monitor reporter gene expression and ultimately therapeutic gene expression for gene therapy in all regions of the brain.”

Results showed there was an increase in 18F-DASA-23 uptake, which correlated with the levels of PKM2 in the cells. This suggests that not only was PKM2 being expressed, but that the radiotracer was correctly detecting its expression in brain tissue.

“This encouraging data suggests PKM2 has the potential to be further developed into a PET reporter gene system for the imaging of gene therapy in the CNS [central nervous system],” the authors wrote.

“Having a reporter gene/reporter probe system that allows monitoring of all areas of the brain opens the door to more accurate and less invasive imaging of the brain and of gene therapies used to tackle diseases of the brain,” Haywood said.

A Phase 1 clinical trial is currently recruiting patients to test the 18F-DASA-23 radiotracer for the early detection of therapeutic response in patients with glioblastoma, a type of brain tumor that develops in certain brain cells called astrocytes.

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Source: Parkinson's News Today