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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

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

AXO-Lenti-PD

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

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

Axovant Obtains Worldwide License to Develop AXO-Lenti-PD, Potential Parkinson’s Gene Therapy

AXO-Lenti-PD

Axovant Sciences licensed the exclusive worldwide rights from Oxford BioMedica to develop and market AXO-Lenti-PD, a gene therapy candidate for Parkinson’s disease.

Formerly known as OXB-102, AXO-Lenti-PD uses a modified, harmless type of virus called lentivirus to deliver three genes that provide instructions to make a key enzyme in the synthesis of dopamine, the neurotransmitter produced at low levels in Parkinson’s patients.

The investigational medication was designed to provide durable restoration of dopamine levels after a single administration.

Oxford recently completed a Phase 1/2 trial of ProSavin (NCT00627588), OXB-102’s predecessor, which demonstrated favorable safety and tolerability and a significant improvement of motor function at six and 12 months in Parkinson’s patients. This benefit was sustained for up to four years in most patients.

Compared with ProSavin, preclinical studies of OXB-102 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.

Axovant plans to start a Phase 1/2 dose escalation trial of AXO-Lenti-PD in patients with advanced Parkinson’s by the end of 2018. Oxford will be the clinical and commercial supplier of AXO-Lenti-PD.

Under the terms of the agreement, Axovant obtained rights to both AXO-Lenti-PD and ProSavin for an initial $30 million. Roivant Sciences, Axovant’s parent company, agreed to purchase $25 million of Axovant’s shares, which will support the development of AXO-Lenti-PD.

“Axovant remains committed to developing innovative treatments for serious neurodegenerative conditions such as Parkinson’s disease, and we are excited to partner with Oxford BioMedica,” Pavan Cheruvu, MD, CEO of Axovant, said in a press release. “We will continue to pursue promising new therapeutic approaches based on transformative science, and will further expand our pipeline with high-quality assets like AXO-Lenti-PD.”

Axovant also announced that Fraser Wright, PhD, co-founder and former chief technology officer of Spark Therapeutics, will join the company as the new chief technology officer, overseeing the gene therapy program.

“I look forward to the opportunity to work closely with Oxford BioMedica and help build gene therapy capabilities at Axovant,” Wright said. “AXO-Lenti-PD is a strong foundation for Axovant’s new pipeline, and I am excited to begin preparing the Phase 1/2 clinical study in advanced Parkinson’s.”

At Spark, Wright oversaw the development and manufacturing of Luxturna (voretigene neparvovec-rzyl). He had previously been involved in the development and human testing of both Luxturna and Kymriah (tisagenlecleucel), developed by Novartis, at the Children’s Hospital of Philadelphia.

Wright’s more than 20 years of experience in gene therapy will help build world-class capabilities at Axovant, Cheruvu said.

John Dawson, CEO of Oxford, believes Axovant’s expertise in neurological disorders, including Parkinson’s, makes it an ideal partner “to advance the development of AXO-Lenti-PD for the treatment of patients with Parkinson’s.”

“We are delighted to sign this significant agreement which not only underlines our LentiVector-enabled platform and product development strategy but further demonstrates Oxford BioMedica’s ability to build multiple partnerships with leaders in their respective therapeutics fields,” he said.

Axovant held a conference call on June 6 to discuss the agreement. A replay of the webcast is now available here.

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Nanoparticle-based DNA Barcoding Could Be Used to Test Gene Therapies, Study Shows

Nanoparticle gene therapy delivery

A new DNA barcoding technique using nanoparticles could be used for large-scale testing of gene therapies for diseases such as Parkinson’s, according to Georgia Tech and Emory University researchers.

The study, “A direct comparison of in vitro and in vivo nucleic acid delivery mediated by hundreds of nanoparticles reveals a weak correlation,” appeared in the journal Nano Letters.

A well-known limitation of gene therapies is the difficulty of delivering DNA or RNA strands into the right cells. So far, scientists have relied on the standard method for studying nanoparticle delivery — lab dishes.

James Dahlman, an assistant professor in the Wallace H. Coulter Department of Biomedical Engineering at Georgia Tech and Emory University, holds a microfluidic chip used to fabricate nanoparticles that could be used to deliver gene therapies. (Credit: Rob Felt, Georgia Tech)

Researchers decided to look at a new technique. It involves attaching small snippets of DNA to different lipid-based nanoparticles, adding them to living cells in lab dishes, then  injecting them into animals.

The team wanted to compare this new screening technique with the standard one, to see which was better.

They delivered 281 nanoparticles into endothelial cells and immune cells called macrophages. They discovered almost no correlation between how well the nanoparticles delivered the bar codes into cells in a lab dish or mice.

The researchers also studied how nanoparticle delivery can alter the microenvironment of certain tissue types. They found that cells derived from the same progenitor cells tend to be targeted by similar nanoparticles.

“If the in vitro [lab] tests had been good predictors, then particles that did well in the dish would also have done well in the animals, and particles that did poorly in the dish would also have done poorly in the animals. We did not see that at all,” James Dahlman, the study’s senior author, said in a Georgia Tech news release.

Importantly, this technique enables simultaneous testing of over 100 nanoparticles in a single animal. Using DNA sequencing methods, scientists are then able to discover which nanoparticles enter the cells of specific organs.

“If you wanted to test 200 nanoparticles in the traditional way, you would need 600 mice —  three for each type of nanoparticle,” Dahlman said. “Using the DNA barcoding technique, which we call Joint Rapid DNA Analysis of Nanoparticles (JORDAN), we are able to do the testing in just three animals.”

The DNA strands used in the study are roughly the size of RNA-based molecules currently in development. Further work is necessary to determine whether the technique can use larger molecules.

The specificity of the new method is particularly important, as treatment of cancer or heart disease, for instance, requires precise targeting of diseased cells, while avoiding healthy tissues.

“These data demonstrate that barcoded lipid nanoparticles can elucidate fundamental questions about in vivo [animal] nanoparticle delivery,” the researchers wrote.

“DNA barcoding has the potential to advance the science of selecting nanoparticles for delivering gene therapies,” Dahlman said. “Using this technique, companies and academic labs could pick out promising nanoparticles much more efficiently. That could accelerate the rate at which nanoparticle-based therapies move into the clinic [clinical trials], while reducing the amount of animal testing required.”

Once promising nanoparticles are identified, scientists can then check their ability to deliver therapies. Only nontoxic nanoparticles can be screened, and inflammation generated by inserted DNA must be controlled.

“We hope this technique will be used widely in the field, and that it will ultimately bring more clarity to how these drugs affect cells — and how we can get them to the right locations in the body,” Dahlman said.

The research was supported by the National Institutes of Health, the Cancer Research Institute, Cystic Fibrosis Foundation, and Parkinson’s Disease Foundation.

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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.”

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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