Potential Oral Treatment Shows Promise in Early Study in Volunteers, Neuropore Says

trial results

A potential oral therapy for Parkinson’s disease and amyotrophic lateral sclerosis (ALS) was seen to be safe and well-tolerated at various doses in a Phase 1 trial in healthy volunteers, its developer, Neuropore Therapies, announced.

Steps are now underway to allow NPT520-34 to be evaluated in patients, the company said in a press release.

NPT520-34 is a small molecule that, in different animal models of Parkinson’s, was found to reduce levels of markers of brain inflammation and to improve motor function. Likewise, it was shown to ease inflammation and the buildup of toxic proteins in the central nervous system (brain and spinal cord) in animal models of Alzheimer’s disease and ALS.

The medication is administered orally and small enough to cross the blood-brain barrier, the highly selective and semipermeable membrane that encases and protects the brain.

The recently completed and placebo-controlled study (NCT03954600) investigated the safety, tolerability, and pharmacokinetic properties of oral NPT520-34 at multiple doses in 49 healthy volunteers. (Pharmacokinetics is the study of how a medicine is absorbed, distributed, metabolized, and eliminated from the body.)

The trial included an initial single-dose ascending phase, in which a one dose of NPT520-34 (125 mg, 250 mg, 500 mg and 1000 mg) or a matched placebo were given all study participants, with the possibility of incremental adjustments. This was followed by a second phase, in which participants received multiple-ascending doses (250 mg and 500 mg) of the compound, also with the possibility of incremental adjustments, or a placebo.

“We are excited to complete the Phase 1 clinical trial with NPT520-34″ and believe it “believe NPT520-34 represents a promising new small molecule therapeutic opportunity for patients living with Parkinson’s disease and amyotrophic lateral sclerosis,” Douglas Bonhaus, PhD, chief executive officer and chief scientific officer of Neuropore, said in the release.

“NPT520-34 proved to be safe and tolerable at all doses tested, including those believed to be therapeutically relevant,” Bonhaus added. “The results of this study support moving forward to a safety study in patients. Our team is currently evaluating the optimal study design and patient population for the next study.”

Trials of NPT520-34 in patients with neurodegenerative disorders are expected to begin this year.

We believe NPT520-34 represents a promising new small molecule therapeutic opportunity for patients living with Parkinson’s disease and amyotrophic lateral sclerosis.

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Affiris Announces Phase 2 Study of Potential Parkinson’s Vaccine


Affiris is preparing for a Phase 2 clinical trial to test Affitope (PD01A), an experimental medicine that, if successful, could lead to a vaccine against  Parkinson’s disease.

Affitope triggers the production of antibodies — molecules that recognize specific targets — against alpha-synuclein, a protein found in the brain that may be involved in transmitting information between neurons. While its precise function remains unknown, in the context of Parkinson’s disease toxic forms of this protein contribute to the death of neurons by clumping together into spherical structures called Lewy bodies.

By encouraging one’s body to develop its own defenses against molecules that contribute to Parkinson’s, Affitope works like a vaccine against the disease. In this way, a limited number of doses of Affitope might be able to replace other medicines that must be taken on a continual basis.

In its series of Phase 1 trials (NCT01568099, NCT01885494, NCT02618941, NCT02758730, and NCT02216188), Affitope showed long-term safety, effectiveness and tolerability, and appeared to provide the longest benefit when given as an initial injection, followed by a booster, as is done now for tetanus.

In general, vaccines work by creating a cellular “memory” of defense against the target molecule. As with other memories, this one fades with time. The booster shot serves as a “reminder.”

“Patients with neurodegenerative diseases such as Parkinson’s disease face an all-too-predictable future and are in urgent need of therapies that alter the course of disease progression. Although there are many treatments available to manage the devastating symptoms, sadly none of these acts on the underlying cause of the disease. However, AFFiRiS’ unique immunological approach provides a disease-modifying therapy with an excellent competitive [profile] in the field of neurodegenerative treatments,” Rossella Medori, MD, chief medical officer at AFFiRiS, said in a press release.

Although vaccinating against Parkinson’s is not a widespread strategy, Affiris is not alone. In late 2018, United Neuroscience developed its own candidate molecule to induce an immune response against alpha-synuclein, and Prothena is currently conducting a Phase 2 trial of an injectable antibody against alpha-synuclein (NCT03100149).

Founded in 2003, Affiris has been dedicated to using the immune system to cure neurodegenerative diseases. They currently investigate therapies for Parkinson’s, Alzheimer’s, multiple system atrophy, dementia with Lewy bodies, and Huntington’s disease.

Affiris has not announced when or where its upcoming Phase 2 Affitope trial will take place.

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Cerevance’s Phase 2 Trial Recruiting Patients to Test Oral CVN424 Therapy for Motor Symptoms

CVN424 Phase 2 trial

Cerevance has initiated a Phase 2 clinical trial to evaluate the safety and efficacy of its oral investigational therapy CVN424 for treating Parkinson’s disease motor symptoms.

CVN424 is small molecule that can penetrate the brain and modulate the activity of specific nerve cells in the striatum region that control body movement. In contrast to available therapies, CVN424 specifically targets a non-dopaminergic protein involved in signaling pathways that can activate brain cells.

This new strategy is anticipated to induce positive therapeutic effects similar to current standard-care treatments for Parkinson’s while avoiding side effects such as dyskinesia.

“We are pleased to further advance the clinical development of CVN424 in Parkinson’s, as there remain significant shortcomings with current therapeutics,” Brad Margus, Cerevance’s CEO, said in a press release.

Preclinical studies have shown that CVN424 can improve locomotor activity in animal models of Parkinson’s disease.

Results from a previous Phase 1 study (NCT03657030) showed that CVN424 was safe and well-tolerated compared with placebo. The trial enrolled 64 healthy volunteers who received either single doses or seven daily doses of CVN424, ranging from 1 mg to 225 mg, or placebo. No serious or severe adverse events or clinically significant changes were reported or associated with the therapy.

Oral administration of CVN424 was rapidly absorbed by the body and its stability profile supported a once-daily dosing regimen as the optimal treatment approach for future studies.

These positive data supported the launch of the multicenter, placebo-controlled Phase 2 trial that will now evaluate CVN424’s efficacy and safety in Parkinson’s patients with motor fluctuations who are being treated with levodopa.

The trial is expected to enroll approximately 70 participants, ages 30 to 80, who will be randomly assigned to receive one of two doses of CVN424 or a placebo.

The researchers will evaluate CVN424’s potential for reducing “off” time — periods of the day when Parkinson’s symptoms return despite ongoing medication — as well as other functional outcome measures.

“CVN424 activates key motor pathways, but not the neurons implicated in dyskinesias, a common side effect of dopaminergic Parkinson’s disease treatments,” said David H. Margolin, MD, PhD, senior vice president of clinical and translational medicine at Cerevance. “This selectivity should allow CVN424 to augment the positive effects of the current standard of care, levodopa, without exacerbating its side effects.”

More information about the trial, including participating clinical sites and contacts, is available here.

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Active Ingredient of Overactive Bladder Treatment Eases Urinary Problems in Parkinson’s Patients, Study Suggests

fesoterodine fumarate

Fesoterodine fumarate, the active compound of a medication for overactive bladder, can help reduce urinary symptoms in Parkinson’s disease patients, a clinical study has found.

The findings, “Randomized, controlled trial of fesoterodine fumarate for overactive bladder in Parkinson’s disease” were published in the World Journal of Urology.

Although a high percentage (27% to 80%) of Parkinson’s patients experience lower urinary tract problems, little is known about effective treatments. Urinary symptoms such as urgency, frequency, nocturia (excessive urination at night), dysuria (pain or discomfort when urinating), and incontinence are indicative of an overactive bladder and can affect patients’ quality of life considerably.

A class of medications known as antimuscarinic drugs has been shown to effectively reduce overactive bladder symptoms. However, these medicines also affect the central nervous system and cognitive function. Antimuscarinics target receptors in the bladder’s smooth muscle, suppressing premature contractions and enhancing urine storage.

To date, there are not enough randomized controlled trials to allow doctors to confidently prescribe antimuscarinic treatment to manage lower urinary tract symptoms in Parkinson’s disease.

A team of Turkish researchers now evaluated the short-term effectiveness and safety of fesoterodine fumarate in Parkinson’s patients with overactive bladder symptoms. Fesoterodine fumarate is the active substance in Toviaz (fesoterodine) a medication for overactive bladder that also is an antimuscarinic treatment.

Sixty-three Parkinson’s patients (32 women and 31 men, aged between 46 and 87 years) with troublesome bladder problems were included in the randomized, double-blind and placebo-controlled study. Participants were first randomly assigned to either fesoterodine fumarate 4 mg (32 subjects) or placebo (31 subjects) for four weeks. This was followed by a one-week washout period and a four-week open-label extension phase in which all patients, including those who were on placebo previously, received 4 mg daily of fesoterodine fumarate.

“The researchers and the participants were unaware of the content of medication,” the team noted.

At the beginning of the study, most participants (96.8%) had urgency  incontinence and 4.7% of them also reported stress incontinence.

Following the first four weeks of treatment, the average daily number of urinations significantly decreased in the fesoterodine fumarate group, compared to the control sample (7.9 versus 18.7 urination episodes in 24 hours). Participants on fesoterodine also had their nocturia and urgency episodes reduced.

Four patients on the fesoterodine fumarate group recovered from urgency urinary incontinence and patients on placebo maintained their urinary complaints.

By the end of the open-label phase of the study, overactive bladder treatment was found to significantly decrease the number of urinations, urgency and urgency urinary incontinence episodes. The number of nocturia episodes remained unchanged.

Because of the previously described risk for cognitive impairment following antimuscarinic treatment, researchers evaluated the patients’ cognitive status, using the widely used Mini Mental State Examination (MMSE). Cognition was stable after one month of treatment.

The therapy was well-tolerated and caused no serious side effects. However, one patient on fesoterodine experienced dryness of the mouth and one other reported constipation, which resolved after treatment discontinuation.

“While short-term results from this study are encouraging, further studies with long-term follow-up are needed to evaluate the efficacy and safety of fesoterodine fumarate in PD [Parkinson’s disease] patients with OAB [overactive bladder],” the researchers concluded.

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Potential Therapy for Dopaminergic Neurons, CNM-Au8, Enter Phase 2 Trial in Parkinson’s Patients

CNM-Au8 studies

CNM-Au8, an investigational therapy by Clene Nanomedicine, improved the survival of dopaminergic neurons, helped prevent loss of mitochondria, and rescued motor function in a rat model of Parkinson’s disease, a study reports.

The effects of CNM-Au8 will now be assessed in an open-label (no placebo group) Phase 2 trial, called REPAIR-PD (NCT03815916). This pilot study is enrolling up to 24 patients who will undergo treatment at the University of Texas Southwestern Medical Center. More information can be found here.

Karen Ho, Clene’s head of translational medicine, presented the preclinical findings in the scientific poster, “Gold nanocatalysis as a novel therapeutic for neuroprotection in Parkinson’s disease,” during the recent 2019 Society for Neuroscience (SfN) Annual Meeting in Chicago.

Parkinson’s disease is characterized by the degeneration and death of a particular group of nerve cells — called dopaminergic neurons —  in two brain regions, the striatum and the substantia nigra.

To work as intended, these nerve cells require large amounts of energy, which is provided by mitochondria: small organelles within cells that work as their powerhouses. Failure to provide the energy cells need contributes to their death.

Another key player in Parkinson’s is oxidative stress, an imbalance between the production of harmful free radicals and the ability of cells to detoxify them. These free radicals, or reactive oxygen species, are produced during certain metabolic reactions in which mitochondria are involved, and damage cells.

CNM-Au8 is a suspension of nanocrystalline gold that acts to increase the speed of certain intracellular reactions. Specifically, CNM-Au8 is designed to increase the conversion of nicotinamide adenine dinucleotide (NADH) to its oxidized form (NAD+), resulting in greater production of ATP, a key energy-carrying molecule used by mitochondria. In addition, CNM-Au8 has antioxidant properties that may help to protect cells against oxidative stress.

In the preclinical study, researchers treated co-cultures of rat dopaminergic neurons and glial cells (cells that surround neurons and provide them with support) with CNM-Au8. This significantly increased the total intracellular levels of NAD+ compared to treatment with the control, a reaction that leads to greater release of ATP.

Exposing these co-cultures to two neurotoxins — substances that damage the nervous system and mimic what occurs in Parkinson’s — called MPP+ (1-methyl-4-phenylpyridinium) and 6-OHDA, led to damage and death of dopaminergic neurons. However, treatment with CMN-Au8 significantly increased these neurons’ survival and helped to preserve the network generated by nerve cells.

In cells exposed to 6-OHDA, use of CNM-Au8 led to fewer clumps of alpha-synuclein protein, an established hallmark of Parkinson’s disease.

CNM-Ai8 treatment also halted the accumulation of reactive oxygen species, and significantly lessened the loss of mitochondria induced by exposure to the neurotoxin MPP+.

“We are excited to share these latest Parkinson’s disease neuroprotection data regarding our lead nanocatalyst, CNM-Au8, with the neuroscience research community,” Rob Etherington, the president and CEO of Clene, said in a press release.

“Coupled with prior neuroprotection and remyelination data presented at major scientific congresses, this new Parkinson’s data demonstrate how improvements in bioenergetics with CNM-Au8 may preserve neuronal viability across multiple neurodegenerative disorders,” Etherington added.

CNM-Au8 was also tested in vivo (living organism) in a rat model of Parkinson’s disease. 6-OHDA was injected into the right side of the animals’ striatum. These rats were then given CNM-Au8 or a sham solution daily, delivered orally, beginning the next day (early treatment) or 14 days later (late treatment group).

Locomotor function in the rats was assessed using the vertical cylinder paw placement test after six weeks. Results showed that animals treated with CNM-Au8, either early or later, had improvements in motor activity compared to control (untreated) mice.

Early treatment with CNM-Au8 also reduced the number of apomorphine-induced rotations (circling, which signals problems) in rats with lesions at week six by 42% compared to control rats.

Notably, rats treated with CNM-Au8 in this test also showed better results compared to rats treated with carbidopa/levodopa, a standard Parkinson’s therapy.

“These data support our belief that treatment with CNM-Au8 may improve the survival of dopaminergic neurons in patients with PD, thereby helping slow the progression of this devastating disease. Disease modifying therapies remain a key, unmet treatment goal in Parkinson’s disease,” Etherington said.

CNM-Au8 was shown to be safe in a Phase 1 clinical trial involving healthy volunteers (NCT02755870).

In the REPAIR-PD study, participants will first undergo a four-week screening period, after which they will drink two ounces of CNM-Au8 daily each morning for 12 weeks. Treatment will be followed by a four-week follow-up period.

The study’s primary outcome is to determine improvements in oxidative stress in the central nervous system (brain and spinal cord), assessed by the ratio of NAD+/NADH measured using magnetic resonance spectroscopy (MRS).

Additional (secondary) measures include assessing the effects of CNM-Au8 on energy production and nerve cells’ metabolism. Results are expected by mid-2020.

“We are excited to be advancing CNM-Au8 into studies in Parkinson’s patients starting with the REPAIR-PD Phase 2 study,” said Robert Glanzman, Clene’s chief medical officer. “This study will advance our understanding how CNM-Au8 treatment affects central nervous system biomarkers related to bioenergetics, neuronal metabolism, and oxidative stress, as potential indicators of target engagement for CNM-Au8.”

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Early Trial for Prevail’s One-time Gene Therapy PR001 to Start Soon

PR001 GBA1 trial

Prevail Therapeutics will soon start its Phase 1/2 clinical trial evaluating the safety, tolerability, and early efficacy of its one-time gene therapy — called PR001 — for Parkinson’s disease associated with mutations in the GBA1 gene.

The trial is expected to enroll up to 16 people with confirmed GBA1 mutations. Participants will be randomly assigned to receive two escalating doses of PR001, or placebo, administered as a single injection.

The company expects that dosing will start during 2019.

“We are excited to begin dosing patients in our Phase 1/2 clinical trial for PD-GBA this year,” Asa Abeliovich, MD, PhD, founder and CEO of Prevail, said in a press release. “We believe PR001 has tremendous potential to slow or stop disease progression in patients with PD-GBA … who currently have no disease-modifying therapeutic options.”

People with GBA1 mutations have up to a five-fold higher risk of developing Parkinson’s disease. Indeed, estimates point to a link to GBA1 mutations in 7 to 10% of all Parkinson’s cases.

The GBA1 gene contains all the information necessary to produce the enzyme beta-glucocerebrosidase (GCase) — an important component of cells’ recycling factories, called lysosomes. Lack of this enzyme, or its faulty activity, will make cells accumulate toxic substances inside them, which may contribute to the neurodegeneration seen in Parkinson’s disease.

PR001 was designed as a single-dose gene therapy that will provide nerve cells with a fully working copy of the GBA1 gene. This new method uses a modified and harmless version of an adeno-associated virus (AAV9) to deliver the gene to cells, which will then be able to recover GCase function.

This gene therapy is expected to ease Parkinson’s disease symptoms triggered by the mutated gene.

Studies in mice and primates with Parkinson’s disease demonstrated that PR001 was well-tolerated. The gene therapy also was found to promote an increase in GCase enzyme activity, which resulted in reduced accumulation of toxic fatty molecules, and improvements in motor function.

The U.S. Food and Drug Administration (FDA) granted fast track designation to PR001 in July 2019 for the treatment of people with Parkinson’s disease associated with GBA1 gene mutations. The designation accelerates the therapy’s development and may help expedite its approval by providing more frequent meetings with the FDA and discussions about the therapy’s development plan.

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Gene Therapy Candidate AXO-Lenti-PD Continues to Benefit Parkinson’s Patients in SUNRISE-PD Trial


A single dose of Axovant’s gene therapy candidate AXO-Lenti-PD continues to improve motor function and has been well-tolerated after six months in two patients with advanced Parkinson’s disease, according to early results of an ongoing Phase 1/2 clinical trial.

“We continue to be encouraged by the consistency of the data and improvements in quality of life seen at six months in the two low-dose cohort patients, as we enroll additional patients in the second cohort of the SUNRISE-PD study,” Gavin Corcoran, chief research and development officer at Axovant, said in a press release.

Patient enrollment is ongoing for up to 30 participants, ages 48–70, who have been diagnosed with idiopathic (of unknown cause) Parkinson’s for at least five years. More information on contacts and trial locations (in Europe) is available here.

AXO-Lenti-PD is a gene therapy that uses a harmless virus-based system to deliver three genes that generate three enzymes — tyrosine hydroxylase, cyclohydrolase 1, and aromatic L-amino acid decarboxylase for the production of dopamine, the brain-signaling molecule that is present in low levels in Parkinson’s patients.

The therapy is administrated surgically directly into the brain to restore dopamine levels and provide long-lasting benefits with a single administration.

“Our patient-focused goal of improving motor function, reducing dyskinesia, lowering the requirement for oral levodopa, and improving quality of life is made possible by the continuous dopamine replacement strategy of AXO-Lenti-PD gene therapy,” Corcoran said.

The SUNRISE-PD (NCT03720418) study consists of two parts. Part A is an open-label, dose-escalation phase in which patients receive one of approximately three escalating doses of the gene therapy. In part B of SUNRISE-PD, patients are then randomized to receive either the selected dose from part A or an imitation surgical procedure (control group). The goal is to test the safety, tolerability, and effectiveness of the potential treatment.

The first two patients enrolled received the lowest dose (4.2×106 transducing units) of AXO-Lenti-PD. In March, Axovant revealed results of three months of follow-up.

Now, at six months of follow-up, the patients experienced an average improvement of 17 points in motor function, as measured using the physician-rated Unified Parkinson’s Disease Rating Scale (UPDRS) Part III, which represents an average 29% change from the beginning of the study.

The patients also showed an average improvement of about 20 points from baseline on the UPDRS Part II (activities of daily living) off score, and an average improvement of 3 points from baseline on the UPDRS Part IV (dealing with complications of therapy) off score. “Off time” is when medication — namely levodopa — is not working optimally, and Parkinson’s motor and non-motor symptoms return.

Treatment with AXO-Lenti-PD also was associated with an average reduction of 21% in levodopa equivalent daily dose — the amount of levodopa with a similar effect as the medication taken — at six months.

Data also revealed a mean 18% improvement in dyskinesia — involuntary, jerky movements — at six months, determined with the Rush Dyskinesia Rating Scale “on time” score, which measures functional disability during activities of daily living while on treatment with levodopa.

According to a patient-recorded diary, both patients experienced an improvement in on time without dyskinesia of 2.7 hours, a reduction in on time with non-troublesome dyskinesias of 2.4 hours, a reduction of on time with troublesome dyskinesia of 1.5 hours, and an increase in off time of 0.9 hours.

In addition, the patients reported significant improvements in their quality of life, achieving a reduction of 32 points (65% improvement) from baseline in the Parkinson’s Disease Questionnaire-39 Summary Index score.

“These data at six months highlight the potential for a clinically meaningful improvement over the currently available standard of care for those patients with moderate to advanced Parkinson’s disease,” Corcoran said.

Three-month data from SUNDRISE-PD patients treated with the second dose of AXO-Lenti-PD is expected to be announced during the fourth quarter of this year.

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GDNF Shows Potential as Neurorestorative Treatment for Parkinson’s

GDNF studied

Infusion of a naturally occurring protein, GDNF, into a motor control area of the brain may restore cells damaged by Parkinson’s disease and ease patients’ symptoms, results from a European clinical trial suggest.

The study, “Extended Treatment with Glial Cell Line-Derived Neurotrophic Factor in Parkinson’s Disease” was published in the Journal of Parkinson’s Disease.

Evidence shows that glial cell line-derived neurotrophic factor (GDNF) supports the growth, survival, and differentiation of dopaminergic neurons — those that produce dopamine and progressively degenerate in Parkinson’s disease. In animal models of Parkinson’s, GDNF has consistently demonstrated both neuroprotective and neurodegenerative effects when provided continuously.

Researchers developed a three-part clinical trial (EudraCT Number: 2013-001881-40) to study the safety and effectiveness of GDNF infusions in Parkinson’s patients. The trial first recruited six patients to assess the safety of the treatment. Then, 35 more participants entered the nine-month, double blind trial in which half were given monthly infusions of GDNF. The other half received placebo infusions through an implant that delivered the treatment directly to the brain through a port placed behind the ear.

This part of the study showed that patients who received monthly doses of GDNF into their putamen — a brain region involved in movement control that’s deeply damaged in Parkinson’s — had a significant increase of dopamine levels in the brain compared to the placebo group. However, the apparent increase in dopamine levels were not reflected on patients’ clinical status.

“The spatial and relative magnitude of the improvement in the brain scans is beyond anything seen previously in trials of surgically delivered growth-factor treatments for Parkinson’s,” principal investigator Alan L. Whone, PhD, said in a press release. Whone is in Translational Health Sciences, Bristol Medical School, University of Bristol, and Neurological and Musculoskeletal Sciences Division, North Bristol NHS Trust, Bristol, UK,  “This represents some of the most compelling evidence yet that we may have a means to possibly reawaken and restore the dopamine brain cells that are gradually destroyed in Parkinson’s,” he said.

Using the same patient sample (41 subjects, ages 35–75) researchers further assessed the effects of continued (21 patients who had received GDNF) or new (20 patients who had received placebo) exposure to GDNF for another nine months in the open-label extension phase of the trial. Dosing followed the same protocol as before with GDNF infusion given every month.

Although all patients knew they were receiving GDNF, they remained oblivious to what their treatment in the previous study was.

The primary goal of the study was measure the percentage change from parent trial week zero to week 80 (or week 40, depending on the study group) in the “off” state Unified Parkinson’s Disease Rating Scale (UPDRS) motor score. As disease progresses, patients experience off periods more frequently. Such episodes are characterized by the reappearance or worsening of symptoms due to diminishing effects of levodopa therapy.

The treatment had no treatment-emergent safety issues, but all patients experienced at least one adverse side effect, including application site infection, headache, back pain, and uncontrollable muscle contraction (dystonia).

By 18 months (all participants had received GDNF), both groups showed a trend toward score reduction, indicating motor function improvement. GDNF also was found safe when administered over this length of time. However, there were no significant differences in off state UPDRS motor score between patients who received GDNF for 18 months and those who received it for nine months only (parent study placebo group).

Importantly, total off time and good-quality “on” time per day improved in both study groups.

In comparison to the beginning of the parent trial, mean total off time per day decreased by an average of 1.5 hours in patients who received GDNF throughout the whole study, and by 0.8 hours in the those who received placebo and GDNF. “Good-quality ON time increased by [an average of 1.6] hours in the GDNF/GDNF group and by [0.5] hours in the placebo/GDNF group,” researchers wrote.

“This trial has shown that we can safely and repeatedly infuse drugs directly into patients’ brains over months or years. This is a significant breakthrough in our ability to treat neurological conditions, such as Parkinson’s, because most drugs that might work cannot cross from the blood stream into the brain due to a natural protective barrier,” said senior author Steven Gill, honorary professor in neurosurgery at the University of Bristol, and designer of the GDNF delivery system (Convection Enhanced Delivery, CED).

“I believe that this approach could be the first neurorestorative treatment for people living with Parkinson’s, which is, of course, an extremely exciting prospect,” Gill stated.

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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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Researchers Evaluate Computer-based Therapy to Ease Fatigue, Improve Motor Function

motor function, nonpharmacological intervention

An ongoing pilot trial is evaluating a computer-based, non-pharmacological cognitive approach to improve motor function and ease fatigue in people with Parkinson’s disease.

Study protocol for a randomised pilot study of a computer-based, non-pharmacological cognitive intervention for motor slowing and motor fatigue in Parkinson’s disease,” appeared in the journal Pilot and Feasibility Studies.

Non-pharmacological therapies may offer effective alternatives to the complications and significant cost of dopaminergic treatment. A team of English researchers set out to develop an approach based on cognitive tasks to lessen fatigue and improve motor function in this patient population.

Advances in the understanding of the brain’s anatomy — such as links between motor and cognitive processes — and of Parkinson’s underpinnings provide the required scientific ground to develop such an approach. Also, previous work from the same team and other researchers had shown that people with Parkinson’s have an impairment in visuospatial tasks, such as mental rotation and mental grid navigation. These tasks were found to activate brain regions such as the supplementary motor area, typically involved in motor control.

Mental rotation is the ability to rotate mental representations of two-dimensional and three-dimensional objects and is related to the brain’s capacity for visual representation; mental grid navigation is the ability to compute a series of imagined location shifts in response to directional cues around a mental grid.

Prior work in 16 people with early-stage Parkinson’s showed improved motor performance after a visuospatial intervention task of mental grid navigation, as evidenced by faster mean onset and velocity. Such results, the team said, indicate that cognitive tasks with visuospatial processing can improve resilience to motor slowing and improve motor function. Such a strategy could become a low-cost option for patients and suitable for home use.

But before this intervention can be considered for a large-scale clinical trial, researchers needed to understand whether the computer-based cognitive training intervention (spatial grid navigation) could lead to significant motor benefits. They also wanted to see whether the improvements extend to aspects such as lessened rigidity and increased motor fluency.

The team designed a randomized single-blind (only patients are unaware of which intervention is expected to be beneficial) pilot study (ISRCTN1256549) to evaluate the feasibility of a larger-scale clinical trial. The trial set out to determine the usability of the devices used to capture movement and finger-tapping data. Tests of finger tapping are routinely conducted to assess bradykinesia, or slowness of movement, and may indicate motor fatigue.

Secondary objectives included assessing changes of at least five points in the Unified Parkinson’s Disease Rating Scale Part III (UPDRS-II) motor examination measure, as well as improvements in movement response times and eased motor fatigue over five 45- to 70-minute sessions involving sequential subtraction or spatial memory control tasks.

Patients were tested at home, at local hospitals or at Wales’ School of Psychology, Bangor University. They did not change their medication or other nonpharmacological regimens. Patients’ hand dominance was assessed before starting the study. Evaluations of quality of life, fatigue, sleep quality, and non-motor symptoms were conducted.

In finger tapping, each hand was tested separately, with the number of taps over 15 seconds and the time between taps analyzed. To evaluate measures of velocity and trajectory, patients held down a button on a response box for four seconds and then reached for a green circle on a screen as quickly and accurately as possible. Eighteen trials were conducted per hand. Action completion time, including movement initiation time and reaching time/velocity, were the primary outcome measures on this task.

The spatial grid navigation task includes an empty grid made up of nine squares, shown for 10 milliseconds. Then, a red start square is displayed for 2.5 seconds and participants are asked to memorize its position. A sequence of five screens is then shown, with two, three or four arrows that indicate movement of the red starting square. The participants must track the position of the red square based on the observed sequence.

At the end of the task, a blue target square is shown with a test grid. The patients then decide whether the position of the blue square matches that of the final position of the presented sequence.

“The results of this study will provide information regarding the feasibility of conducting a larger randomized control trial of non-pharmacological cognitive interventions of motor symptoms in  [Parkinson’s disease],” the researchers stated.

“The longer-term view is to develop an evidence-based, online or app-based platform that could be accessed by people in their own homes alongside other pharmacological or physical treatments to support maintenance of motor slowing and motor fatigue symptoms,” they said.

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