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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For First Time, Precursors of Dopamine Neurons Implanted in Brain of Parkinson’s Patient

Parkinson's stem cells

Precursors of dopamine-producing cells were implanted into the brain of a Parkinson’s patient for the first time. The patient in Japan is the first of seven to receive this experimental therapy.

The approach uses induced pluripotent stem cells (iPSCs), which are developed by reprogramming cells collected from the skin or blood of adults so that they revert to a stem cell-like state and are able to differentiate into almost any cell type.

Scientists at Kyoto University can transform iPSCs into precursors of dopamine-producing neurons. In Parkinson’s, progressive loss of these neurons in a brain area called substantia nigra, and reduced dopamine release in a connected region called striatum, lead to the characteristic motor symptoms.

Last month, neurosurgeon Takayuki Kikuchi implanted 2.4 million dopamine precursor cells into the brain of a Parkinson’s patient in his 50s. The team implanted the cells into 12 centers of dopamine activity over three hours. Stem cell researcher Jun Takahashi and colleagues derived the dopamine precursor cells from iPSCs originally developed from skin cells of an anonymous donor.

“The patient is doing well and there have been no major adverse reactions so far,” Takahashi said in a Nature press release, written by David Cyranoski. The man will be observed over six months. If he does not develop complications, an additional 2.4 million dopamine precursor cells will be implanted into his brain.

Six more Parkinson’s patients are expected to receive this stem cell therapy, which will allow researchers to collect safety and efficacy data by the end of 2020. According to Takahashi, the treatment could reach the market as early as 2023 under Japan’s fast-track approval system for regenerative medicines. “Of course it depends on how good the results are,” he said.

In 2017, Takahashi and his team showed that dopamine-producing neurons transplanted into the brains of monkeys enabled them to move spontaneously over two years. Also, the transplanted cells did not lead to abnormal and jerky movements (dyskinesia), did not develop into tumors — a key concern with iPSCs-based treatments — and did not trigger an immune response not treatable with an immunosuppressive therapy.

In 2014, a Japanese woman in her 70s became the first patient to receive retinal cells derived from iPSCs to treat an eye condition called age-related macular degeneration.

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Investigational Herbal Therapy DA-9805 Shows Neuroprotective Effects in Parkinson’s Mouse Model

DA-9805 herbal treatment

An investigational herbal product called DA-9805 exerts its neuroprotective activity by preventing mitochondria damage in brain cells, a mouse study has found.

This compound is currently being evaluated in a Phase 2a clinical trial (NCT03189563) in early Parkinson’s disease patients.

The study, “Triple herbal extract DA-9805 exerts a neuroprotective effect via amelioration of mitochondrial damage in experimental models of Parkinson’s disease,” appeared in the journal Scientific Reports.

DA-9805 is an investigational compound being developed by the South Korean company Dong-A ST. It combines natural compounds extracted from three plants widely used in traditional Asian medicine: Moutan cortex, Angelica Dahurica root, and Bupleurum root.

Each of these plants is rich in compounds with broad therapeutic activities, including anti-inflammatory, antioxidant, anti-cancer, and analgesic proprieties.

Supported by their long history of use in traditional medicine for diseases caused by oxidative stress and inflammation, researchers hypothesized that they may also have the potential to treat Parkinson’s disease.

DA-9805 was obtained by extracting the main natural compounds of the three dried plants with 90% ethanol for 24 hours. A detailed analysis of the extracted compounds revealed the mixture was enriched for the active molecules paeonol, saikosaponin A, and imperatorin.

To evaluate the potential of the mixture, researchers exposed a cell line model often used to study Parkinson’s disease to increasing doses of DA-9805 or other reference compounds.

The treatment significantly prevented cell death induced by impaired activity of mitochondria — small cellular organelles that provide energy and are known as the “powerhouses” of cells — compared with the other tested compounds. The neuroprotective effect of DA-9805 was further confirmed when tested in cells collected from the superficial brain layer of rats.

Next, the team evaluated the effects of oral DA-9805 in a mouse model of Parkinson’s disease. This model was achieved by injecting animals with a neurotoxin called MPTP and its active metabolite MPP+, both of which exert neurotoxic effects on dopaminergic neurons — those that are mainly affected in Parkinson’s disease.

They found that treatment with DA-9805 effectively improved animals’ balance (bradykinesia) compared with placebo-treated mice. This positive effect on balance was similar to that observed in mice treated with approved Parkinson’s therapy Azilect (rasagiline).

Evaluation of dopamine levels in the striatum — the brain area most affected by the disease — showed that DA-9805, similar to Azilect, could also prevent dopamine reduction in the brain associated with Parkinson’s disease in these mice.

Importantly, although both compounds protected striatum dopaminergic neurons from death upon exposure to MPTP, DA-9805 showed a greater neuroprotective effect than Azilect.

These findings “suggest that DA-9805 has neuroprotective effects” in mice with Parkinson’s disease, according to the researchers.

Additional experiments revealed that DA-9805’s therapeutic effects were mediated by enhanced protection of mitochondria and their function, while reducing the levels of damaging oxidative molecules, also known as reactive oxygen species (ROS).

Oxidative stress is an imbalance between the production of free radicals and the ability of cells to detoxify them. These free radicals, or ROS, are harmful to the cells and are associated with a number of diseases, including Parkinson’s.

“Given that mitochondria are involved in the pathogenesis of neurodegenerative diseases, we propose that DA-9805 may be a suitable candidate for disease-modifying therapeutics against Parkinson’s disease,” the researchers wrote.

DA-9805 is now being evaluated in a Phase 2a trial in patients with early Parkinson’s disease at the HealthPartners Institute in Minnesota.

Currently recruiting participants, the randomized, double-blind study is expected to enroll about 60 patients between the ages of 30 and 79 who have had mild to moderate Parkinson’s for two years or less.

Participants will be randomly assigned to receive a daily 45 or 90 mg dose of DA-9805, or a placebo for 12 weeks. Researchers will evaluate the safety and tolerability of the treatment, as well as its ability to improve patients’ motor function.

The study is expected to be completed by March 2019.

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Trial to Test New Imaging Agent for Visualizing Synapses in Living Brain

Imaging agent for synapses

Rodin Therapeutics will evaluate a new imaging agent that allows the visualization of human synapses — the junctions between two nerve cells that allow them to communicate — in the living brain.

Results from the study will guide the company’s upcoming Phase 1b trial of a new therapeutic compound designed to strengthen and increase the number of synapses in patients with neurologic diseases, including Parkinson’s.

Several neurological and psychiatric diseases are characterized by defective synapses. However, there is currently no way to visualize synapses in the living brain. Tissues would need to be sampled, an invasive and unwanted procedure.

The new imaging agent, a radiotracer called [11C]UCB-J, targets the synaptic vesicle glycoprotein 2A (SV2A) and is used in positron emission tomography (PET). This protein regulates the release of neurotransmitters — chemical messengers used by the nervous system to transmit messages between neurons, or from neurons to muscles — at the synapse.

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

The trial, which will include both healthy volunteers and patients with Alzheimer’s disease, will produce brain scans following administration of the radiotracer. Participants will undergo scans at the beginning of the trial (baseline) and 28 days later.

The trial will determine the radiotracer’s robustness and potential usefulness in future trials.

“Most neurodegenerative disorders, including Alzheimer’s disease and Parkinson’s, are associated with deteriorating synapses — but until now, physicians and researchers have not been able to measure synaptic density in a living patient. This PET scan should allow us to visualize brain synaptic density in patients and possibly track their response to therapies over time,” J. Michael Ryan, MD, Rodin’s chief medical officer, said in a press release.

“Measuring synaptic density in a living human being holds tremendous potential for the diagnosis and treatment of a variety of neurologic diseases. We’re excited to be one of the first research centers to utilize this new imaging technology,” said Peter Paul De Deyn, MD, Ph.D., director of the Alzheimer’s Research Center Groningen, the Netherlands, one of the centers where the trial will take place.

“This tool has the potential to shape future clinical trials by offering an early signal about whether an investigational drug is driving molecular and structural changes in the brain,” said Philip Scheltens, MD, Ph.D., who directs the Alzheimer’s Center at VUmc, Amsterdam, another trial center. “We can then take the next step and assess whether those changes lead to functional and cognitive improvements in patients with neurodegenerative diseases.”

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Aptinyx’s Investigational Parkinson’s Therapy NYX-458 Enters Phase 1 Clinical Testing

NYX-458 Parkinson's therapy

Aptinyx has launched a Phase 1 clinical trial of NYX-458, a potential treatment for cognitive impairment in Parkinson’s disease patients.

The randomized, double-blind, placebo-controlled trial will be conducted in roughly 62 healthy volunteers to evaluate the safety, tolerability, and pharmacokinetics of the compound. Pharmacokinetics refers to a drug’s absorption, bioavailability, distribution, metabolism, and excretion in the body.

Patients will receive both single and repeat dosing of NYX-458 at multiple dose levels to determine the optimal dosage for future Phase 2 studies. The company is planning studies to test the effectiveness of the investigational therapy next year.

“Based on the compelling preclinical evidence of NYX-458 in reversing cognitive impairment, we are excited to initiate this first-in-human study and advance NYX-458 as a potential treatment for this very common and highly limiting, but poorly treated, symptom of Parkinson’s disease,” Torsten Madsen, MD, PhD, chief medical officer of Aptinyx, said in a press release.

NYX-458 is a small molecule therapy that functions by regulating the activity of N-methyl-D-aspartate (NMDA) receptors, which are found in nerve cells, enhancing synaptic plasticity and improving nerve cell communication. Synapses are the junctions between two nerve cells that allow them to communicate; synaptic plasticity refers to the ability of synapses to strengthen or weaken over time.

Synaptic plasticity contributes to learning, memory, and cognition, all of which are often impaired in Parkinson’s patients.

Earlier this year, Aptinyx presented positive preclinical data of NYX-458 during the 2018 Advances in Alzheimer’s and Parkinson’s Therapies Focus Meeting in Torino, Italy.

The study, which was conducted in a non-human primate model of Parkinson’s disease, showed that NYX-458 significantly increased attention, improved cognitive flexibility, and enhanced working memory as quickly as two hours after the administration of a single oral dose. Those effects were maintained for up to three weeks. No major safety or tolerability issues were observed.

“… NYX-458 has the potential to be a meaningful therapy for patients suffering from some of the most devastating symptoms of Parkinson’s disease,” Cassia Cearley, PhD, vice president of research at Aptinyx, said in a press release at the time. “These results in a relevant and highly translatable model warrant the advancement of NYX-458 into clinical studies.”

So far, Aptinyx’s chemistry and discovery platform has generated three therapeutic candidates, NYX-2925, NYX-783, and NYX-458, currently in clinical development for the treatment of various nervous system disorders. This platform is unique in that it discovers compounds that work to regulate — rather than block or over-activate — NMDA receptors to enhance synaptic plasticity, which is the foundation of nerve cell communication.

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Source: Parkinson's News Today

Feedback from Parkinson’s Patients Can Help Improve Trial Recruitment, Retention, Study Says

clinical trial feedback

Getting the perspective of Parkinson’s disease patients on their motivations and experiences participating in clinical trials can help increase recruitment and retention of future studies, a report suggests.

Although preventable, one of the most common reasons Phase 2 or 3 trials fail is because not enough patients participate. This could be due to inadequate recruitment or because patients drop out during the trial.

The report, “Recruitment and Retention in Clinical Trials of Deep Brain Stimulation in Early-Stage Parkinson’s Disease: Past Experiences and Future Considerations,” published in the Journal of Parkinson’s Diseaseevaluated patient responses after a pilot study on the safety and tolerability of subthalamic (STN) deep brain stimulation (DBS) for the treatment of early-stage Parkinson’s disease.

DBS is commonly used to treat patients with advanced Parkinson’s who no longer respond to available medications and are unable to adequately manage their symptoms.

The U.S. Food and Drug Administration also recently expanded the use of DBS — which requires surgery to implant a device to stimulate targeted regions of the brain — to patients with mid-stage disease who also respond poorly to standard medications.

Vanderbilt University in Nashville, Tennessee, completed a clinical trial (NCT00282152) that included 30 patients, ages 50 to 75, with early-stage Parkinson’s disease. The participants were randomized to receive either optimal drug therapy (ODT) or ODT plus STN-DBS and followed for two years.

At the end of this pilot study, participants were asked to complete a survey regarding their experiences participating in the trial. Their responses were compared with those from an independent survey that used Fox Insight, an online clinical study platform established by The Michael J. Fox Foundation for Parkinson’s Research, to survey early-stage Parkinson’s patients who were considering possibly participating in a trial for DBS.

The pilot trial was specifically designed to collect preliminary safety and tolerability data necessary to conduct an FDA-approved Phase 3 trial (IDE#G050016) to investigate the hypothesis that DBS in patients with early Parkinson’s can slow disease progression.

Importantly, patient experiences were expected to inform the feasibility of scaling up recruitment for the future trial.

Results revealed that the primary motivation for participating in a clinical trial was the desire to advance medical research, cited by 85% of trial respondents. This was followed by a desire for the best medical treatment, for 70%, and for 59%, a desire to learn more about Parkinson’s disease. Similarly, altruistic motivations were also seen in the Fox Insight survey.

The most frequently listed fear that could impact trial participation was surgery-related concerns, in 44% of participants. Although 37% of the pilot study participants did not report any burdens, the most common burdens associated with clinical trials were financial commitments such as time off work and traveling costs (30%), as well as some of the therapeutic interventions such as neuropsychological testing (26%), and the weeklong therapeutic washout periods — without medication (26%).

The pilot study implemented a rigorous informed consent progress aimed at educating potential participants on their role in the study. Most participants responded positively to this approach. Providing sufficient education at the start of the trial may decrease the drop-out rate. In fact, only 3% of participants did not complete the study. As a result, this approach of informed consent will be used in the upcoming Phase 3 trial, according to the authors.

Getting patient perspectives is a new strategy that could improve clinical trial recruitment and retention. Whereas most clinical trials were solely designed by physicians, now, as the authors suggest, by asking patients about their experiences and including their feedback in trial development, “the focus shifts away from the physician and toward the patient.”

“By understanding the motivations and barriers to trial participation of past and potential subjects, we attempt to predict feasibility of recruitment in the future pivotal trial,” the authors wrote. “The fundamental similarities of these two cohorts of patients with early-stage [Parkinson’s disease] suggest that the planned multicenter, pivotal trial will experience similarly successful recruitment and retention as the single-center pilot trial.”

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Source: Parkinson's News Today

Identifying Biomarkers of Inflammation Among Goals of Parkinson’s Study by Longevity Biotech and Veterans’ Center

Longevity Biotech study

Longevity Biotech announced plans for a clinical study aiming to identify potential blood-based markers of inflammation that originates in the immune system, biomarkers that may work to better diagnose Parkinson’s and recognize the disease’s different stages.

The study, being run with the support of The Michael J. Fox Foundation for Parkinson’s Research, will also advance early evaluations of the company’s therapeutic candidate LBT-3627.

The two-year study will launch at the Corporal Michael J. Crescenz Veterans Affairs Medical Center,  part of the Philadelphia Parkinson’s Disease Research, Education and Clinical Centers.

The immune system plays a critical role in neurodegenerative diseases, including Parkinson’s. The study will use machine learning techniques to identify immune-based inflammatory biomarkers “that could provide clinically relevant diagnostic information,” Scott Shandler, PhD, co-founder and CEO of Longevity Biotech, said in a press release.

“The identification of these [immune-based inflammatory] markers would have a tremendous impact on the pace of disease modifying therapeutic development for Parkinson’s disease patients by providing a new metric to track disease progression while possibly identifying new disease targets as well,” he added.

Study researchers will be looking not only to expand knowledge into the underlying mechanisms of Parkinson’s, but also to correlate new and existing blood-based markers, such as the protein alpha-synuclein, with standard clinical scores from the Unified Parkinson’s Disease Rating Scale (UPDRS). This scale uses questions to assess both motor and non-motor symptoms associated with Parkinson’s.

In a preclinical setting — ex vivo, meaning outside a living organism — researchers will also examine the potential efficacy of LBT-3627 using human immune cells. The investigative compound is a small protein designed to mimic naturally occurring molecules that activate a family of receptors known for their neuroprotective and anti-inflammatory activities. As such, LBT-3627 is expected to work to balance immune responses and reduce inflammatory damage done to the brain by immune cells.

Previous studies in mice disease models found evidence that LBT-3627 can protect dopaminergic neurons from degeneration, one of the hallmarks of Parkinson’s disease.

“The goal is to convert T cells, which are key actors in the adaptive immune system, from an inflamed, neurodegenerative state to a more healthy, neuroprotective one,” said Jenell Smith, PhD, a lead scientist at Longevity Biotech.

“LBT-3627 has demonstrated robust neuroprotective results in animal models of Parkinson’s disease to date and we will continue testing the effects of LBT-3627 on human immune cells as part of this study,” Smith concluded.

The release did not specify if this study is already underway.

The post Identifying Biomarkers of Inflammation Among Goals of Parkinson’s Study by Longevity Biotech and Veterans’ Center appeared first on Parkinson’s News Today.

Source: Parkinson's News Today