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Requip Skin Patch Better Than Placebo at Improving Motor Function in Patients with Advanced Parkinson’s

Requip skin patch

When used in combination with levodopa, Requip (ropinirole) patches result in greater improvements in motor function compared to placebo for patients with advanced Parkinson’s disease, a Phase 3 clinical trial has found.

Trial findings also demonstrated the effectiveness of the new skin patch formulation was not inferior to Requip’s oral extended-release tablet formulation, suggesting the Requip skin patch may be a viable alternative option for patients.

Findings were reported in the study, “Ropinirole Patch Versus Placebo, Ropinirole Extended-Release Tablet in Advanced Parkinson’s Disease,” published in the journal Movement Disorders.

Parkinson’s disease is a neurodegenerative disorder characterized by the gradual loss of dopamine-producing neurons in the substantia nigra — a region of the brain responsible for movement control — leading up to a series of motor impairments.

Levodopa, a chemical that can be converted to dopamine in the brain,  currently is the main form of treatment used to ease the motor symptoms of Parkinson’s.

However, its long-term use can have multiple side effects, including a “wearing-off” effect (off periods), in which the medication ceases to be effective at preventing symptoms, and levodopa-induced dyskinesia (LID), a condition in which patients start having involuntary muscle movements.

Requip, marketed by GlaxoSmithKline (GSK), is a dopamine agonist — a substance that has similar properties to dopamine and can mimic some of its effects in the brain — that also has been approved to treat Parkinson’s motor symptoms.

The medication often is prescribed alongside levodopa to extend its effect and reduce the duration of off periods, and is currently available in the form of immediate and extended-release tablets.

“In addition to immediate- and extended-release tablets, a once-daily patch containing ropinirole hydrochloride was recently developed in Japan as a new transdermal formulation,” researchers wrote.

According to the researchers, the new transdermal formulation — in which the medication is slowly absorbed through the skin — being developed by Hisamitsu Pharmaceutical has the potential to improve treatment adherence, since it could provide patients who have problems swallowing and eating with a safer and easier-to-administer option.

Hisamitsu Pharmaceutical researchers conducted a Phase 3 trial (JPRN-JapicCTI-152870) to investigate if the the new skin patch formulation of Requip was as effective and safe as its original extended-release tablet formulation, and if it maintained its superiority over a placebo at reducing motor symptoms of Parkinson’s.

A total of 587 patients with advanced Parkinson’s were assigned randomly to be treated with either the Requip patch (up to 64 mg), the Requip oral extended-release tablet (up to 16 mg), or a placebo, all given once a day alongside levodopa.

The study’s main goal was to assess changes in patients’ motor function, based on the Unified Parkinson’s Disease Rating Scale (UPDRS) Part III scores, from the beginning of the study (baseline) to week 16.

From the 587 patients randomized, 159 were excluded for not complying with the study’s randomization protocol, yielding a total of 428 participants who were included in the final analyses.

Findings revealed that patients receiving the skin patch had a mean reduction (lessening of motor symptoms) of 9.8 points in their UPDRS Part III total score, while those receiving the placebo experienced only a mean reduction of 4.3 points.

“The difference between the ropinirole patch and placebo groups was –5.4, demonstrating superiority of the patch over placebo,” the researchers wrote.

The difference in UPDRS Part III total scores between patients receiving the skin patch or the extended-release tablet was only 0.3 points, suggesting the new transdermal formulation was not inferior to Requip’s currently approved oral extended-release formulation.

Safety assessments revealed that most side effects observed in patients from all treatment groups were only mild or moderate in severity. No serious safety concerns were identified.

“The present study demonstrated the superiority of ropinirole patch over placebo with regard to the decrease of the UPDRS Part III total score, as well as non inferiority of the patch to ropinirole tablets that are currently marketed world-wide,” the researchers wrote.

The team also emphasized the new skin patch may give patients the option to “choose a favorable formulation to meet [their] own unmet medical needs, which is expected to contribute to the improved adherence.”

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New Therapy Using Patients’ Own Cells May Halt Parkinson’s Progression, Case Study Suggests

transplanting cells

A new therapeutic approach in which patient-derived dopamine-producing neurons are transplanted into the brain may halt Parkinson’s disease progression, a case report suggests.

The approach uses patient-derived induced pluripotent stem cells (iPSCs),  which are cells collected from the skin or blood that researchers can reprogram in a lab dish to revert them back to a stem cell-like state that has the capacity to then differentiate into almost any cell type.

“Because the cells come from the patient, they are readily available and can be reprogrammed in such a way that they are not rejected on implantation. This represents a milestone in ‘personalized medicine’ for Parkinson’s,” Kwang-Soo Kim, PhD, said in a news story. Kim is co-senior author of the study and director of the Molecular Neurobiology Laboratory at McLean Hospital in Massachusetts.

Two-year data following the first of two interventions suggest the therapy resulted in at least a stabilization of the patient’s motor function and an improved quality of life. However, clinical studies with longer follow-up periods are needed to confirm the therapeutic potential of this approach in Parkinson’s patients, the researchers noted.

The case study, “Personalized iPSC-Derived Dopamine Progenitor Cells for Parkinson’s Disease,” was published in the New England Journal of Medicine.

Parkinson’s is characterized by the gradual loss of dopamine-producing (dopaminergic) neurons in the substantia nigra, a region of the brain responsible for movement control. The death of dopaminergic neuron results in lower dopamine levels, affecting the regulation of muscle movement and coordination.

While the potential use of tissue transplants to replace the lost dopaminergic neurons in Parkinson’s patients has been studied since the 1980s, the creation of iPSCs offered the hope to transplant precursors of dopaminergic neurons into a patient’s brain.

In 2018, a team of researchers in Japan reported the implantation of precursors of dopaminergic neurons into the brain of a Parkinson’s patient. Six other patients were expected to receive this experimental therapy that used iPSCs developed from skin cells of an anonymous donor. Researchers plan to collect all safety and effectiveness data by the end of this year.

When implanting cells derived from other individuals, patients need to receive immunosuppressive therapies (for an undetermined period of time) to prevent the development of immune responses against the implanted cells. However, the use of a patient’s own cells would make the need for immunosuppression unnecessary.

Now, a team of researchers at the McLean Hospital and Massachusetts General Hospital (MGH) reported the case of a 69-year-old man treated with a similar approach using the patient’s own iPSCs.

The man had a 10-year history of progressive Parkinson’s disease with no signs of dyskinesia (abnormal involuntary movements that characterize advanced Parkinson’s). He was treated with extended release carbidopalevodopa tablets, Neupro patches (by UCB), and Azilect (by Teva Pharmaceuticals).

He reported poor control of his symptoms, with three hours of “off”-periods — when the medications’ effects wear off and symptoms worsen before a new dose can be taken. Higher levodopa doses caused him lightheadedness associated with a drop in blood pressure when changing to a standing position (orthostatic hypotension).

The researchers used the man’s skin cells to create iPSCs and develop them into precursors of dopaminergic neurons, which were tested extensively, including a mouse model used in human-derived transplant studies.

Using these data, Kim applied to the U.S. Food and Drug Administration (FDA) for a single-patient, investigational new drug application and also received approval from the hospital board to implant the cells into the patient’s brain.

The man underwent two surgeries, in 2017 and 2018 (separated by six months) at the Weill Cornell Medical Center in New York, and at MGH.

At each surgery, four million cells were delivered into the putamen, a large brain structure involved in movement control that is filled with dopamine receptors and receives signals from the substantia nigra. The first intervention targeted the putamen on the left hemisphere of the brain, while the second targeted the one on the right hemisphere.

The cells were delivered using a new minimally invasive neurosurgical implantation procedure developed by Jeffrey Schweitzer, MD, PhD, the study’s lead author, a Parkinson’s specialized neurosurgeon, in collaboration with other neurosurgeons at MGH and Weill Cornell. Schweitzer is director of the Neurosurgical Neurodegenerative Cell Therapy program at MGH.

The patient’s motor function was assessed through the Movement Disorder Society-Unified Parkinson’s Disease Rating Scale (MDS-UPDRS) Part III and quality of life with the 39-item Parkinson’s Questionnaire.

Two years after the first intervention, imaging tests showed that the transplanted cells were alive and working correctly as dopaminergic neurons, highlighting the technical success of this personalized cell-replacement approach.

There were no reports of side effects or immune reactions against the cells (without the need for immunosuppressive therapy), or signs that the cells caused any unwanted growth or tumors.

Notably, there was at least a stabilization in the man’s motor function, with MDS-UPDRS scores varying over time, but never reaching the initial values, and he reported improvements in his day-to-day activities and quality of life.

The man reported less than one hour of “off” period per day and the levodopa equivalent daily dose was lowered by 6%, “a reduction of uncertain clinical importance,” the researchers wrote.

“This strategy highlights the emerging power of using one’s own cells to try and reverse a condition — Parkinson’s disease — that has been very challenging to treat. I am very pleased by the extensive collaboration across multiple institutions, scientists, physicians, and surgeons that came together to make this a possibility,” said Bob Carter, MD, PhD, another co-senior author of the study and MGH’s chief of Neurosurgery.

Despite these apparently positive results, the researchers emphasized this is just a first step in this therapy’s development.

“These results reflect the experience of one individual patient and a formal clinical trial will be required to determine if the therapy is effective,” said Schweitzer.

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Study Suggests Mechanism Behind Levodopa-induced Dyskinesia in Parkinson’s

dyskinesia

The protein RasGRP1 is a key culprit for involuntary movements that arise from dopamine replacement therapies used to treat Parkinson’s disease, a new study done in animals suggests.

Targeting this protein may be a therapeutic strategy to prevent these motor problems, while still receiving the benefits of treatment.

The study, “RasGRP1 is a causal factor in the development of l-DOPA–induced dyskinesia in Parkinson’s disease,” was published in Science Advances.

Parkinson’s disease is caused by the death of nerve cells in the brain that make the neurotransmitter dopamine. Therapies designed to increase the amount of dopamine in the brain, including levodopa (l-DOPA) and its derivatives, are staples of Parkinson’s treatment.

Although the effectiveness of these treatments is well-established, long-term use is associated with the development of involuntary movements called dyskinesia. However, exactly which molecular mechanisms are responsible for this side effect is not clear.

Previous research implicated a protein called Rhes in the development of  dyskinesia. In the new study, researchers examined the role of a related protein, RasGRP1 (Ras-guanine nucleotide-releasing factor 1). This protein is known to activate Rhes, and it has been shown to be active in certain blood cells. But its role in the brain is less clear.

Researchers first used a mouse model of Parkinson’s in which dopamine-producing neurons are killed by means of a specific toxin (6-hydroxydopamine). The researchers modeled Parkinson’s both in wild-type mice and in mice that had been genetically engineered to lack RasGRP1.

Both types of mice displayed similar Parkinson’s-like symptoms, and l-DOPA treatment resulted in similar improvement in these symptoms in both types. However, mice lacking RasGRP1 displayed significantly fewer abnormal involuntary movements with long-term l-DOPA treatment.

Additionally, in wild-type mice, l-DOPA treatment induced significantly higher levels of RasGRP1 in the mice’s brains. This finding also was replicated in a macaque (a type of monkey) model of Parkinson’s disease.

“Since monkey model for PD [Parkinson’s disease] can mimic more signs and symptoms of human PD, our finding strengthens the translational relevance of RasGRP1 in PD treatment,” the researchers wrote.

Additional biochemical studies indicated that RasGRP1 is involved in dyskinesia through the activation of the proteins mTOR and ERK (as well as other associated proteins).

These proteins have been implicated previously in l-DOPA-induced dyskinesia (LID). However, they play many important roles in different types of cells throughout the body, so it’s difficult to therapeutically target them without significant side effects. In contrast, the lack of functional RasGRP1 in mice did not result in noteworthy physiological problems, apart from some mild deficits related to the development of cells in the thymus, an organ that’s part of the immune system.

Because of this, “… we think that blocking RasGRP1 with drugs, or even with gene therapy, may have very little or no major side effects,” study co-author Srinivasa Subramaniam, PhD, a professor at Scripps Research, said in a press release.

Since mice and humans are biologically distinct in many important respects, further research will be needed to determine the safety profile of treatments intended to block RasGRP1. Nonetheless, this study provides a theoretical foundation for the possible utility of such treatment strategies.

“There is an immediate need for new therapeutic targets to stop LID,” Subramaniam said. “The treatments now available work poorly and have many additional unwanted side effects. We believe this represents an important step toward better options for people with Parkinson’s.”

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Spinal Cord Stimulation Fails to Improve Mobility in Advanced Parkinson’s Patients

spinal cord stimulation trial

Despite being safe, spinal cord stimulation does not lead to significant improvements in mobility in patients with advanced Parkinson’s disease, including those taking levodopa, a prospective trial has found.

The trial findings were reported in the study, “Spinal Cord Stimulation for Very Advanced Parkinson’s Disease: A 1-Year Prospective Trial,” published in the journal Movement Disorders.

Like deep brain stimulation (DBS), spinal cord stimulation (SCS) is a form of treatment that involves implanting a small device that sends electrical signals. In the case of SCS, these electrical signals go through nerves in a patient’s spinal cord, masking pain signals before they reach the brain. This form of therapy is approved in the U.S. for treating chronic pain.

Lately there has been increasing interest in SCS as a form of treatment for Parkinson’s, based on data from studies reporting that patients who underwent SCS experienced improvements in their gait and motor function.

To explore the therapeutic potential of SCS at alleviating Parkinson’s motor symptoms, researchers at the University of Toronto in Canada conducted a prospective, open-label trial in which they assessed the safety and effectiveness of the therapy in six pain-free patients with advanced disease.

Trial participants — three men and three women, ages 31–76, who had Parkinson’s for 12–18 years — underwent surgery to have two cylindrical electrodes implanted. After surgery, all patients were followed for a period of one year.

The Unified Parkinson’s Disease Rating Scale (UPDRS) and the freezing of gait (FOG) questionnaire were used to evaluate patients’ motor function and gait impairments, respectively. Assessment evaluations were performed in all patients before, one, three, six, and 12 months after surgery.

Apart from one patient who had a temporary delirium episode after surgery, none of the study participants experienced any adverse side effects.

However, SCS had no significant effects on patient’s motor function, balance, or gait, at any time-point. Additionally, investigators found no evidence suggesting that SCS could work together with levodopa at alleviating motor symptoms of the disease.

“Despite the (…) promising outcomes reported in short, small, and open-label PD [Parkinson’s disease] studies, our study confirms safety but shows no clinically meaningful effect on patientsmobility, particularly while on L-dopa, thus failing to improve the motor signs resistant to dopaminergic treatment,” the researchers wrote.

“[W]e need further studies, enrolling larger samples and using a double-blind design, which will be possible thanks to more recent SCS modalities (e.g., burst stimulation), [to assess the therapeutic potential of SCS for Parkinson’s disease],” they added.

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Foliglurax Fails to Minimize Long-term Use Side Effects of Levodopa, Phase 2 Trial Shows

foliglurax study

Despite being safe and well-tolerated, foliglurax (PTX002331), an investigational therapy for Parkinson’s disease, failed to significantly reduce some of the effects associated with long-term use of levodopa, including its “wearing-off” effect and motor complications, according to data from a Phase 2 clinical trial.

As a result, Lundbeck, the company that currently holds the therapy’s development and commercial rights, has decided to terminate its development program and to write-down foliglurax’s current value of €100 million (about $108 million).

“We are disappointed that foliglurax did not demonstrate sufficient efficacy for patients living with Parkinson’s disease. We have made the difficult decision to discontinue the development of the foliglurax program to focus our resources on more promising programmes,” Johan Luthman, executive vice president and head of research and development at Lundbeck, said in a press release.

Levodopa, a dopamine replacement therapy, is the mainstay of treatment used to ease the symptoms of Parkinson’s. However, its long-term use can have multiple side effects, including a “wearing-off” effect (off periods), in which the medication ceases to be effective at preventing symptoms, and levodopa-induced dyskinesia (LID), a condition in which patients start having involuntary muscle movements.

Foliglurax, originally developed by Prexton Therapeutics and then acquired by Lundbeck, is an experimental treatment for Parkinson’s that is intended to lessen  the symptoms of the disease using an alternative strategy that does not involve the brain’s dopaminergic system targeted by levodopa.

Instead, foliglurax activates metabotropic glutamate receptor 4 (mGluR4), a type of brain receptor that is thought to be a promising therapeutic candidate to alleviate both motor and non-motor symptoms of Parkinson’s.

The recently-completed, proof-of-concept, Phase 2 trial (NCT03162874), called AMBLED, investigated the safety, tolerability, and effectiveness of foliglurax when used as an add-on therapy to levodopa at reducing LID and off periods in 157 patients with Parkinson’s who had been treated with levodopa for at least three years.

During AMBLED, participants were assigned randomly to receive either foliglurax, at a dose of 10 or 30 mg, or a placebo, both administered orally, twice daily, for a period of 28 days. Then came a follow-up period of 14 days.

The main goal of the study was to assess changes in the daily awake off time, based on patients’ diary entries, from the beginning of the trial (baseline) to the end of the 28-day treatment period. Secondary goals included assessing changes in LID, which was evaluated based on the Unified Dyskinesia Rating Scale (UDysRS) score, within the same time-frame.

Findings from the trial now announced by Lundbeck showed both doses of foliglurax failed to meet the study goals of demonstrating a significant positive effect at reducing levodopa’s “wearing-off” effect and LID compared to a placebo.

Foliglurax had an acceptable safety and tolerability profile, which was consistent with data from a previous Phase 1 trial (NCT02639221) assessing the safety, tolerability, and pharmacokinetic properties of the medication in a group of healthy volunteers. (Pharmacokinetics is the study of how a medicine is absorbed, distributed, metabolized, and eliminated from the body.)

The company is still conducting additional analyses to understand the full extent of these findings. Data from AMBLED will be published in a medical journal in the coming months.

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Stalevo May Be More Effective Than Other Medications for Early Parkinson’s, Meta-analysis Shows

Stalevo for Parkinson's

Stalevo (levodopa, carbidopa, and entacapone combination therapy) may be more effective but seems to be associated with more side effects than other medications to treat early Parkinson’s disease, researchers report.

The study, “Levodopa/carbidopa/entacapone for the treatment of early Parkinson’s disease: a meta-analysis,” was published in Neurological Sciences.

Levodopa (L-DOPA) is the mainstay treatment for Parkinson’s. As the disease progresses, patients typically need to gradually increase their dosage. Even after that, symptoms sometimes reappear or worsen (“off” periods) due to the dopaminergic therapy’s gradual loss of efficiency. Administration of levodopa in combination with both carbidopa and entacapone (LCE, sold by Novartis as Stalevo) has been shown to lessen symptoms and the number of “off” periods.

Although a large number of studies have investigated the treatment of Parkinson’s motor and non-motor symptoms, “there are still many controversies about the diagnosis and treatment of early [Parkinson’s disease] patients,” the researchers wrote.

In the study, a team led by researchers at University of Electronic Science and Technology of China studied the available data regarding the efficacy and safety of Stalevo in people with early Parkinson’s disease. These patients were identified as having idiopathic (of unknown cause) Parkinson’s, Hoehn and Yahr scale stage 3 or less (indicative of mild symptoms in one or both sides of the body), no motor complications history, no treatment, or limited use (generally less than six months) of anti-Parkinson’s medications.

The researchers searched the records of four biomedical databases up through October 2018. They looked for randomized clinical trials, written in English, that used Stalevo to treat early Parkinson’s.

The team analyzed six randomized clinical trials, which involved 1,983 participants (mean age of 60 to 70 years), with a mean average disease duration of 5.3 years.

The Stalevo group consisted of 983 participants and the control group had 1,000 participants. One study used levodopa/dopa decarboxylase inhibitor/entacapone and the remaining five adopted a levodopa/carbidopa regimen in the control group.

In all studies, treatment duration ranged from six to 134 weeks (about 2.5 years).

The Unified Parkinson’s Disease Rating Scale (UPDRS) and Parkinson’s Disease Questionnaire (PDQ-39) were used to assess symptom severity and quality of life in four of the analyzed studies. The Clinician Global Impression of Change, which measures the change in a doctor’s global impression relative to the beginning of the study, was used as an outcome measure in two trials.

Stalevo was found to improve patients’ motor and non-motor experiences of daily living as measured by the UPDRS part 1 and 2, respectively.

Nonetheless, investigators did not notice any obvious differences between before and after treatment with Stalevo in the Clinician Global Impression of Change, which, according to the authors, could be explained “by a small amount of included studies.”

Also, when PDQ-39 was used as the outcome measure, Stalevo was found not to be as effective as levodopa-carbidopa alone. One possible reason for this is that using PDQ-39 scores may not be sensitive enough to detect changes in these measures in early Parkinson’s patients.

“LCE therapy also increased the risk of total AEs [adverse events], nausea, diarrhea, dyskinesia, dizziness, urine abnormality, and discontinuation risk when compared with traditional therapy,” the researchers wrote.

Around 80.4% of patients treated with Stalevo experienced side effects, compared with 66.8% of those in the control group. Importantly, patients on Stalevo had nearly three times the risk of developing urine abnormality at some point than controls.

Compared to other Parkinson’s medications, and despite the higher percentage of side effects, Stalevo appears to be more effective in the treatment of early Parkinson’s. Still, the researchers advise that these results should be interpreted carefully as this meta-analysis included only six studies.

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Gene Therapy Seen to Raise Response to Levodopa Given as IV Infusion in Trial

gene therapy trial results

An investigational gene therapy, called VY‐AADC01, boosts motor responses to levodopa that is given intravenously —particularly at a low dose — in people with Parkinson’s disease, a sub-study within a Phase 1b trial shows.

These findings, along with positive data from the main PD-1101 study (NCT01973543), support the potential benefits of this approach and further clinical development of VY‐AADC01.

The study, “Aromatic L‐Amino Acid Decarboxylase Gene Therapy Enhances Levodopa Response in Parkinson’s Disease,” was published in the journal Movement Disorders.

Parkinson’s is characterized by the death of dopamine-producing neurons, resulting in lower dopamine levels and affecting how muscle movement and coordination are regulated.

In addition, as the disease progresses, patients are thought to produce less of L-amino acid decarboxylase (AADC), an enzyme that mediates the conversion of levodopa into dopamine. This loss would make a dose of levodopa, one of the main therapies for Parkinson’s symptoms, less effective.

VY-AADC01, being developed by Neurocrine Biosciences and Voyager Therapeutics, consists of a modified and harmless adeno-associated virus (AAV) that delivers the AADC gene — which contains the instructions to produce the AADC enzyme — directly into the putamen, a large brain structure filled with dopamine receptors and involved in movement control.

By providing AADC to these brain cells, VY-AADC01 is thought to promote levodopa’s conversion into dopamine, increasing its levels directly where it is needed and potentially easing disease symptoms.

The open-label, Phase 1b PD-1101 study evaluated the safety and preliminary effectiveness of a single administration of ascending doses of VY-AADC01 (7.5 × 1011 vector genomes (vg), 1.5 and 4.7 × 1012 vg) in 15 people with moderately advanced Parkinson’s disease and fluctuating responses to levodopa treatment.

VY-AADC01 was administered directly into the striatum (a brain area that includes the putamen) via a surgical procedure through the top of the head, aided by real-time magnetic resonance imaging (MRI).

Participants — 13 men and two women — had a mean age of 57.7 and a Parkinson’s diagnosis for 10 years. During the study, patients continued their antiparkinsonian medications, including levodopa.

Interim results showed that VY-AADC01, given as a single administration, was well-tolerated and resulted in robust and durable dose-dependent improvements in patients’ motor function, quality of life, and a reduction of antiparkinsonian medications — and for up to three years.

Now, researchers evaluated VY‐AADC01 in the context of patients’ motor response to levodopa (administered intravenously, or directly into a vein, rather than orally) within the PD-1101 study, which concluded in January.

A total of 13 patients participated in this sub-study: all 10 from the lower and intermediate dose groups, and three of the five given the higher dose.

Patients’ response to two different doses of levodopa (0.6 mg/mL and 1.2 mg/mL; only the higher dose was expected to almost certainly lead to clinical responses) was assessed before and six months after VY‐AADC01 administration.

Changes in AADC enzymatic activity, motor function — measured by the Unified Parkinson’s Disease Rating Scale Part III — and dyskinesia (abnormal involuntary movements that characterize advanced Parkinson’s) were assessed before and after levodopa was administered.

Patients’ responses to levodopa (in both motor and dyskinesia scores) were seen to be greater when levodopa was given after VY‐AADC01 administration, indicating that VY‐AADC01 boosted levodopa’s responses.

The researchers noted that greater levodopa responses after VY‐AADC01 administration were a result of increases in AADC activity associated with the gene therapy’s use, and not because of an increase in levodopa blood levels (which was not detected after gene therapy administration).

Notably, VY‐AADC01-associated improvements were more pronounced with the lower dose of levodopa. The scientists noted this suggests that clinically relevant dopamine levels may be reached with lower levodopa doses, which is consistent with the previously reported reductions in medication use by these patients.

Furthermore, after receiving VY‐AADC01, patients showed a trend toward better motor function and lesser dyskinesia during an off-period (when patients had been without levodopa and other antiparkinsonian medications overnight).

This observation was consistent with data from previous studies, the researchers said, and may be a result of greater dopamine production from the brain’s own levodopa.

“A lingering question is whether the administration of [into-the-vein] levodopa at a clinical research center translates to the clinical setting with oral levodopa and the use of other antiparkinsonian medications,” the researchers wrote.

They also concluded that this sub-study provides further evidence that this type of gene therapy may be of meaningful therapeutic benefit to Parkinson’s patients, and supports further clinical development of VY‐AADC01.

A Phase 2 trial (NCT03562494), called the RESTORE-1  study, was opened based on PD-1101’s positive results and those of another open-label Phase 1 trial (NCT03065192).

The new trial, which is still recruiting at sites across the U.S., is evaluating the gene therapy’s safety and effectiveness against a placebo in up to 42 people with advanced Parkinson’s, who have failed to respond properly to levodopa treatment.

Main efficacy goals include changes in motor fluctuations in gene therapy patients, against placebo, one year after a single treatment, and changes in AADC enzyme activity.

The AAV vector used in this trial is slightly different (adeno-associated viral vector serotype 2), and as such the therapy has been designated VY‐AADC02.

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NLX-112 Eases L-dopa Dyskinesia in Marmosets With Parkinson’s, Study Says

dyskinesia

An investigational therapy known as NLX-112 (befiradol) may hold promise to treat levodopa-induced dyskinesia, a complication of long-term levodopa therapy that affects people with Parkinson’s disease, a study found.

The study, “The selective 5-HT1A receptor agonist, NLX-112, exerts anti-dyskinetic and anti-parkinsonian-like effects in MPTP-treated marmosets,” was published in Neuropharmacology.

Motor symptoms of Parkinson’s disease include tremor; slow movement (bradykinesia); stiffness (rigidity); uncontrolled, involuntary movements that can affect the arms, legs, head, or the whole body (dyskinesia); and poor balance.

As the disease progresses, patients typically need to gradually increase treatment doses for maximum benefit. Even after that, symptoms sometimes reappear or worsen due to the dopaminergic therapy’s gradual loss of efficiency.

Dyskinesia is one of the complications of long-term levodopa therapy that affects many patients with advanced Parkinson’s disease. Currently, the main medication available to manage dyskinesia is amantadine. However, it can have side effects and may not be effective for every patient.

Studies indicate that Parkinson’s progression and symptoms may be associated with impaired signals from another important brain chemical, serotonin. Serotonin is involved in smooth muscle contraction, and serves as the “feel-good” chemical in the brain, influencing one’s sense of well-being and happiness.

Serotonin-producing neurons have an enzyme that is crucial to producing dopamine. This enzyme can be stored in vesicles and released as a “false neurotransmitter.” This results in excessive and inappropriate dopamine release, which generates dyskinesia.

NLX-112 (also known as befiradol or F13640) is an experimental medicine being developed by Neurolixis that activates a type of serotonin receptor called 5-HT1A. This investigational therapy has been shown to inhibit the “false neurotransmitter” release, thereby minimizing or even abolishing dyskinesia in rodent models of Parkinson’s disease.

In a study funded by Parkinson’s Virtual Biotech, the drug development arm of Parkinson’s UK, researchers tested NLX-112 in a marmoset model of levodopa-induced dyskinesia.

Animals were treated with 1-methyl-4-phenyl1,2,3,6-tetrahydropyridine (MPTP), a neurotoxin that induces the death of dopamine-producing neurons and mimics Parkinson’s symptoms. Dyskinesia was then induced by chronic levodopa/benserazide combination therapy administered up to twice daily for up to a month.

NLX-112 treatment was administered alone or in combination with levodopa twice a week. Scientists also tested levodopa therapy combined with (+)8-OH-DPAT, another compound that activates the serotonin receptor 5-HT1A.

When administered together with levodopa at three different doses (0.025, 0.1 and 0.4 mg/kg ), NLX-112 reduced dyskinesia in a time and dose-dependent manner. The most prominent effects were at a dosage of 0,4 mg/kg.

In addition, NLX-112 was found to marginally interfere with the anti-parkinsonian effects of levodopa, unlike (+)8-OH-DPAT, which lessened levodopa-induced dyskinesia but also eliminated levodopa’s therapeutic efficacy.

When given alone (not combined with dopaminergic therapy), NLX-112 elicited anti-parkinsonian-like activity, easing disease-related motor disability in marmosets modeling Parkinson’s.

“Interestingly, the higher dose of NLX-112 (0.4 mg/kg) appeared less active than the lower doses, only reducing disability at a single, early time-point, suggesting an inverted dose-response relationship,” the researchers wrote.

Both NLX-112 and (+)8-OH-DPAT produced dose-dependent unusual behavior in marmosets, including sedation, scratching, wet-dog shakes, and sustained muscle contractions in the tail. These manifestations are all consistent with serotonin syndrome, a disorder that can occur when taking serotonin-boosting medications, and manifests itself with both behavioral and other general symptoms such as sweating and diarrhea.

Despite its effects, NLX-112 was not kept in animals’ blood circulation for long, which may limit its pharmacological effects in this particular species.

“This promising research on NLX-112 offers hope that we can find a treatment that can tackle dyskinesia, which can make everyday tasks, such as eating, writing, and walking, extremely difficult,” Arthur Roach, PhD, director of research at Parkinson’s UK, said in a press release.

“People with Parkinson’s tell us it is one of the most critical issues that impacts quality of life, so we’re delighted that this project is progressing so positively,” Roach said. “With 145,000 people living with Parkinson’s in the UK, we are desperately in need of a breakthrough treatment, and we’re committed to delivering one by 2024.”

“It is vital we continue to work with biotech companies like Neurolixis to drive forward new treatments that may slow, stop, or reverse Parkinson’s, and also those, like NLX-112, that could bring relief from symptoms or side effects,” said Roach.

“We are excited that NLX-112 has shown such positive results in reducing dyskinesia in marmosets,” said Adrian Newman-Tancredi, PhD, co-founder and CEO of Neurolixis. “If the striking preclinical data are reproduced in clinical trials, NLX-112 could significantly alleviate the troubling dyskinesia that prevent many Parkinson’s patients from performing routine daily tasks, thereby improving their quality of life.”

“We are currently making plans and seeking funding to take NLX-112 into clinical trials, and hope to be able to initiate these before the end of 2020,” Newman-Tancredi said.

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Study Finds Tai Chi Improves Motor Function in Parkinson’s Patients

tai chi, Parkinson's

Tai chi improves motor function in people with mild to moderate Parkinson’s disease and may slow down disease progression, a new study has found.

The study, “Tai Chi versus routine exercise in patients with early- or mild-stage Parkinson’s disease: a retrospective cohort analysis,” was published in the Brazilian Journal of Medical and Biological Research.

Tai chi is a Chinese martial art that involves a series of fluid motions, generally accompanied by deep, meditative breathing. The slow-moving and low-impact practice offers some benefits of exercise, particularly in people who may not be able to engage in more intense physical activity.

Tai chi has been recommended as a supportive therapy for people with Parkinson’s disease. However, there hasn’t been much data to support these recommendations.

In the new study, 500 people with mild-to-moderate Parkinson’s were divided into two groups. The tai chi (TC) group received tai chi lessons, 80 minutes per day, three days per week, for two months. The routine exercise (RE) group received classes in routine exercises (including treadmill training, aerobic training, and dance) for 90 minutes per day, three days per week, for two months.

Prior to enrollment in the study, there were no significant differences between the two groups. The study population was predominantly male.

Before and after the training, the participants’ motor function was evaluated through a number of routine measurements, such as recording the time it took to walk 50 feet. Both groups showed improvement over the two months of the intervention, but across measures, improvements were significantly higher in the TC group. For example, after the intervention, the time to walk 50 feet was, on average, 8.37 seconds in the TC group and 9.71 seconds in the RE group.

Participants in the TC group also reported a significantly reduced number of falls (average of 3.45 vs. 7.45 over the past six months), and many of them discontinued or reduced the use of other therapies, such as levodopa.

When hypothesizing about why tai chi produces such positive outcomes in Parkinson’s patients, the researchers believe that it normalizes the levels of neurotransmitters that are present at lower levels in this patient population — such as dopamine and acetylcholine — in various regions of the brain.

“When tai chi is practiced daily, it promotes the development of various de novo neural pathways in a [Parkinson’s] patient that results in fast response to posture challenges,” the researchers said.

Interviews were conducted with participants after the intervention. In general, participants in both groups were positive: “Participants reported that exercises helped them improve their confidence and balance,” the researchers wrote. Notably, a greater proportion of TC participants said their intervention felt safe and helped with balance.

No adverse events were reported in the study.

“Although the study spanned over a short period of time, its results supported tai chi as an effective therapy for [Parkinson’s] patients,” the researchers wrote. They noted that further studies, evaluating such exercises over a longer period of time, will be necessary to fully understand the impact of the practice on patients.

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Radiotracer May Improve Differential Diagnosis of Parkinson’s

An interdisciplinary team of researchers has developed a substance that may improve the differential diagnosis of Parkinson’s disease based on brain imaging — potentially allowing physicians to distinguish between patients who are sensitive to the side effects of parkinsonian medications and those who are not.

Levodopa is one of the main medications used to alleviate the symptoms of Parkinson’s disease. However, when administered for long periods of time, it causes significant side effects.

A major challenge that doctors face when treating Parkinson’s patients is the lack of a specific test to determine whether a patient is sensitive to the side effects of parkinsonian medications. Instead, doctors must rely on certain symptoms for diagnosis, such as motor dysfunction.

“[W]e don’t yet have a suitable method for differential diagnosis, i.e. to detect at early stage whether a patient is sensitive to the side effects,” chemist Thu Hang Lai, PhD, a researcher on the project, said in a press release.

Lai is part of the research team at the Institute of Radiopharmaceutical Cancer Research, at Helmholtz-Zentrum Dresden-Rossendorf (HZDR) in Germany, that has now developed a method to aid in the differential diagnosis of Parkinson’s — a radiotracer molecule called [18F]FLUDA.

Radiotracers are compounds prepared with radioactive elements that are used for medical applications. These compounds emit radioactivity which allows them to be detected by positron emission tomography (PET) scans.

A PET scan is an imaging technique that uses small amounts of radioactive materials, a special camera, and a computer to help detect emitted radiation and image biological function in vivo.

[18F]FLUDA was specifically designed to attach itself to receptors in the brain called adenosine receptors. Adenosine is a neurotransmitter (chemical molecule) that is used to send signals between nerve cells in the brain and allows them to communicate. When adenosine attaches to an adenosine receptor, the whole nerve cell slows down. Caffeine, for example, has a similar molecular structure to adenosine and as such can bind to its receptors, blocking adenosine from performing its function and producing the stimulating effect of caffeine-containing beverages such as coffee and tea.

When [18F]FLUDA attaches itself to adenosine receptors, it can be detected by PET scans. This means that the areas of the brain that reflect increased radioactivity have a higher density of adenosine receptors and can be monitored.

So far, [18F]FLUDA performed well in pre-clinical experiments. The radiotracer was stable, readily detected in PET scans, did not suffer any degradation on its way to the brain, and did not show significant toxicity when tested in animal models. Radiation protection studies also showed positive results.

“With a suitable radiopharmaceutical for use in humans, we hope to be able to make correct differential diagnoses and thus differentiate between Parkinson’s patients who are sensitive to side effects and those who are not,” said team member Rodrigo Teodoro, PhD.

The team now wants to test its radiotracer in clinical trials. The researchers have already filed for a patent, but the first step in proving the usefulness of [18F]FLUDA will be to demonstrate its safety and effectiveness in healthy volunteers and in Parkinson’s patients. They are currently looking for a clinical partner to aid with these trials.

This discovery has won the team HZDR’s Innovation Contest.

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