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In Search of Acceptance: Starting Small

acceptance

Researchers have said that combining acceptance with meditation works better than meditation alone. That sounds like a fantastic idea. I’ve been having trouble with meditation ever since the ruin of stagnation. Maybe if I search for and discover how to combine acceptance with meditation, it will make a difference in my pursuit of well-being. The research supports this approach.

It’s winter and we are barricaded in our house by 6-foot snowbanks. Getting out to my sanctuary in the garden and the forest is almost impossible. Without a physical sanctuary, it’s difficult for my mind to find peace. But I’m going to give this “acceptance” idea serious consideration.

Family members have said to me, “You’re disabled. Accept it and get on with your life.” It can’t be that hard. I just need to say to myself, “Accept your chronic disease, and accept your vision loss.” With a pint of ice cream in hand, I repeat this acceptance mantra. Half an hour later, with the ice cream gone, I feel nothing from the mantra. But there is a touch of pleasure from the ice cream devoured.

It doesn’t seem right to tell myself that I accept everything about my chronic disease and vision loss. Repeating the “mantra” turned me into a zombie. It’s an outright lie. I don’t accept everything as it currently stands, because I believe that the pursuit of wellness contains vast undiscovered territory. My wellness map is only the beginning of the journey. For me to accept everything about my condition feels like resignation, as if I’m giving up and allowing life with Parkinson’s to take over. There must be a better way for me to embrace acceptance.

Pacing the floor and fidgeting with my tablet and video game, I try something different. “I accept that I am responsible for managing how the disease affects my behaviors and how those behaviors affect my quality of life.” This is my new mantra. I repeat these words as often as possible between smashing monsters on my video game. After an hour of mantra repetition, I find no new levels of peace. But I go up a couple of levels in my game, leaving me with a touch of happiness.

Acceptance has this utopian vision connected to its construct. If I can drink successfully from the cup of acceptance, the elixir will help to heal my troubled being. But I don’t even have my hands on the cup — half empty or half full! I put the video game down and pace the floor, wringing my hands, mumbling. With a drink in one hand, I reach for a bowl of chips and miss. Crash! Bowl and chips scatter on the floor.

My partner comes into the room with a worried look. “It’s OK. I can clean that up for you.” I say I’ll get it. I turn without thinking, relying on my body to remember how to move, and reach too quickly for a broom. My body doesn’t engage as fast as my mind and I stumble. She smiles and says calmly, “You seem a little out of sorts. What’s going on?”

I look away from her and my head hangs low. “I’ve been struggling with this idea of acceptance. I just can’t accept everything.”

She comes over and gives me a light hug. “You do tend to overthink things. Just start small. Start with something easy, like accepting mumbles, fumbles, and stumbles. You can say, ‘I accept these things will happen in my life. I will do what I can to decrease their impact. Ultimately, I must accept that these things are happening and will continue to happen.’”

I collapse in my chair almost dumbfounded. “You’re amazing. Acceptance doesn’t have to be this wave that washes everything clean. It’s not about perfection. It’s about baby steps. It’s a calm, meditative acceptance of those small steps: mumbles, fumbles, and stumbles.”

I sink back into my chair and repeat my new mantra between deep meditative breaths. “I accept mumbles, fumbles, and stumbles. I’m doing all that I can using my wellness map.” Gentle peace is discovered in this special combination of acceptance mantra and meditative breath. The two seem to enhance each other — each one acting as a catalyst to the other. It’s an unusual sensation, a soothing comfort lasting for hours — and something that had been undiscovered before I’d written this column.

This is the path of possibilities that runs through my wellness map and leads me to moments of well-being despite the chronic disease.

***

Note: Parkinson’s News Today is strictly a news and information website about the disease. It does not provide medical advice, diagnosis, or treatment. This content is not intended to be a substitute for professional medical advice, diagnosis, or treatment. Always seek the advice of your physician or another qualified health provider with any questions you may have regarding a medical condition. Never disregard professional medical advice or delay in seeking it because of something you have read on this website. The opinions expressed in this column are not those of Parkinson’s News Today or its parent company, BioNews Services, and are intended to spark discussion about issues pertaining to Parkinson’s disease.

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Case Report Describes Secondary Parkinsonism Due to Cavernoma in the Striatum

secondary parkinsonism

Secondary parkinsonism can be caused by a cavernoma — a cluster of abnormal blood vessels — located in a brain region involved in voluntary movement control, a case report shows.

The case-study, ”Nine-years follow-up of cavernoma located in basal ganglia mimicking Parkinson’s disease,” was published in the journal Clinical Neurology and Neurosurgery.

Most patients (about 80–85%) diagnosed with Parkinson’s disease have what is called primary parkinsonism or idiopathic Parkinson’s disease (meaning the disease has no known cause). This type tends to respond well to therapies that work by increasing or substituting dopamine molecules in the brain.

The remaining types of Parkinson’s are known as secondary parkinsonism. In these cases, the cause of the disease is often known, but patients fail to respond well to dopaminergic medications intended to replace dopamine or prevent its degradation, such as levodopa.

Secondary parkinsonism can be caused by a variety of factors. In rare cases, it is caused by cavernoma, a cluster of abnormal blood vessels in the basal ganglia (a brain region often affected in Parkinson’s). This occurs in only 0.46% of the general older population, and in 0.037% of  older individuals with Parkinson’s symptoms, according to the report.

In this study, researchers cite the case of a 75-year-old woman with secondary parkinsonism due to a cavernoma in the right striatum — a brain region involved in voluntary movement control — and one of the major components of the basal ganglia.

In 2009, the patient was diagnosed with Parkinson’s after clinical examination by a neurologist. Her symptoms included bradykinesia (slowness of movement) and rigidity of her left limbs, cogwheel phenomenon (a type of rigidity common in Parkinson’s) of the right upper-limb that occured upon contralateral (opposite) hand activation, and an unsteady gait.

“The patient referred to a loss of interest in her hobbies in the preceding years and difficulties in initiating speech and movement,” the researchers wrote.

The neurologist, suspecting Parkinson’s disease, recommended brain magnetic resonance imaging (MRI), a Dopamine Transporter Single Photon Emission Computerized Tomography (DaTscan), and an olfactory (smell) test.

DaTscan is a tool used to confirm the diagnosis of Parkinson’s disease. It is a specific type of single-photon emission computed tomography (SPECT) imaging technique that helps visualize dopamine transporter levels in the brain. In Parkinson’s, there is a steady loss of dopamine transporters (DaT) in the brain. These mediate the flow of the neurotransmitter dopamine between nerve cells.

The results revealed severely decreased dopamine transporter uptake in the right striatum. The brain MRI scan showed that the patient had a 2-centimeter cavernoma in the basal ganglia, as well as small vessel disease (microangiopathy), which also was detected in the brain’s white matter.

The olfactory test showed no impairment in her ability to smell or to detect odors (a condition called hyposmia).

As a result, the patient, who never had received medication that could have caused secondary parkinsonism, was given low-dose levodopa.

Over a nine-year period, however, her left kimb parkinsonism did not appear to progress. The patient never experienced rest tremor, motor fluctuations or dyskinesia (involuntary muscle movement) typical of Parkinson’s. Only the patient’s apathy and gait unsteadiness appeared to deteriorate. Furthermore, the patient stated that she did not respond to levodopa treatment, even following a dose increase to 750 mg/day.

As a result, neurologists re-evaluated her diagnosis. They performed the levodopa test and the apomorphin-challenge-test, both used to determine whether motor symptoms such as tremors in the limbs, rigidity in the muscles, and problems with walking, balance and fine motor coordination, are caused by Parkinson’s.

The tests consist of giving levopoda or apomorphine (brand name Apokyn) to understand if these Parkinson’s-specific treatments improve patients’ symptoms. If it does, the patient likely has Parkinson’s.

The results for both tests were negative. Brain MRI showed that the cavernoma had increased slightly in size. Another DaTscan showed that the dopamine transporter uptake had undergone a mild-to-moderate worsening compared to the first assessment.

One week after progressively discontinuing levopoda treatment altogether, the patient showed no worsening of her symptoms.

Based on all these observations, the patient was diagnosed with secondary parkinsonism caused by cavernoma. “We conclude that a cavernoma in the striatum can cause secondary parkinsonism and apathy mimicking PD at the first neurological assessment,” the researchers wrote.

Unlike Parkinson’s, secondary parkinsonism caused by cavernoma can remain unchanged over many years, and lead to the drop of dopamine receptors detected in the DaTscan.

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Gut Bacteria Protects Against Alpha-Synuclein Buildup in Nerve Cells in Worm Model, Study Shows

alpha-synuclein

A common gut bacteria called Bacilus subtilis (B. subtilis), which aids in digestion, shows the potential to counteract the misfolded alpha-synuclein protein central to Parkinson’s disease, according to a new study.

B. subtilis, a so-called “good” bacteria, slowed the buildup of this protein in the nerve cells of worms engineered to produce human alpha-synuclein, and was found to clear some of its harmful clumps.

The study, Probiotic Bacilus subtilis Protects against α-Synuclein Aggregation in C. elegans,”was published in Cell Reports.

In order to function correctly in the body, proteins are folded into specific shapes, like making biological origami cranes. In Parkinson’s, the alpha-synuclein in nerve cells misfolds and then clumps together into structures that are toxic to these neurons.

Several recent studies have drawn links between what happens in the gut and in the brain. That led researchers at the University of Edinburgh and the University of Dundee, both in the U.K., to ask whether changes in the gut could affect alpha-synuclein aggregation, or buildup.

As a proof-of-principle — a study designed to evaluate whether further research should take place — the team fed various over-the-counter probiotics, or so-called “healthy bacteria,” to a roundworm model of synucleinopathy. Synucleinopathy are neurodegenerative diseases such as Parkinson’s that are characterized by the abnormal buildup of alpha-synuclein protein in nerve cells.

The goal was to see which, if any, of the pribiotics could alter the formation of these toxic alpha-synuclein clumps in the roundworm model, known as C. elegans.

Worms raised on a specific strain of B. subtilis, called PXN21, showed a near-total absence of these clumps, compared with worms on other diets. B. subtilis also managed to clear away clumps that had already formed in older worms, which were later switched to the B. subtilis diet. The probiotic’s protective effects lasted over the worms’ lifespan and improved locomotion defects associated with the toxic clumps.

Importantly, the observed anti-aggregation effect was found to be a general property of the B. subtilis species, and not only of the particular strain used.

B. subtilis’s capacity to protect against alpha-synuclein aggregation later in adulthood was partly mediated by the action of the DAF-16 gene, the worm equivalent of the human FOXO1 gene, and also by the bacteria’s capacity to produce a biofilm matrix — a three-dimensional bacterial community embedded in a self-produced matrix.

However, this mechanism was not the same one responsible for the strong protection observed in early adults. The team found that protection was partially mediated by the action of an active and stable bacterial metabolite.

Importantly, in both early and older adults, B. subtilis changed how the worms processed fats called sphingolipids. More specifically, B. subtilis produced chemicals that changed how certain enzymes — ceramide synthase, acid sphingomyelinase and serine palmitoyltransferase — processed sphingolipids.

Previous studies have suggested that sphingolipid metabolism modifies alpha-synuclein pathology, or disease manifestation, in Parkinson’s.

While encouraging, these findings are quite early and must be corroborated in other settings. Mice, a model organism much more closely related to humans than worms, will be a logical next step. If all goes well and a probiotic-based Parkinson’s therapy makes it to clinical trials, these could be fast-tracked, as probiotic B. subtilis is already commercially available.

“The results from this study are exciting as they show a link between bacteria in the gut and the protein at the heart of Parkinson’s, alpha-synuclein,” Beckie Port, research manager at Parkinson’s UK, one of the study’s funders, said in a press release.

“Studies that identify bacteria that are beneficial in Parkinson’s have the potential to not only improve symptoms but could even protect people from developing the condition in the first place,” Port said.

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Cerevel Therapeutics Initiates Phase 3 Program Testing Tavapadon for Improved Motor Function

Tavapadon Phase 3 trials

Cerevel Therapeutics announced its launch of a series of Phase 3 clinical trials to evaluate its investigational therapy tavapadon, designed to improve motor function in people with Parkinson’s disease.

The company will conduct three 27-week trials to evaluate tavapadon’s efficacy, safety, and tolerability in fixed doses — TEMPO-1 (NCT04201093) — and flexible doses — TEMPO-2 (NCT04223193) and TEMPO-3 (not yet assigned an NCT number). Cerevel also will conduct a fourth 58-week, open-label, safety extension trial.

TEMPO-1 and TEMPO-2 are currently recruiting participants at a single site in south Florida. More information on enrollment can be found here and here. TEMPO-3 will begin screening prospective participants later this year.

Tavapadon is a dopamine receptor agonist, meaning that it connects with dopamine receptors on the surface of nerve cells to make them act as though dopamine were present. This is vital in treating Parkinson’s, as the disease’s defining feature is the death of dopamine-producing (dopaminergic) neurons. Dopamine is a neurotransmitter that plays a key role in coordinating movement, which is why its loss results in the motor control problems seen in Parkinson’s.

In its Phase 2 trial (NCT02847650), Tavapadon successfully eased motor symptoms in and was well-tolerated by patients with early stage Parkinson’s. The results showed that the 57 participants, ages 45 to 80, lowered their scores — indicating improvement — on the Movement Disorder Society – Unified Parkinson’s Disease Rating Scale (MDS-UPDRS) Part III for motor function over the course of 15 weeks.

The upcoming Phase 3 trials will further test tavapadon’s ability to improve motor function, evaluating the therapy in more patients and over a longer period of time. Cerevel intends to enroll approximately 1,200 patients, ages 40 to 80, across all three trials.

For the TEMPO-1 and TEMPO-2 studies, Cerevel is seeking participants with early stage Parkinson’s, while people with late-stage disease, who are experiencing motor fluctuations on levodopa treatment, will be recruited for the TEMPO-3 trial. Early-stage patients will receive tavapadon alone, whereas those with late-stage Parkinson’s will be given the therapy alongside levodopa.

TEMPO-1 participants will receive a single daily oral dose of up to 5mg of tavapadon. TEMPO-2 and TEMPO-3 participants will receive between 5 mg and 15 mg on a flexible dosing schedule.

All three trials will be placebo-controlled. The primary goal of TEMPO-1 and TEMPO-2 is changes in motor function as assessed by MDS-UPDRS parts II and III. Secondary goals include safety, improvement in non-motor aspects of daily living, reduction in disease severity, lessening of daytime sleepiness, and improvements in participant-reported outcomes as measured by the Patient Global Impression of Change (PGIC) score.

The company expects to begin reporting data from the studies in the second half of 2022.

“We believe tavapadon has the potential to improve outcomes for patients with both early-stage and late-stage Parkinson’s. It is our expectation that the innovative design of each of these Phase 3 trials will allow us to demonstrate tavapadon’s ability to improve patients’ motor symptoms and functioning,” Raymond Sanchez, MD, chief medical officer of Cerevel Therapeutics, said in a press release.

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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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Living with Dignity and Parkinson’s Disease

dignity

Respect for oneself can often be hard to come by. We can see our mistakes and failures. We recognize the missed opportunities to become who we wanted to be, and the times we fell short of our goals. Couple the inadequacies we carry with us alongside having a chronic illness such as Parkinson’s disease, and we can begin to lose our dignity within the disability. 

Brokenness

We can feel like broken crayons or an irreplaceable piece of china that lies shattered in a pile on the floor.

The awkwardness in our walk can cause us to be self-conscious. The stuttering in our talk leaves us embarrassed and carrying around a sense of misplaced shame. Uncontrollable tremors can create discomfort when strangers’ eyes are drawn to our constant movements. We think that we give off an air of clumsiness. We feel anything and everything but dignity. Our self-respect has been replaced by insecurity and a lack of grace, leading us to withdraw from those we care about and who care about us. 

Looking inward

While others can see only what is happening on the outside, they may forget that there is still a sensitive, kind, gentle being behind that masked face. When someone relies on the assistance of an old, crudely made cane, others might believe the person to be drunk due to their swaying, unbalanced gait. 

But alcohol has no place in this life with Parkinson’s — and neither do mind-altering substances. We shuffle about and freeze in place, stumbling over our two feet as we struggle to make our way across the room. Onlookers don’t know our struggles or that we battle the Parkinson’s beast, moment to moment, day by day.

Is there any dignity in our lives?

I believe that there is dignity to be found in our determination to keep going as long as God gives us breath. There is dignity in our refusal to give up. We all fall, whether we have Parkinson’s or not. We all fail sometimes when trying to reach our goals. We can keep our dignity in this disability if we don’t allow others’ stares to increase our insecurities or our stuttering to fluster us. On the inside, we are the same person, even if the outside appears to have changed.

***

Note: Parkinson’s News Today is strictly a news and information website about the disease. It does not provide medical advice, diagnosis or treatment. This content is not intended to be a substitute for professional medical advice, diagnosis, or treatment. Always seek the advice of your physician or another qualified health provider with any questions you may have regarding a medical condition. Never disregard professional medical advice or delay in seeking it because of something you have read on this website. The opinions expressed in this column are not those of Parkinson’s News Today or its parent company, BioNews Services, and are intended to spark discussion about issues pertaining to Parkinson’s disease.

The post Living with Dignity and Parkinson’s Disease appeared first on Parkinson’s News Today.

Project Aiming to Create Working Neurons Awarded $4M Grant

grant award

A team of researchers at Purdue University won a $4 million grant from the National Science Foundation to advance the development of a synthetic neuron platform to support future studies into brain health and neurodegenerative diseases like Parkinson’s.

Diseases like Parkinson’s progressively damage and kill nerve cells, or neurons, in the brain. Although treatments may help ease disease-related symptoms, a way to effectively slow neurodegeneration has yet to be determined.

For almost a century, the scientific community believed the brain could not replace dead neurons. While evidence now indicates that may be possible within several brain structures — including, but not limited to, the amygdala, hippocampus, and cortex — for the most part, the brain cannot replenish dead nerve cells.

“When the neuron dies or becomes impaired like that, the brain has to get rid of the damaged neurons, and once they’re gone, they’re just gone,” Chongli Yuan, PhD, a professor of chemical engineering at Purdue and team leader of the project, said in a press release. “That’s why there’s no effective treatment for neurotrauma diseases.”

Yuan’s team is working on developing synthetic neuronal cells that could potentially be used to study the brain’s complex inner workings without depending so much on animal or human-derived models. The goal is to address dead or damaged neurons in a disease scenario.

“If we can replace part of those neurons, then we can have infinite possibilities in disease treatment in the future,” Yuan said, noting that “creating a synthetic neuron could essentially be the solution for anything that requires the replacement of neurons in the brain or the nervous system.”

Yuan’s four-year project proposal won her group the $4 million award from the National Science Foundation’s 10 Big Ideas Challenge, which funds pioneering research and pilot activities to support emerging opportunities that serve the nation’s future.

The team has already received part of the awarded funding. The work will be developed in collaboration with researchers at the University of Michigan, Stanford University, Johns Hopkins University, Rochester Institute of Technology, Baylor University and the University of California, Santa Barbara.

The researchers will first divide neurons into essential building blocks, and create each building block by integrating several inanimate materials, such as proteins and lipids. The blocks will then be assembled into functional sub-units capable of performing part of a neuron’s or neuronal network’s functions.

“This project is about using a bottom-up approach to make a synthetic neuron,” Yuan said. “We will take all the information that biologists and neuroscientists have generated in terms of understanding how the brain works and how the neuron works, and we’ll use an engineering approach to construct it.”

When researchers have a minimal neuron with all its essential functions, they will move into neuronal processing information and aim to synthetically recreate neurons’ ability to communicate with each other. If successful, the researchers will have a working binary response — positive and negative signals — that is essential for information processing.

The work could be the start of a neuron-based platform that allows scientists to study the functioning of the brain and add components as they go.

“We think the work is going to be challenging, because whenever you try to mimic something that nature has made, nature has millions of years to do its very best job. We only have four years,” Yuan said.

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Biogen Acquires Pfizer’s PF-05251749, a Potential Disease-modifying Therapy for Parkinson’s, Alzheimer’s

Biogen, Pfzier

Biogen is adding Pfizer’s PF-05251749 — a regulator of the body’s inner clock — to its group of potential disease-modifying therapies for Parkinson’s and Alzheimer’s diseases.

Biogen plans to test PF-05251749 in an upcoming Phase 1 clinical trial as a treatment to correct irregular sleep wake rhythm disorder in Parkinson’s and sundowning in Alzheimer’s.

Non-motor symptoms associated with Parkinson’s disease include alterations in patients’ circadian rhythm, or the body’s inner clock, which is synchronized by natural light-dark patterns. This clock also controls key body features, including wake/sleep cycles, body temperature, digestion, hormonal cycles, and behavior patterns.

Parkinson’s patients often show difficulties in sleeping, such as insomnia, nightmares, and restless sleep, a condition collectively called irregular sleep wake rhythm disorder (ISWRD). ISWRD’s frequency increases over the course of the disease and with disability progression.

The circadian clock also plays a role in sundowning — a sudden worsening of confusion, agitation and aggression occurring in the late afternoon and spanning into the night — experienced by at least 20% of Alzheimer’s patients.

In mammals, a tiny region within the brain’s hypothalamus is responsible for controlling circadian rhythms, and an enzyme called casein kinase 1 (CK1), which exists in two forms, is a key regulator of this clock.

PF-05251749 is an oral, brain-penetrable, highly selective, inhibitor of both forms of CK1 that can alter circadian rhythms significantly. Inhibiting CK1 disrupts the function of two genes, CLOCK and BMAL1, which are thought to influence the regulation of circadian rhythms.

Two Phase 1 trials in healthy adults ages 18–55 (NCT02443740) and an older group ages 18–85 (NCT02691702) have assessed the compound’s safety, pharmacokinetics and pharmacodynamics (essentially how a compound behaves inside the body and how the body affects it) and exposure in cerebral spinal fluid (that which surrounds the brain and spinal cord). In these trials, PF-05251749 showed an acceptable safety profile.

“This asset is highly complementary to our existing pipeline of potential disease-modifying therapies in Alzheimer’s and Parkinson’s diseases,” Alfred Sandrock Jr., MD, PhD, executive vice president, research and development and chief medical officer at Biogen, said in a press release.

“Many patients with Alzheimer’s and Parkinson’s suffer from debilitating sleep disorders and agitation, and we believe that the regulation of the circadian rhythm may hold promise in addressing these challenging behavioral and neurological symptoms,” he said.

Pfizer will receive an upfront payment of $75 million for PF-05251749. Additional milestone payments may reach $635 million.

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One-year Results in 2 Given Gene Therapy at Low Dose Showing Promise, Axovant Reports

early trial results

Two Parkinson’s patients treated with AXO-Lenti-PD, an investigative gene therapy, in an ongoing clinical trial continue to show improvement 12 months later, Axovant, the therapy’s developer, said in a release.

These findings at one year after treatment are important because this timepoint allows for a better assessment of therapy durability, and a more assured differentiation between placebo effects and therapeutic response, the company added.

AXO-Lenti-PD has shown encouraging results in these two people given a first low dose in the SUNRISE-PD (NCT03720418) Phase 1/2 clinical trial, which is now enrolling up to 30 patients at sites in France and England.

The treatment works by delivering three genes involved in dopamine production directly to the brain via a surgical procedure.

Dopamine is a neurotransmitter — a molecule involved in transmitting information between neurons — that is critical to coordinating movement. Dopamine-producing (dopaminergic) neurons are lost in Parkinson’s, and the resulting drop in dopamine levels is the cause of many disease symptoms.

By ‘infecting’ brain cells with the genetic instructions to increase dopamine production, AXO-Lenti-PD aims to turn other cells into dopaminergic neurons.

Current dopamine replacement therapies require continual oral doses of dopamine, whose effectiveness fades over time. The period between when one dose’s effectiveness wanes and the taking of a next dose can result in “off periods,” wherein patients report a return of symptoms such as poor motor control, stiffness, fatigue and mood changes.

Helping the brain to again produce adequate levels of dopamine would, in theory, eliminate the need for periodic oral doses, which could significantly limit off periods.

Previous studies in primate models of Parkinson’s found AXO-Lenti-PD to be safe and effective, and SUNRISE-PD results at three months’ post-treatment found that a one-time delivery of the therapy significantly improved patient scores on the Unified Parkinson’s Disease Rating Scale (UPDRS), a standard assessment of motor and non-motor symptoms associated with Parkinson’s.

The trial consists of two parts. Part A is an open-label, dose-escalation phase in which patients receive one of potentially three escalating doses of the gene therapy. In part B, a new group of patients will be randomized to either the ideal part A dose or to a sham procedure as an untreated control group. SUNRISE-PD’s goal is to test the safety, tolerability, and effectiveness of the potential treatment.

Both patients here, the first two enrolled, received the lowest dose (4.2×106 transducing units) of AXO-Lenti-PD.

One-year results show positive changes of 24 points and 20 points (respectively for the two patients) on the UPDRS Part III “Off” score, representing a 37% improvement in off-period motor symptoms, Axovant reported. Improvement at six months was 29%, as measured on the same scale.

These patients also showed an average 13-point positive change from baseline (study start) — representing a 44% improvement — on the UPDRS Part II “Off” score, which assesses daily life activities. On the PDQ-39 score index, another quality-of-life measure in Parkinson’s disease, these two showed an average 15-point positive change, or a 30% improvement from baseline to 12 months.

Both patients tolerated AXO-Lenti-PD well, and neither reported any serious side effects. One maintained a diary of on/off periods, which is useful in evaluating changes that might be due to therapy across time.

People being enrolled in SUNRISE-PD have had Parkinson’s for at least five years, have motor fluctuations and dyskinesia (jerky, involuntary movements), and are between the ages of 48 and 70.  More information can be found here.

The company expects to soon release six-month results on the first two patients given a second and higher dose of AXO-Lenti-PD. This dose is three times higher than that given the first cohort.

If dose-escalation results allow, Axovant expects to begin the randomized and placebo-controlled part B of the SUNRISE-PD as a Phase 2 study by the close of 2020.

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Affiris Announces Phase 2 Study of Potential Parkinson’s Vaccine

Affiris

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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