Clinical Trial Suggests Parkinson’s Drug Is Safe In Humans
A large team of researchers from Denali Therapeutics, working with colleagues from multiple entities in the U.S. and one in Canada, has found that a LRRK2 inhibitor called DNL201 showed no ill effects to volunteers in a clinical trial. In their paper published in Science Translational Medicine, the group describes their clinical trial of the Parkinson’s drug and what they learned during its run. Patrick Lewis, with Royal Veterinary College London has published a Focus piece in the same journal issue outlining the work being done by the team at Denali.
Parkinson’s disease is a disease that results from the destruction of neurons in the brain that produce dopamine, which is critical for motor function. Prior research has suggested it comes about most often due to environmental factors in people with a genetic risk for it. Prior research has also shown that mutated versions of a certain gene lead to overproduction of an enzyme called LRRK2, which leads to inflammation and other problems. Currently, there are no therapies available to slow its progression.
Science Translational Medicine
Protein Discovered In Parkinson’s Disease Could Lead To New Treatments
Currently, there are no disease modifying therapies for Parkinson’s disease that can change the progression of the disease. An international team of scientists led by faculty at the University of Colorado Anschutz Medical Campus is hoping to change that.
Today, they published new research in the journal Brain that takes scientists one step closer to understanding a key protein -synuclein , that they found links inflammation and Parkinson’s disease.
The protein Syn is predominantly expressed in neurons and is associated with neurodegenerative diseases like Parkinson’s disease and dementia with Lewy bodies. This new study identifies the novel mechanism that links interferon activation and Syn function in neurons as a potential trigger for developing Parkinson’s disease.
“It’s critical to understand further the triggers that contribute to the development of Parkinson’s disease and how inflammation may interact with proteins found in the disease. With this information, we could potentially provide new approaches for treatments by altering or interfering with these inflammatory pathways that may act as a trigger for the disease,” said David Beckham, MD, associate professor in the department of infectious disease at the University of Colorado School of Medicinelocated on the CU Anschutz Medical Campus.
Understanding Sleep Problems To Prevent Parkinsons
Brain scans of people who experience RBD show increased inflammation the bodys natural response to injury, coming from immune cells in the brain called microglia. Research suggests that excessive levels of inflammation in the brain may cause damage to brain cells and play a role in the progression of Parkinsons.
The involvement of immune cells in Parkinsons has peaked researchers interest in the possibility of dialling down inflammation in the brain. And there is ongoing work through the Parkinsons Virtual Biotech to find and develop potential anti-inflammatory drugs.
Project Galaxy is focusing on developing molecules that can get into the brain and target a specific protein on the surface of microglia that has been shown to be present at much higher levels in the brains of people with Parkinsons than in people without the condition. This could pave the way for a future treatment to slow or stop the progression of the condition.
Targeting inflammation at the earliest stages of Parkinsons may also be important when aiming to slow the loss of cells and delay the onset and progression of symptoms. While identifying Parkinsons early is challenging, doing so opens the door to treating the condition before symptoms become problematic and potentially even preventing people from developing Parkinsons.
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Study In Parkinson Disease Of Exercise
open to eligible people ages 40-80
This study is a Phase 3 multi-site, randomized, evaluator-masked, study of endurance treadmill exercise on changes in the Movement Disorder Society-Unified Parkinson Disease Rating Scale Part III score at 12 months among persons with early stage Parkinson disease. 370 participants will be randomly assigned to 2 groups: 1)60-65% HRmax or 2)80-85% HRmax 4 times per week. The primary objective is to test whether the progression of the signs of Parkinson’s disease is attenuated at 12 months in among persons who have not initiated medication for Parkinson Disease when they perform high-intensity endurance treadmill exercise.
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Using Machine Learning In Research
The available treatments for Parkinsons disease to date are only partially effective and fail to markedly delay disease progression. Thus, there is growing interest in repurposing existing medications as an accelerated method of therapeutic development.
Such approved treatments, having already been rigorously tested in clinical trials, generally have established safety profiles.
Studies have suggested that people treated with certain medications, including immunosuppressants or those that widen the airways, called bronchodilators, have a lower risk of developing Parkinsons.
These findings prompted researchers based at the Université Paris-Saclay, in France, to use machine learning tools to automatically screen a large database of marketed therapies to detect those related to a lower risk of Parkinsons.
This study is part of a research effort aimed at identifying already-developed compounds associated with reduced risk, the researchers noted.
Data were collected from the French national health data system. A total of 40,760 incident Parkinsons patients were identified based on the details of at least one claim for an anti-Parkinsons medication from 2016 to 2018. A control group of 176,395 individuals of similar age, sex, and area of residence were included as a comparison.
Given that, the team assessed therapeutic exposure and related factors during the two years before the lag period to find associations to a reduced risk of developing Parkinsons disease.
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What The Experiments Showed
Initially, the researchers tested the nanobody on mouse brain tissue in vitro. They found that PFFNB2 could bind to aggregates of alpha-synuclein, but could not prevent the formation of clumps.
Further experiments revealed that the nanobody could bind to and disrupt fibrils of alpha-synuclein that had already formed, destabilizing the misshapen proteins.
The researchers then tested this in live mice and found that the nanobody prevented alpha-synuclein from spreading to the cortex of the brain. The cortex is the largest part of the brain and is responsible for most higher brain functions.
Dr. Petrossian explained for MNT that he results showed that they were able to specifically target the preformed fibrils of alpha-synuclein in cell and mouse models, that they were able to reduce the clumping of alpha-synuclein in cell models, and they were able to reduce alpha-synuclein pathology in mouse models.
Where Is Drug Development Headed
Overall, experts say the Parkinson’s disease field aims to develop therapies that can slow or stop disease progression. Kordower notes several promising gene therapy and stem cell therapy approaches are entering the early stages of clinical development.
Most ongoing PD trials are at the Phase II stage, according to GlobalDatas Clinical Trial Database. While institutions are sponsoring 84 trials of the 133 ongoing Phase II studies , pharma companies are running 44 trials of the 56 ongoing Phase I studies .
As the field awaits results from the slew of ongoing trials, experts agree that the PD trials reading out in the remainder of 2022 could have a substantial impact. These four trials are all very timely, Eidelberg says. The community of movement disorder specialists and neurologists would use these drugs because the indications we’re talking about are really very common.
A Study To Evaluate The Efficacy And Safety Of Intravenous Prasinezumab In Participants With Early Parkinson’s Disease
open to eligible people ages 50-85
This is a multicenter, randomized, double-blind, placebo-controlled study that will evaluate the efficacy and safety of intravenous prasinezumab versus placebo in participants with Early Parkinson’s Disease who are on stable symptomatic PD medication.
San Francisco, California
Adaptive Deep Brain Stimulation To Improve Motor And Gait Functions In Parkinson’s Disease
Sorry, accepting new patients by invitation only
This is a single-center phase I clinical study aiming to improve gait functions in patients with Parkinson’s disease by using adaptive neurostimulation to the pallidum. The investigators will use a bidirectional deep brain stimulation device with sensing and stimulation capabilities to 1) decode the physiological signatures of gait and gait adaptation by recording neural activities from the motor cortical areas and the globus pallidus during natural walking and a gait adaptation task, and 2) develop an adaptive deep brain stimulation paradigm to selectively stimulate the pallidum during different phases of the gait cycle and measure improvements in gait parameters. This is the first exploration of network dynamics of gait in PD using chronically implanted cortical and subcortical electrodes. In addition to providing insights into a fundamental process, the proposed therapy will deliver personalized neurostimulation based on individual physiological biomarkers to enhance locomotor skills in patients with PD. Ten patients with idiopathic Parkinson’s disease undergoing evaluation for DBS implantation will be enrolled in this single treatment arm study.
San Francisco, California
Sorry, in progress, not accepting new patients
This study will investigate cortical stimulation to treat mood and behavioral symptoms in Parkinson’s disease patients.
San Francisco, California
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Summary: The Main Takeaways
The amount of research being conducted is a very positive sign, and it suggests that 2022 will be an extremely productive year for Parkinsons research. The breadth of approaches now being applied to Parkinsons is also very encouraging, and in the next few years we may have answers to some fundamental questions regarding the biology that may be underlying many cases of PD .
There is certainly going to be a lot of clinical trial results being announced in 2022! The top 5 clinical trial results that I will be looking out for this year are:
- The Phase II UP study results evaluating UDCA in Parkinsons
- The Phase II Lixisenatide study results more data on GLP-1R agonists in PD
- The Phase II Liraglutide study results even more data on GLP-1R agonists in PD
- The Phase II Peptron study results lots of data on GLP-1R agonists in 2022
- The Phase II Deferiprone study results addressing an important question
And with bulging pockets, we can expect more acquisitions and partnering deals to come in 2022. Any fears that big pharma companies are quitting neurodegeneration appear to be misplaced with aging demographics in the Western world, the market opportunities are simply too big for these enormous companies to ignore.
All of this collective activity provides encouraging signs for future research focused on finding new therapies for slow, stopping and reversing Parkinsons.
But now its time to give the fingers a wee rest.
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Survival In Parkinson’s Disease Psychosis
LaFaver: Let’s switch gears a little bit with our next abstract here, which is titled, “Survival Differences Among Patients with Parkinson’s Disease and Parkinson’s Disease Psychosis: a Population-based Study .” This comes from Dr Rodolfo Savica, who is at the Mayo Clinic and is a friend of mine, and his colleagues. They’ve done amazing epidemiologic studies based on the Rochester Epidemiology Project.
I found this study very interesting, because it’s something that hasn’t been looked at specifically. Patients will always ask, how does Parkinson’s disease affect my long-term prognosis and so on. We know that in general, there’s not a large difference in life expectancy. But this study looked at how patients who experience psychosis do using this amazing database. They looked at 69 patients out of 225 with Parkinson’s disease over a 10-year time span.
They found that patients who had met criteria for Parkinson’s disease psychosis showed higher rates of cognitive impairment . That’s probably not too surprising. They also had higher rates of orthostatic hypotension and a significantly higher rate of all-cause mortality.
We know that Parkinson’s disease is not one disease, but it’s really a spectrum. Knowing which patients we really need to pay a lot of attention to and who might be frailer and higher-risk is important.
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Parkinsons Disease: Major Drug Trial Results To Watch In 2022
Four clinical trials in Parkinsons disease with readouts the second half of 2022 target motor symptom fluctuations and cognitive impairment.
In a slate of major Parkinsons disease trial readouts, drug developers are taking aim at the diseases most common symptom: motor fluctuations.
Around 80% of people with PD have some motor symptom fluctuations, says Dr Jeffrey Kordower, founding director of Arizona State University s Banner Neurodegenerative Disease Research Center. The rationale behind going after these symptoms is really strong.
Four major trials have readouts expected in the next six months, three of which target motor symptoms, also known as dyskinesia. Two trials focus on dyskinesia resulting from sustained use of generic levodopa, which is widely considered the standard of care in PD. A third study tests a new formulation of levodopa that could reduce treatment side effects such as dyskinesia, while a fourth trial takes aim at cognitive impairment in PD.
Parkinsons disease is a progressive central nervous system disease associated with deficiencies in the neurotransmitter dopamine. There are no disease-altering treatments available, but levodopa can increase dopamine levels in the brain and reduce symptoms.
Treatments In Phase Ii Trials
Another strategy in the therapeutic research space is drug repurposing. This is when an existing medication for one condition is repurposed to treat an entirely different condition. Working with repurposed medications comes with many advantages including understanding its general safety. Repurposing an existing medication, rather than starting from scratch, typically requires fewer tests for safety as the drug has already met these requirements. This can reduce costs and speed up the process through the clinical trial pipeline. It can also lead to faster approvals, getting much-needed treatments into the hands of people with Parkinsons as soon as possible. There are a total of 74 therapies in Phase II trials and 44% are repurposed medications.
One exciting takeaway from Phase II trials this year is the progress made with stem cell therapies. While there are nine stem cell therapies being explored in Phase I, two stem cell therapies graduated to Phase II trials this year! Moving into Phase II means these treatments are being administered to a larger group of people to monitor their effectiveness and further evaluate their safety.
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Component #3 Some Form Of Restorative Therapy
Once the condition has been slowed/halted and a neuroprotective/nurturing environment is in place to protect the remaining cells , a curative treatment for Parkinsons will require replacing some of the cells that have been lost.
And until we have developed methods that can identify Parkinsons long before the motor features appear , some form of cell replacement therapy is required to introduce new cells to take up lost function.Cell transplantation currently represents the most straight forward method of cell replacement therapy.
Traditionally, the cell transplantation procedure for Parkinsons has involved multiple injections of developing dopamine neurons being made into an area of the brain called the putamen . These multiple sites allow for the transplanted cells to produce dopamine in the entire extent of the putamen. And ideally, the cells should remain localised to the putamen, so that they are not producing dopamine in areas of the brain where it is not desired .
Targeting transplants into the putamen. Source: Intechopen
Transplanted dopamine neurons. Source: Sciencedirect
The transplanted cells take several years to develop into mature neurons after the transplantation surgery. This means that the actually benefits of the transplantation technique will not be apparent for some time . Once mature, however, it has also been demonstrated that these transplanted cells can produce dopamine.
Ok, thats it.
I think we are done.
The Motor Network In Parkinson’s Disease And Dystonia: Mechanisms Of Therapy
open to eligible people ages 21-75
This is an exploratory pilot study to identify neural correlates of specific motor signs in Parkinson’s disease and dystonia, using a novel totally implanted neural interface that senses brain activity as well as delivering therapeutic stimulation. Parkinson’s disease and isolated dystonia patients will be implanted unilaterally or bilaterally with a totally internalized bidirectional neural interface, Medtronic Summit RC+S. This study includes three populations: ten PD patients undergoing deep brain stimulation in the subthalamic nucleus , ten PD patients with a globus pallidus target and five dystonia patients. All groups will test a variety of strategies for feedback-controlled deep brain stimulation, and all patients will undergo a blinded, small pilot clinical trial of closed-loop stimulation for thirty days.
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Component #2 A Neuroprotective Agent
Once a drug or a treatment has been determined to slow down the progression of Parkinsons, it will be necessary to protect the remaining cells and provide a nurturing environment for the third part of the cure .
Neuroprotection is the area of research that has had the most attention over the years. Drug companies have employed vast resources in this area in the hope of discovering a treatment which will work across conditions , and thus provide them with tremendous profits. Unfortunately, conditions of the brain have proven to be a lot more complicated than first perceived and cross-condition therapies seem unlikely as we move towards greater stratification and personalisation of disease and treatment, respectively.
But there has been the hint of a potential neuroprotective effect in one class of drugs for Parkinsons: GLP-1R agonists.
Neuroprotective approach: GLP-1R agonists
Exenatide is a glucagon like peptide-1 receptor agonist. This is a class of drug that has traditionally been used for treating diabetes, but has recently been repurposed for Parkinsons.
After multiple studies suggested neuroprotective properties in models of Parkinsons, a clinical trial program was intiated, and in 2017, a Phase II Exenatide trial reported the stablisation of Parkinsons motor features over the course of the 48 week trial .
Reduction in motor scores in Exenatide group. Source: Lancet
In late 2019, we saw the initiation of a Phase III clinical trial for .