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Equfina, Known as Xadago in US, Approved in S. Korea as Levodopa Add-on

therapy approval

Equfina (safinamide) has been approved in South Korea as an add-on therapy to levodopa for Parkinson’s disease patients who experience “off” episodes, Eisai, which is marketing this medication in parts of Asia, announced.

The approval makes South Korea the first country in Asia outside of Japan to sell Equfina.

Under the brand name Xadago, the add-on therapy was approved for the same indication in Europe in 2015 and in the U.S. in 2017. In Canada it is marketed under the name Onstryv.

“Off” periods in Parkinson’s are characterized by the reappearance or worsening of motor symptoms — such as tremors and dyskinesia (involuntary movements) — due to a gradual decline in levodopa’s effectiveness throughout the day.

Safinamide, developed by Newron Pharmaceuticals, increases the level and function of dopamine — the neurotransmitter, or signaling molecule, missing in those with Parkinson’s — in the brain. It does so by inhibiting the enzyme monoamine oxidase B that normally breaks down dopamine, and also by inhibiting (blocking) transporters that are responsible for its uptake, meaning its absorption and retention.

Safinamide also inhibits an excessive release of the neurotransmitter glutamate.

Equfina’s approval in South Korea was based on clinical results from the SETTLE Phase 3 study (NCT00627640). The global trial enrolled 549 patients experiencing off episodes while on a stable regimen of levodopa plus benserazide or Lodosyn (carbidopa).

Participants were randomized to either oral safinamide (50 mg per day, increased to 100 mg per day if tolerated) or a placebo as an add-on therapy for 24 weeks.

The study’s main goal was changes in mean daily “on” time (the period in which motor symptoms are efficiently controlled) about six months of treatment or placebo use.

Results showed that adding safinamide to levodopa significantly increased the length of “on” periods without dyskinesia by almost one hour (57.6 minutes) compared with placebo.

Adverse treatment reactions were seen in 28.5% of patients in the safinamide group and in 27.6% of those given a placebo, with the most frequent including dyskinesia, nausea, and somnolence (sleepiness).

Newron entered a licensing agreement with Meiji in 2011, granting the company exclusive rights to manufacture and commercialize safinamide in Asia. Based on a licensing agreement between Eisai and Meiji, Eisai now has exclusive rights for developing and marketing safinamide in much of Asia.

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Awakening Dormant Neurons Could Provide Disease-modifying Parkinson’s Treatment, Early Study Suggests

dormant neurons

Together with dying nerve cells, dormant neurons also may be at the root cause of Parkinson’s disease, according to a recent study in animal models.

Reawakening these neurons by targeting a type of brain cells called astrocytes can restore dopamine production in the brain and reverse Parkinson’s motor symptoms, the study found. These findings could lead to a potential new disease-modifying treatment, especially at the early stages of Parkinson’s.

The study, “Aberrant Tonic Inhibition of Dopaminergic Neuronal Activity Causes Motor Symptoms in Animal Models of Parkinson’s Disease,” was published in the journal Current Biology.

Despite its prevalence and debilitating consequences, current medical therapy for Parkinson’s relies on alleviating symptoms. Research investigating ways of modifying the disease or reversing its symptoms is scarce, based on the firm belief that Parkinson’s is caused by the irreversible death of nerve cells — also called neurons — in a region of the brain called the substantia nigra.

In this brain region, nerve cells known as dopaminergic neurons are responsible for producing the neurotransmitter dopamine, a chemical messenger that allows nerve cells to communicate. Dopamine plays a key role in motor function control and also is involved in behavior and cognition, memory and learning, sleep, and mood.

Levodopa, a mainstay of Parkinson’s treatment, works by supplying extra dopamine to the brain. However, it only alleviates motor symptoms and does not alter the disease course. Moreover, its long-term use can cause serious side effects, including involuntary, erratic, and writhing movements.

Now, a team of Korean researchers have discovered additional clues about the underlying mechanisms of Parkinson’s that may offer hope for the development of disease-modifying treatments that could reverse the condition.

Using mouse and rat models of Parkinson’s, they found that the motor abnormalities that mark the disease begin earlier than was previously thought. They are triggered when dopaminergic neurons in the substantia nigra are still alive but in a dormant state, unable to produce dopamine.

However, what holds the key to that dormant state is another type of cells called astrocytes, star-shaped cells present in the brain and spinal cord that play important roles in the protection and regulation of the nervous system.

When neurons die, nearby astrocytes react by proliferating, and start to release an inhibitory neurotransmitter called gamma-aminobutyric acid (GABA) at excessive levels. This puts neighboring neurons “on hold,” suspending their production of dopamine.

GABA prevents the neurons from firing electrical impulses and causes them to stop making an enzyme, called tyrosine hydroxylase, that’s essential for the production of dopamine. In effect, GABA puts the neurons into a dormant, or sleeping state.

One of the most important discoveries of the study was that surviving dormant neurons could actually be “awakened” from their “sleeping” state and rescued to alleviate motor symptoms.

“Everyone has been so trapped in the conventional idea of the neuronal death as the single cause of PD. That hampers efforts to investigate roles of other neuronal activities, such as surrounding astrocytes,” C. Justin Lee, PhD, the study’s corresponding author, said in a press release.

“The neuronal death ruled out any possibility to reverse PD. Since dormant neurons can be awakened to resume their production capability, this finding will allow us to give PD patients hopes to live a new life without PD,” Lee added.

Treatment with two different compounds that block GABA production in astrocytes, called monoamine oxidase-B, or MAO-B, inhibitors, was sufficient for neurons to recover the enzymatic machinery necessary to produce dopamine, the study found. This significantly alleviated Parkinson’s motor symptoms in the study animals.

In fact, the MAO-B inhibitors used for the study — selegiline (brand names EldeprylCarbex, Zelapar, among others), and safinamide (brand name Xadago) — are already prescribed to Parkinson’s patients as an add-on therapy to levodopa. They are believed to prevent the break down of dopamine in the brain.

Importantly, the existence of dormant neurons was observed in the brains of human patients. Analysis of postmortem brains of individuals with mild and severe Parkinson’s had a significant population of dormant neurons surrounded by numerous GABA-producing astrocytes.

The researchers hope that “awakening” neurons using MAO-B inhibition could be an effective disease-modifying therapeutic strategy for Parkinson’s, especially for patients in the early stages of the disease. At that time, inactive, yet live dopaminergic neurons are still present.

Although the results from several clinical trials have cast doubt on the therapeutic efficacy of traditional MAO-B inhibitors, researchers say they have recently developed a new inhibitor, KDS2010. KDS2010 effectively inhibits astrocytic GABA production with minimal side effects in Alzheimer’s animal models and also could be effective for alleviating Parkinson’s motor symptoms, the investigators said.

“This research refutes the common belief that there is no disease-modifying treatment for PD due to its basis on neuronal cell death,” said Hoon Ryu, PhD, a researcher at KIST Brain Science Institute, in South Korea, and one of the senior authors of the study.

“The significance of this study lies in its potential as the new form of treatment for patients in early stages of PD,” Ryu said.

The fact that inhibition of dopaminergic neurons by surrounding astrocytes is one of the core causes of Parkinson’s should be a “drastic turning point” in understanding and treating not only Parkinson’s but also other neurodegenerative diseases, added Sang Ryong Jeon, MD, PhD, also a researcher at KIST and a study co-author.

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Parkinson’s Forum Offers Patients and Caregivers Place to Learn, Share, and Foster Community

patient-caregiver forums

Online forums have markedly altered how patients, caregivers, and healthcare professionals communicate and connect. Even when miles apart, individuals can establish supportive relationships, share experiences and information, and sometimes simply vent.

BioNews Services, a leading online health, science and research publication company, has been rolling out its own forums, including one for Parkinson’s disease (PD), a progressive neurodegenerative disorder that affects roughly 1 million U.S. residents, and more than 10 million people worldwide. Moderated by patients and caregivers — nearly all of them BioNews columnists — these forums complement the company’s news and information websites, such as Parkinson’s News Today.

It’s that synergy of science and personal experience that sets BioNews’ forums apart.

“Patient forums are certainly not a new concept, but BioNews has something unique to offer our communities,” said Chris Comish, BioNews’ founder and CEO. “No other company has the ability to deliver such relevant content to our readers and use that as a starting point for driving conversation and discourse. We’ve had some really touching conversations occur, and have seen patients, particularly those newly diagnosed, find sources of hope and inspiration. It’s touched everyone involved.”

The company has introduced nine forums since last January — Parkinson’s was launched last July —  with more launching by year’s end. Its plan is to have a forum, customized by moderators, for each of its 60-plus rare disease sites. Every forum requires registration and moderator approval, and offers features such as private messaging and keyword search.

BioNews is working to add multimedia to each forum, including podcasts, YouTube videos, and flash briefings.

Within each forum are categories, also known as subforums. In A Forum for Parkinson’s Disease Caregivers, for example, members can connect with other caregivers and learn news ways to overcome challenges and practice self-care, like those presented here. Other posts examine Parkinson’s caregiving and income loss, and how to speak to a loved one with this disease.

In the subforum Diagnosis Information and General Questions, people newly diagnosed along with their caregivers and friends can ask questions about the disease and find information, all while supporting each other. Discussion topics range from personal reactions to a diagnosis to reasons for a misdiagnosis, like those detailed in this posted article.

The Living with Parkinson’s Disease subforum is a place for those who understand the day-to-day challenges the disease poses, including difficulties with walking and speaking. It’s also a resource for information about living with a chronic illness. There are posts about disease progression, for instance, and books by those with Parkinson’s about their journey.

Members can use the Parkinson’s Disease Symptoms space for resources to help them understand and cope with how Parkinson’s uniquely affects them. Because symptoms vary from person to person, the subforum is particularly popular. Subjects include trouble rolling over in bed, difficulty swallowing waterimproving handwriting, and the effects of dyskinesia — those uncontrolled and involuntary muscle movements.

In Parkinson’s Disease Alternative Treatments, participants can ask questions and share information about alternative or experimental therapies they’ve tried or are curious about, with the proviso that many suggestions are not science based, and that effects can vary. There are posts about medical cannabis, for example, gluten-free diets and rosemary essential oil.

The subforum Parkinson’s Disease Medications is for sharing information and experiences related to therapies, including levodopa and Xadago (safinamide). The platform Parkinson’s Research News keeps members apprised of the latest study and treatment advances. Members can connect with researchers, healthcare professionals, and other patients. Posts range from a study about sex and Parkinson’s to the preclinical results on a molecule that might reduce toxic protein buildups in the brain and reverse motor symptoms.

In Parkinson’s Disease and Exercise, participants can learn about, and share the benefits and challenges of, exercising. Entries touch on specific forms of exercise like swimming, or being overwhelmed by the volume of exercise required. Members can use the Parkinson’s Disease Awareness and Advocacy subforum to learn how to educate others about Parkinson’s, and to discover current and future efforts to heighten disease awareness.

In all, Jean Mellano, who is the Parkinson’s forum co-moderator along with Ally MacGregor, said she and others have found that levity is often most effective in disease management.

“Laughter is the best medicine,” said Mellano, who was diagnosed in 2015. “Having a sense of humor about the absurdity of some PD symptoms can help with the healing process. If we can share our stories with others, it may lessen the embarrassment caused by our symptoms.”

To help generate conversation, forum moderators regularly post topics within subforums. Sometimes the topic is based on a new column or news article. Other times, it’s something about day-to-day life. Moderators also post about their own lives, for instance, sharing thoughts on movies they’ve seen or their vacation photos. Some forums also have groups, both public and private subforum offshoots.

The forums’ framework was mostly developed by Kevin Schaefer with help from the social media team at BioNews. Schaefer is the company’s community development manager and an SMA forum moderator. He’s excited about the forums, and their growth and future potential.

“It’s just really cool to see a community evolving in each of them,” said Schaefer, who has SMA type 2. “They are as much about fostering community as they are about providing information. We want to do everything we can to engage with our members.”

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Onstryv Now Available to Patients with Parkinson’s Disease in Canada

Canada Onstryv launch

Patients in Canada with diagnosed Parkinson’s disease can now receive Onstryv (safinamide) to help manage their symptoms and their “off” episodes.

This follows the approval of Onstryv by Health Canada in January 2019 as an add-on treatment to improve motor function in Parkinson’s patients who experience “off periods” while taking other therapies such as levodopa.

The oral therapy will be available under prescription in 50 mg and 100 mg tablets, and be marketed in Canada by Valeo Pharma — under a license agreement with Zambon. Valeo has launched a physician awareness and information campaign to facilitate and expedite patients’ access to Onstryv.

“The number of Canadians afflicted with Parkinson’s Disease is expected to grow by more than 50% over the next decade as the Canadian population ages,” Steve Saviuk, CEO of Valeo, said in a press release. “Onstryv is the first new oral treatment for Parkinson’s Disease to be approved in Canada in well over a decade.”

“Valeo is committed to building and supporting relationships with healthcare professionals, patients and other stakeholders to build awareness and ensure access to this new treatment for Parkinson’s Disease,” he added.

Known as Onstryv in Canada and Xadago in the rest of the world, the compound is an oral, once-a-day add-on therapy that works by selectively and reversibly inhibiting the MAO-B enzyme that can degrade several neural signaling molecules such as dopamine, which is deficient in Parkinson’s disease. The therapy was approved in the United States in March 2017 by the U.S. Food and Drug Administration.

Onstryv was developed by Newron Pharmaceuticals and has demonstrated effectiveness in helping to control the motor symptoms and complications of Parkinson’s disease for over two years in patients. Zambon acquired rights from Newron Pharmaceuticals to develop and commercialize Onstryv globally.

Clinical trial data has shown that Onstryv can significantly reduce motor fluctuations (on/off time) when used in combination with levodopa and/or Lodosyn (carbidopa) without increasing the risk of dyskinesia (involuntary movements).

“Now, with the Canadian launch, safinamide is available across the North American region,” Stefan Weber, Newron CEO, said in a press release.

“This marks another key milestone for Newron and its commercial partners in providing availability of safinamide in Canada for the treatment of patients suffering from Parkinson’s disease,” he added.

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Top 10 Parkinson’s Stories of 2018

Top 10, Parkinson's

Parkinson’s News Today provided you with daily coverage of important findings, treatment developments, and clinical trials related to Parkinson’s during 2018.

We look forward to bringing more news to Parkinson’s patients, as well as their family members and caregivers, during 2019.

Here are the Top 10 most-read articles of 2018, with a brief description of what made them interesting to the Parkinson’s community.

 No. 10 – “Phase 2 Trial Shows Nilotinib Potential to Modulate Dopamine in Parkinson’s

Results of a Phase 2 trial (NCT02954978) of Novartis’ nilotinib in 75 patients with mid-stage Parkinson’s and mild cognitive impairment suggested the therapy increased production and metabolism of dopamine within one to four hours after a single treatment. Also, low-dose nilotinib (150 mg and 200 mg) — marketed as Tasigna for certain types of leukemia — was associated with lower levels of an altered and toxic form of alpha-synuclein, the main component of Parkinson’s hallmark protein clumps known as Lewy bodies.

No. 9 – “Potential Parkinson’s Vaccine, Affitope PD01A, Safe and Possibly Effective in Long-term, Phase 1 Trial Series Finds

The long-term safety, tolerability, and immune response associated with an experimental vaccine called Affitope PD01A were studied in a series of four consecutive Phase 1 trials: AFF008 (NCT01568099), AFF008E (NCT01885494), AFF008A (NCT02216188), and AFF008AA (NCT02618941). Twenty-one treated and five control patients completed the series. The results showed that both 15 μg or 75 μg doses of Affitope were well-tolerated, only causing mild injection-site reactions. The vaccine, being developed by Affiris, induced a clear immune response against its target — alpha-synuclein — that was stabilized with “boost” injections. At week 26 of treatment, it induced a trend toward lower levels of a toxic form of alpha-synuclein in the blood and cerebrospinal fluid, the liquid surrounding the brain and the spinal cord.

No.8 – “MRI-Focused Ultrasound Undergoing Phase 3 Clinical Trial for Parkinson’s Treatment

A Phase 3 trial (NCT03319485) of a potential nonsurgical treatment, known as magnetic resonance imaging (MRI)-guided focused ultrasound, also attracted significant interest. The InSightec-sponsored study — still recruiting patients with advanced disease — is exploring the procedure’s safety and effectiveness. It follows a pilot trial demonstrating lesser upper-limb tremors in patients with tremor-dominant Parkinson’s who did not respond to other therapies. In this non-invasive approach, ultrasound waves destroy damaged tissue in a brain structure called the globus pallidus, which is involved in the regulation of voluntary movement. The team expects to enroll 80 to 100 participants.

No. 7 – “Key to Effective Parkinson’s Treatment May Lie in Stem Cells, Researchers Say

Advancements in stem cell therapy for Parkinson’s were also of clear interest to our readers. Two articles assessed the replacement of dopamine-producing neurons, progressively lost during the course of disease. The first focused on patient-derived induced pluripotent stem cells (iPSCs), fully matured cells that researchers are able to reprogram in vitro (in the laboratory) to revert them to a stem cell state in which they are able to grow into any type of cell, including dopaminergic nerve cells. The second study focused on an alternative approach to stem cell therapy that, instead of iPSCs, uses parthenogenetic-derived neural stem cells. These cells are obtained by chemical manipulations in unfertilized human oocytes, or immature egg cells, which are also able to grow into neurons. A Phase 1 trial (NCT02452723) of this approach is underway in patients with moderate to severe disease at a single site in Australia.

No. 6  “Psychosis in Parkinson’s Linked to Volume Changes in Specific Area of Brain, Study Says

Atrophy, or shrinkage, of the hippocampus — a critical brain area involved in memory — correlates with psychosis in patients with Parkinson’s disease. Specifically, researchers found that the volume of distinct subzones of the hippocampus was associated with psychosis severity and impaired cognitive functions. Greater volume was also seen in another specific brain area, the hippocampal fissure, and seems to correlate with poorer visual memory and visuospatial functions. Previous data had suggested that change in this area is a radiological hallmark of ongoing brain atrophy in the hippocampus.

No. 5 – Tiny Brain Bleeds Associated with Parkinson’s Disease Dementia, Study Reports

The link between tiny bleeds in the brain — cerebral microbleeds (CBMs) — with both cognitive impairment in Parkinson’s disease and risk of associated dementia was No. 5 among the year’s most-read stories. CBMs are small (2-10 mm as assessed by MRI), chronic brain hemorrhages believed to be caused by structural abnormalities of the brain’s small vessels. Scientists found that CBMs were more common in Parkinson’s patients with dementia than in those without dementia, and were associated with lower cognitive scores. Other findings showed that patients with CBMs were older, and had more severe Parkinson’s symptoms and cerebrovascular lesions.

No. 4 – “Vitamin B12 Supplements May Help Slow Parkinson’s Progression, Study Finds

Patients at early stages of Parkinson’s with low levels of vitamin B12 may experience faster motor and cognitive decline. Prior work had shown that B12 deficiencies can induce neurological and motor symptoms associated with Parkinson’s, including depression, paranoia, muscular numbness, and weakness. This study differed in that it was conducted in untreated patients earlier in the disease course, and found slower progression in those taking a multivitamin supplement. Overall, the findings suggest that vitamin supplements may help slow symptom progression.

No. 3  “Xadago, Cannabinoids, Opioids May Be Best to Manage Parkinson’s Pain, Review Suggest

Pain is a frequent non-motor symptom of Parkinson’s disease. A review study found that its management may be most effective with Xadago (safinamide, by US WorldMeds) or with cannabinoids and opioids.  Other approaches, such as multidisciplinary team care, Comtan (entacapone) and Tasmar (tolcapone) may also provide pain relief. In turn, the investigational treatment pardoprunox (SLV-308) and surgery reported only moderate benefits on reducing pain severity.

No. 2 – “Medical Cannabis Helps Older People with Parkinson’s, Other Diseases, Study Finds

Medical cannabis is a safe and effective option to ease pain in older patients with Parkinson’s, cancer, or other illnesses. In a study involving 2,736 people 65  years or older, its use over six months enabled a reduction or discontinuation of opioid pain medications in over 18% of patients. Participants also reported an improved quality of life. The most common adverse events were dizziness and dry mouth, reported by 7.1% of patients.

No. 1 – “Vitamin B3 Compound May Prevent Motor Decline in Parkinson’s Disease, Study Says

Out most widely read article of 2018 reported that a form of vitamin B3 — nicotinamide riboside — prevented the loss of motor function and lessened nerve cell death in a fly model of Parkinson’s. It also increased the levels of a metabolic compound called NAD+ and improved energy balance in fish neurons with a defective GBA gene — the most frequent gene risk for Parkinson’s — and defects in mitochondria, the cell’s powerhouse. The researchers suggested that this form of vitamin B3 may help treat impaired mitochondria function, which has been linked to Parkinson’s development.

 

At Parkinson’s News Today, we hope that these articles,  along our continuing reporting throughout 2019, help to educate, inform, and improve the lives of patients and their loved ones.

We wish all our readers a happy 2019.

 

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Xadago, Cannabinoids, Opioids May Be Best to Manage Parkinson’s Pain, Review Suggests

pain management

Treatment with Xadago (safinamide) or cannabinoids and opioids may the best therapeutic options to effectively manage pain in patients with Parkinson’s disease, researchers suggest.

The study, “Comprehensive Examination of Therapies for Pain in Parkinson’s Disease: A Systematic Review and Meta-Analysis,” was published in the journal Neuroepidemiology.

Parkinson’s disease is known mostly for its motor symptoms such as muscle rigidity and tremors, but other non-motor symptoms are very common. About 68-95% of Parkinson’s patients suffer with pain, which can significantly affect their quality of life and promote both depression and anxiety.

There are several therapeutic strategies available for Parkinson’s disease, however their potential to manage disease-associated pain is not established.

Parkinson’s Clinic of Eastern Toronto researchers reviewed available data from 24 published reports to explore current treatments’ capacities for pain relief. The reports covered the results of 25 randomized clinical trials and a total of 1,744 patients undergoing therapeutic interventions and 1,610 patients undergoing a control intervention.

The mean age of study participants was 66 years and most were male (61% and 60% in treatment or control groups, respectively). Mean disease duration was of 7.9 in the treatment group, and 7.2 years in the control group.

The treatment with the biggest capacity to reduce pain severity was Xadago, followed by cannabinoids and opioids, multidisciplinary team care and COMT inhibitors, such as Comtan (entacapone) and Tasmar (tolcapone).

Electrical and Chinese therapies also had some capacity to reduce pain, although results between studies were very heterogeneous.

Treatment with the investigative pardoprunox (SLV-308) and surgery had only moderate effect on reducing pain severity, while the weakest effects were in dopaminergic agonists and miscellaneous therapies.

Collectively these findings revealed that Xadago “is an important adjunct to the standard parkinsonian medications for alleviating pain” in Parkinson’s, while analgesics in the form of opioids and cannabinoids can “be effective but not nearly to the same extent,” researchers wrote.

In addition, the team believes this study shows that adjusting levodopa levels with Comtan rather than with dopaminergic therapies may provide greater pain relief.

Still, additional trials focusing on pain management, as well as in its underlying mechanisms in Parkinson’s patients, are warranted to “form a consensus on the effectiveness of these therapies.”

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Source: Parkinson's News Today