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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Alzheimer’s Treatment Not Seen to Aid Patients’ Balance After 6 Weeks, Small Study Suggests

Parkinson's and balance

Treatment with Aricept (donepezil) for six weeks does not seem to improve balance, either while standing or walking, for Parkinson’s patients with a minimal history of falls, according to results from a single-site Phase 2 trial.

The study, “Effects of augmenting cholinergic neurotransmission on balance in Parkinson’s Disease,” was published in the journal Parkinsonism and Related Disorders.

Motor and cognitive abilities depend on the coordinated interaction in the brain of two neurotransmitters — chemical substances that act as messengers and allow brain cells to communicate — called dopamine and acetylcholine.

In the brain of people with Parkinson’s, damage to neurons that produce dopamine and acetylcholine affect balance and gait. As the disease progresses, difficulties with such skills increase.

Impaired balance and gait impacts patients’ quality of life and risk falls. “Loss of mobility in the home and community affects tasks required for independent living and participation in family and community affairs. Falls cause minor to major trauma; the injuries restrict a person’s activities and add to the fear of falling which further reduces mobility,” the researchers wrote.

These symptoms cannot always be controlled by using dopaminergic therapies such as levodopa, suggesting the treatments targeting the production of acetylcholine might also help patients.

Aricept is a cholinesterase inhibitor that increases the levels of acetylcholine in the brain by preventing its breakdown. It is used to treat the symptoms of dementia caused by Alzheimer’s disease.

In a previous a small trial, Aricept (marketed by Eisai and Pfizer) was shown to lower the number of falls in Parkinson’s patients who were frequent fallers.

Researchers at Oregon Health & Science University hypothesized that measuring standing balance and dynamic (walking) balance, problems in both of which can cause falls, would allow them to assess if Aricept was of benefit to people with mild to moderately severe Parkinson’s disease.

Static balance is the ability to maintain postural stability and orientation with the body at rest, while dynamic balance is the ability to maintain postural stability and orientation while the body is in motion.

They designed a randomized, crossover Phase 2 trial (NCT02206620) in 49 Parkinson’s patients, mean age of 69. Participants were randomly assigned to a six-week treatment with Aricept, followed by a six-week treatment with placebo, or vice-versa, with six weeks of “washout” between each treatment. A washout period is the time in a clinical study during which a participant is taken off the investigative therapy, or other medication/placebo, so as to eliminate its effects on further treatment.

Oral capsules of Aricept were initially given at 5 milligrams (mg) a day, increasing to 10 mg a day after the first three weeks. Forty-five people completed the study; all had no or a limited fall history (could stand and walk unassisted for at least one minute) and reasonably healthy cognition.

The study’s main goal (endpoint) was to measure patients’ static and dynamic balance. Static balance was evaluated while they were standing with their feet together looking straight ahead at a fixed point with eyes open.

For dynamic balance assessments, participants were instructed to walk for two minutes at a comfortable pace up and down a 20-meter hallway.

As secondary goals researchers measured two parameters used as a readout of acetylcholine levels: the Attention Network Test, a 15-minute computerized test that measures attention and can determine whether changes in gait and balance are associated with changes in attention; and the Short Latency Afferent Inhibition (SAI), a transcranial magnetic stimulation method to evaluate cortical cholinergic activity.

Results showed that Aricept treatment had no effects on patients’ static and dynamic balance compared to the placebo. Secondary outcome measures of attention and SAI were also not significantly affected by treatment. Only one single parameter of static balance — postural sway — improved after treatment with donepezil.

“Contrary to our hypothesis, cholinergic augmentation with [Aricept] at 10 mg/day for 6 weeks did not affect measures of static or dynamic balance in people with PD,” the researchers wrote.

These results are in contrast with previous trials but a possible explanation, the researchers said, is the fact that “our participants may have had less impairment of cholinergic systems than the participants in the other studies.” Parkinson’s patients those studies, they added, all had an average history of at least one fall each week, and some had gait “freezing, indicating more advanced” disease.

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Calcium Channels May Be Therapeutic Target in Parkinson’s, Stem Cell Study Suggests

calcium channels, Parkinson's

Targeting specific calcium channels in dopamine-producing neurons may be a therapeutic target for Parkinson’s disease, according to research involving cells derived from Parkinson’s patients.

The study, “T-type calcium channels determine the vulnerability of dopaminergic neurons to mitochondrial stress in familial Parkinson’s disease,” was published in Stem Cell Reports.

For most Parkinson’s patients, symptoms are idiopathic, or of unknown cause, making it difficult to understand the relationship between various factors that may cause disease. However, roughly 10% of patients show the familial incidence of Parkinson’s disease, which allows researchers to study the underlying mechanisms of disease in these patients, helping them understand common causes in all patients, as well as unravel potential therapeutic targets.

Prior generation of induced pluripotent stem cells (iPSCs) from patients with familial Parkinson’s successfully replicated the disease processes. iPSCs are derived from either skin or blood cells that have been reprogrammed back into a stem cell-like state, which allows for the development of an unlimited source of any type of human cell needed for therapeutic purposes.

Aiming to provide iPSCs-based ways to treat neurological diseases, Keio University School of Medicine and Eisai started a collaboration in 2013. Their joint research led to the generation of dopamine-producing neurons — progressively degenerated in Parkinson’s, leading to its motor symptoms — from familial Parkinson’s patients’-derived iPSC.

They also established a drug library of more than 1,000 existing compounds to screen treatment candidates.

The study, partially funded by Eisai, used neural progenitor cells, which differentiate into brain cells, including neurons, derived from two familial Parkinson’s disease patients with mutations in the PRKN gene (PARK2 type). PRKN is the most commonly implicated gene in young-onset Parkinson’s disease.

“The current procedure is more advanced in terms of simplicity and robustness for neuronal differentiation, enabling us to perform screening without complicated work,” researchers noted.

The approach enabled the efficient generation of dopamine-producing neurons in vitro, which, compared to healthy neurons, had reduced size of projections, as well as increased oxidative stress and apoptosis, or “programmed” cell death, as opposed to cell death caused by injury.

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

Gene editing in iPSCs to create similar mutations led to the same disease-related alterations.

Researchers also found that Parkinson’s-derived neurons were more susceptible to mitochondrial stress induced by rotenone, an agrochemical that acts as a mitochondrial inhibitor. Mitochondria are small cellular organelles that provide energy and are known as cells’ “powerhouses”.

Screening their library enabled the identification of several compounds able to suppress rotenone-induced apoptosis, particularly T-type calcium channel blockers benidipine (used for the treatment of blood pressure) and ML218.

These particular calcium channels are present in many neuronal cells within the central nervous system. They help mediate calcium influx into neurons after passing electrical impulses to communicate among themselves.

These blockers also were able to lower stress-induced apoptosis in dopamine-producing neurons derived from patients with a different type of familial Parkinson’s (PARK6), caused by a mutation in the PINK1 gene. These neurons also had higher levels of T-type calcium channels.

“These findings suggest that calcium homeostasis in [dopamine-producing] neurons might be a useful target for developing new drugs for [Parkinson’s] patients,” researchers wrote.

“In summary, we have established a robust platform to model [Parkinson’s] in a dish and revealed an additional layer of the pathogenesis of PD, offering a potential therapeutic target,” they added.

Future work will use experimental approaches to model the brain in vivo and to have different types of brain cells in the same dish with the goal of validating these therapeutic targets.

Of note, six of the study’s authors are employees at Eisai.

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