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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FDA Accepts New Drug Application for Opicapone as Add-on Therapy

opicapone Neurocrine

The U.S. Food and Drug Administration has accepted Neurocrine Biosciences’ new drug application for opicapone as a potential add-on therapy to levodopa/carbidopa for Parkinson’s disease.

The FDA has set a 12-month review process, with a decision expected by April 26, 2020. If approved, the FDA will start its Prescription Drug User Fee Act (PDUFA), which authorizes the agency to collect fees from companies that produce certain human therapies and biological products. Since the passage of PDUFA, user fees have played an important role in expediting therapies’ approval process.

Opicapone, developed by Bial and Neurocrine Biosciences, is an oral, once-per-day add-on therapy to levodopa for adults with Parkinson’s, and end-of-dose motor fluctuations.

Levodopa is considered the gold-standard treatment for Parkinson’s. However, its long-term use is linked with end-of-dose, or wearing-off fluctuations, leading to progressively shorter intervals in which symptoms are adequately controlled.

Opicapone works by blocking the enzyme catechol-o-methyltransferase, or COMT, which breaks down levodopa. This can prolong levodopa effects, known as “on-time” or “on-periods.”

The therapy was approved in Europe for Parkinson’s patients with fluctuations that cannot be treated with lepodova or combinations of similar therapies, and whose motor symptoms re-emerge before the next dose is due. It is marketed by Bial in Europe under the brand name Ongentys. Neurocrine holds the rights for opicapone in North America.

Data from over 30 clinical trials, including two Phase 3 trials, BIPARK-1 (NCT01568073) and BIPARK-2 (NCT01227655), support opicapone’s clinical benefits. The trials enrolled more than 900 Parkinson’s patients who could not effectively control their motor symptoms with standard therapies.

In the BIPARK-1 study, participants were randomly selected to receive 5, 25, or 50 mg daily doses of opicapone, plus either levodopa or Comtan (entacapone, marketed by Novartis), or a placebo. In BIPARK-2, opicapone was given as an add-on to either levodopa or placebo. Treatment was maintained for 14 to 15 weeks, after which participants had the opportunity to continue opicapone add-on therapy for more than one year in an open-label extension study.

Data from the BIPARK-1 trial showed that people treated with 50 mg opicapone had twice longer on-time periods without dyskinesia, or involuntary movements, compared with those receiving placebo (controls).

The BIPARK-2 study showed similar results. Participants taking 50 mg of opicapone had 1.7 hours of absolute on-time without dyskinesia compared with 0.9 hours in the placebo group.

The on-time periods were maintained in long-term extension studies for all opicapone-treated patients, with increases of 2 hours in the BIPARK-1 study, and 1.8 hours in the BIPARK-2 trial.

“People living with Parkinson’s disease often struggle to control their motor fluctuations due to the progressive neurodegenerative effects of the disorder. With opicapone, we aim to prolong the benefits of levodopa by providing a new treatment option to patients with Parkinson’s disease in the U.S.,” Eiry W. Roberts, MD, Neurocrine’s chief medical officer, said in a press release.

“It is our goal to help patients maintain good ON time — the period when their motor symptoms are better controlled — and reduce OFF time — the period when the effects of levodopa have worn off. We look forward to working with the FDA to bring this new treatment option to patients coping with this debilitating disorder,” Roberts added.

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IRL790 Is Safe, Reduces Levodopa-induced Dyskinesia in Parkinson’s, Phase 1b Trial Shows

IRL790 and Parkinson's

IRL790, Integrative Research Laboratories‘ investigational treatment for Parkinson’s disease patients, was safe and reduced levodopa-induced dyskinesia, a Phase 1b trial shows.

The results were published in the journal npj Parkinson’s Disease in the study, “Safety and tolerability of IRL790 in Parkinson’s disease with levodopa-induced dyskinesia—a phase 1b trial.”

Parkinson’s disease is a central nervous system disorder characterized by low levels of dopamine, causing tremors, stiffness, or slowing of movement.

Levodopa, a medication that helps counteract the shortage of dopamine in the brain, is the gold standard for treatment of Parkinson’s patients. But more than half the patients who use levodopa experience abnormal, involuntary movements — dyskinesia — within the first five years of treatment.

Studies have shown that long-term treatment with levopoda increases levels of a dopamine receptor, called dopamine D3 receptor, that seems to correlate with levodopa-induced dyskinesia.

IRL790 is a central nervous system medication that mainly targets the dopamine D3 receptor. In rat models of Parkinson’s disease, the treatment reduced involuntary movements caused by levodopa treatment without compromising the animals’ locomotion. Also, IRL790 showed anti-psychotic properties, suggesting its potential for treating both dyskinesia and psychosis in Parkinson’s patients.

In a prior Phase 1 trial, researchers tested ascending doses of IRL790 in healthy male volunteers. The treatment had a very good safety profile, with no serious adverse events reported, even at doses higher than those planned for patients.

Now, a team at the Karolinska Institutet in Sweden conducted a Phase 1b trial to determine the treatment’s safety and efficacy in Parkinson’s patients experiencing levodopa-induced dyskinesia.

The study (NCT03531060) included 15 Parkinson’s patients (nine men and six women) who randomly received oral capsules of IRL790 (11 patients) or an oral placebo (four patients) for four weeks. During the trial, all patients continued receiving their regular medication.

The study’s main objective was to assess the treatment’s safety — measured through the number of adverse events, physical examination, electrocardiogram, heart rate, blood pressure, and other laboratory measurements — after four weeks.

Secondary measures included changes from baseline in dyskinesia, measured with the Unified Dyskinesia Rating Scale (UDysRS), and Parkinson’s scores, measured with the Unified Parkinson’s Disease Rating Scale (UPDRS) and Parkinson’s Kinetigraph.

Thirteen patients completed the 4-week study, with IRL790 given at an average daily dose of 18 mg.

Overall, 14 patients (93.3%) reported 62 adverse effects. Most were reported during the first two weeks — when the dose of IRL790 was adjusted to each patient — and were mild to moderate, easily mitigated by dose adjustments. No serious adverse effects were reported in any of the groups.

Patients taking IRL790 had a mean reduction of 8.2 percent in dyskinesia scores compared to those taking a placebo.

“Among patients treated with IRL790, 55.5% were assessed as having an improved global clinical condition, as compared with baseline (much improved/minimally improved),” researchers stated.

There were no changes in symptoms relating to parkinsonism, either in the UPDRS or in measurements from the Parkinson’s Kinetigraph, a wrist-worn device that evaluates bradykinesia (slowness of movement) and dyskinesia during activities of daily living.

The results show that “IRL790 can be safely administered to patients with advanced PD,  which will now “be of guidance for the design of phase 2 studies,” researchers said.

IRL790 is already being tested in a Phase 2 trial (NCT03368170), which will assess whether the treatment can reduce dyskinesia in a larger population (74 patients). The trial will also help establish the optimal dose for further testing.

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Xadago as Add-on Treatment for Parkinson’s Now Approved in Australia

Xadago approval Australia

Xadago (safinamide) has been approved in Australia as an add-on therapy to a treatment regimen that includes levodopa for adults with idiopathic (no genetic or other known cause) Parkinson’s disease.

This decision by the Therapeutic Goods Administration of the Australian Government Department of Health adds Australia to the list of countries in which Xadago is approved as an add-on treatment for Parkinson’s, including Switzerland, 13 EU countries, and the U.S., where the compound became available in July 2017.

The announcement was made by Zambon, the pharmaceutical company commercializing the therapy, and its partner, Newron Pharmaceuticals, which developed the therapy. Both companies focus on the development of therapies for patients with diseases of the nervous system.

Seqirus, a provider of pharmaceuticals and vaccines in Australia and New Zealand, is also partnering with Zambon to supply the therapy.

Parkinson’s disease is a neurodegenerative disorder for which there currently is no cure. The disease is characterized by the damage or loss of nerve cells within the brain that are responsible for producing the signaling molecule dopamine, a chemical involved in everyday smooth and purposeful movement, such as using a fork to eat, putting on clothes, and walking.

Current therapy with levodopa and/or carbidopa is partially effective, but results in fluctuations between a state of normal motor function (known as “on episodes,” or on-time) and decreased motor function (“off episodes,” or off-time) as the treatment’s effectiveness wears off. In addition, the higher doses required as the disease progresses often result in dyskinesia — uncontrolled involuntary movements.

Xadago works through the selective and reversible inhibition of the enzyme monoamine oxidase B (MAO-B), which increases levels of functional dopamine, and by blocking voltage-dependent sodium channels, which regulates the release of abnormal glutamate, a neurotransmitter in the brain involved in nerve cell communication.

Xadago is an oral, once-a-day, add-on therapy developed to improve motor function in Parkinson’s patients experiencing off episodes. Clinical trials have established its safety and ability to control motor symptoms and complications for more than two years. Results from a 24-month controlled study showed that Xadago had substantial effects on motor fluctuations (on/off time) without increasing the risk for dyskinesia.

“The approval of safinamide in Australia is a great step forward for patients who need new treatment options for Parkinson’s disease,” said Roberto Tascione, CEO of Zambon. “Our partner Seqirus is committed to launch this product and make this innovative therapy available to patients suffering from Parkinson’s disease in Australia.”

Zambon is also currently leading discussions on additional distribution agreements in Europe and the Middle East. Marketing approval and commercialization of Xadago has been filed in Japan and is under review in Brazil, Canada, Colombia, and Israel.

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