Xadago (safinamide) is an oral, once a day adjunctive therapy developed by Newron Pharmaceuticals to improve motor function in Parkinson’s disease patients experiencing “off episodes”

Xadago was approved in 2015 for use in the European Union as an add-on therapy to levodopa, alone or in combination with other Parkinson’s medications, making it  first new drug approved in 10 years for patients. The U.S. Food and Drug Administration (FDA) followed, approving Xadago as an additional therapy for people using levodopa/carbidopa in March 2017.

Parkinson’s disease is a neurodegenerative disorder for which there is currently 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 smooth and purposeful movement (eating, dressing, shaving, walking).

Current therapy with levodopa and/or Lodosyn (carbidopa) is partly effective, but results in debilitating 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 declines. In addition, the higher doses required as the disease progresses often result in uncontrolled involuntary movements (dyskinesia).

How Xadago works

Xadago works in two main ways. First, it increases the level and function of dopamine in the brain, both via potent reversible inhibition of the enzyme monoamine oxidase B that normally breaks down this chemical, and also by inhibiting (blocking) transporters that are responsible for its uptake, or its absorption and retention. Second, Xadago inhibits the excessive release of the neurotransmitter, or signaling molecule, glutamate.

Studies with Xadago

The treatment’s approval was supported by four randomized, double-blind, and placebo-controlled Phase 3 trials. In the first (NCT01187966) study, about 670 patients with mid- to late-stage Parkinson’s and motor fluctuations received either a placebo, or a low dose (50 mg/day) or high dose (100 mg/day) of Xadago in conjunction with a stable dose of levodopa for 24 weeks. Published results showed that the addition of Xadago (at either dose) increased on-time with no or non-troublesome dyskinesia, decreased off-time, and improved motor function in treated patients using levodopa.

This study was linked to an extension trial (NCT01286935), in which patients continued with their assigned treatment for a further 18 months. While the incidence of dyskinesia did not differ between the Xadago and placebo groups, Xadago was associated with improvement in patients with at least moderate dyskinesia at baseline. On-time and off-time episodes improved (without dyskinesia), as did ability to go about daily life activities, motor function and overall quality of life, and depression was seen to ease.

A further Phase 3 study (NCT00627640, SETTLE)  involved 549 patients with motor fluctuations on a regimen of levodopa plus benserazide or Lodosyn. Patients were randomized to receive Xadago (50 mg per day increased to 100 mg per day if tolerated) or placebo. The length of on-time periods without dyskinesia (again, involuntary movements) and motor function were seen to improve in treated mid- to late-stage Parkinson’s patients. The treatment was also well-tolerated.

Further supportive evidence came through a Phase 3 study (NCT00605683, MOTION)  involving 679 early Parkinson’s patients receiving stable therapy with a single dopamine agonist (a drug which stimulates the dopamine signaling pathway). In these people, treatment with Xadago was seen to significantly improve motor function.

Indications and side effects

The side effects most commonly associated with Xadago include dyskinesia, falls, nausea, and trouble sleeping.

Some patients are advised not take safinamide, including individuals with severe liver impairment, and those taking other monoamine oxidase inhibitors, opioid drugs, St. John’s wort, certain antidepressants, cyclobenzaprine, or the cough and cold medicine dextromethorphan.

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