The European Union Committee for Medicinal Products for Human Use (CHMP) has recommended that the European Commission approve the drug Xadago for Parkinson’s disease (PD) as an add-on treatment to levodopa (see company press release). Going by the generic name safinamide, this is the first new chemical entity for PD to be recommended for approval in Europe in 10 years. Two alternative strategies for delivering levodopa were also approved in the United States. The Food and Drug Administration gave the thumbs-up to an extended-release levodopa capsule called Rytary, as well as a gel form of the drug known as Duopa.
Safinamide exerts dopaminergic and non-dopaminergic actions. Because it inhibits monoamine oxidase B, an enzyme that breaks down dopamine, it raises levels of the neurotransmitter in synapses. The approved PD drugs selegiline and rasagiline work the same way. Safinamide also blocks the release of glutamate, which may cut down on neuronal hyperactivity that causes involuntary, uncontrollable movement—or dyskinesia—when patients are on levodopa. This compound was developed by Newron Pharmaceuticals, based in Bresso, Italy, in partnership with the pharmaceutical company Zambon in nearby Milan.
CHMP recommends safinamide as an adjunctive therapy for patients with mid- to late-stage PD who lose motor control despite long-term levodopa treatment. Two Phase 3 trials evaluated the efficacy of safinamide in these patients. In the six-month SETTLE study of 549 patients, and in the two-year Study 016/018 of more than 544 (see Borgohain et al., 2014), safinamide extended the time patients had motor control by 0.5 to 0.9 hours per day. It improved scores on the Unified Parkinson’s Disease Rating Scale (UPDRS), and on quality-of-life measures, depressive symptoms, and activities of daily living. In both trials, patients tolerated safinamide well and few dropped out.
Newron has filed a new drug application with the FDA, but safinamide has not yet been approved for use in the United States.
“This will be a useful new drug for patients who are being treated with levodopa when it no longer works well,” said David Standaert, University of Alabama at Birmingham. He and C. Warren Olanow, Mount Sinai Hospital, New York, agreed that safinamide’s multiple mechanisms of action make it look particularly promising. However, while preliminary data suggests that this drug will lower dyskinesia, further trials will be needed to confirm that, they said.
CHMP's recommendation coincides with the FDA's recent approvals. On January 8, it gave the green light to an extended-release form of levodopa called Rytary (see company press release). This capsule is filled with immediate- and extended-release beads of levodopa and carbidopa, which prevents metabolism of levodopa, extending its half-life. In clinical trials, Rytary shortened "off time," the periods when levodopa was not working well. Impax Pharmaceuticals of Hayward, California, expects Rytary to be available to patients in February of this year.
On January 12, the FDA approved Duopa, an intestinal gel form of levodopa and carbidopa from the North Chicago-based biopharmaceutical company AbbVie (see company news release). This gel is administered directly into the small intestine through a tube surgically implanted in the abdomen. The idea is to avoid giving the drug through the stomach because it unpredictably empties into the small intestine in people with Parkinson’s, making it difficult to control when oral medications are absorbed. Duopa steadies plasma levels of the drugs. In a 12-week Phase 3 trial, the gel reduced daily "off" time by almost two hours compared with immediate-release carbidopa-levodopa tablets. Duopa was approved in Europe in 2004.
“It’s been a long time since any drug has been approved for Parkinson’s disease,” Olanow told Alzforum. “I’m pleased to see this flurry of activity.” None of these drugs are game-changers, but small improvements are still important.—Gwyneth Dickey Zakaib
- Borgohain R, Szasz J, Stanzione P, Meshram C, Bhatt MH, Chirilineau D, Stocchi F, Lucini V, Giuliani R, Forrest E, Rice P, Anand R, Study 018 Investigators. Two-year, randomized, controlled study of safinamide as add-on to levodopa in mid to late Parkinson's disease. Mov Disord. 2014 Sep;29(10):1273-80. Epub 2014 Jul 10 PubMed.
- Borgohain R, Szasz J, Stanzione P, Meshram C, Bhatt M, Chirilineau D, Stocchi F, Lucini V, Giuliani R, Forrest E, Rice P, Anand R, Study 016 Investigators. Randomized trial of safinamide add-on to levodopa in Parkinson's disease with motor fluctuations. Mov Disord. 2014 Feb;29(2):229-37. Epub 2013 Dec 9 PubMed.