Gabapentin Enacarbil Benefits Patients With Severe RLS

Pauline Anderson

April 28, 2014

PHILADELPHIA — A once-daily dose of gabapentin enacarbil (Horizant, Xenoport Inc/GlaxoSmithKline; GEn) is effective in the most severe cases of restless legs syndrome (RLS) and is associated with an adverse effect profile consistent with use in milder disease, according to results of a pooled analysis of previous randomized trials.

It's important to look at severe RLS for a number of reasons, said lead researcher, Daniel O. Lee, MD, Baptist Health Neurology, Richmond, Kentucky. "For one thing, restless leg syndrome is probably the most common neurologic movement disorder that any clinician will encounter," Dr. Lee told Medscape Medical News.

As well, there appears to be a strong association between severe RLS and cardiovascular risks. "It has been reported that the higher the frequency and severity of RLS, the stronger the association with cardiovascular risks," said Dr. Lee.

This is first study conducted on severe RLS, said Dr. Lee. Most published papers have addressed moderate RLS, he added.

The research was presented here at the American Academy of Neurology (AAN) 66th Annual Meeting.

Pooled Data

GEn is an actively transported prodrug of gabapentin that has been approved in the United States for moderate to severe RLS. Dr. Lee stressed that GEn differs from gabapentin in terms of its chemical structure, pharmacokinetics, bioavailability, and rate of absorption.

From pooled data in 3 previous 12-week double-blind, randomized trials, researchers investigated a subset of patients with severe RLS taking GEn, 600 mg (n = 80); GEn, 1200 mg (n = 119); or placebo (n = 110). Patients in the studies took the drug or placebo once daily with food at 5 pm.

The 3 previous trials were XP052, which compared GEn, 1200 mg once daily, with placebo; XP053, which compared GEn, 1200 mg and 600 mg once daily, with placebo; and XP081, which examined the pharmacokinetics, efficacy, and safety of 600, 1200, 1800, and 2400 mg of GEn and placebo.

In these studies, RLS was defined as presence of symptoms for at least 15 days a month (not during treatment), RLS symptoms for 4 or more of the 7 consecutive evenings or days during the baseline period, and an International RLS (IRLS) total score of at least 15.

In the current analysis, severe RLS was considered as an IRLS total score of 24 or more.

The study found a statistically significant mean differences in IRLS total score for both GEn, 600 mg, vs placebo (–4.0; P = .003) and GEn, 1200 mg, vs placebo (–5.7; P < .001).

Compared with placebo, both doses of GEn significantly improved IRLS total score from baseline at each time point during the 12-week trial. "The benefit was so robust that you see it as early as week 1," commented Dr. Lee.

Although the study wasn't powered to compare 1 dose to another, "if you look a bit closer, it does show that the 1200 mg is slightly better numerically than 600 mg in severe restless leg syndrome," said Dr. Lee.

He and his colleagues also wanted to see whether the drug was clinically relevant in the population with severe RLS. For this, they looked at the Clinical Global Impression-Improvement (CGI-I) scale.

"Once again, at every single time point, you can see the improvement very clearly," said Dr. Lee.

At 12 weeks, patients treated with 600 or 1200 mg of GEn were significantly more likely than placebo recipients to be responders on the CGI-I.

Somnolence and dizziness were the most commonly reported treatment-related adverse events, a finding similar to that seen in the overall study population.

"We're excited to say that this study demonstrated that even those individuals who suffer from severe RLS can benefit from gabapentin enacarbil," commented Dr. Lee.

RLS affects about 10% to 15% of the population, with some 2% to 3% of these having a severe syndrome, said Dr. Lee. "This translates into about 5 million Americans."

Improvements "Impressive"

Asked to comment, Sana Bloch, MD, assistant clinical professor, neurology, Albert Einstein College of Medicine, Bronx, New York, who treats many patients with RLS, said that the improvements seen in this study are "impressive" but that a longer-term study is needed.

"Restless leg syndrome is a disease entity that affects patients for their lifetime and yet the research is done for 26 weeks at best, and so it's difficult to make a comparison," said Dr. Bloch. "I'm still waiting for a comparator study in which one is able to titrate up doses of medication over time and get to the same levels of maximum medication."

To have a "full understanding" of which drug is superior in the treatment of severe RLS, a "head-to-head study between all the medications" that promise improvements needs to be done, said Dr. Bloch.

From a purely economic standpoint, Dr. Bloch said GEn would not be his first choice of drug for his patients with RLS, many of whom are from economically depressed areas of the Bronx.

The study was supported by Xenoport Inc. Dr. Lee is a speaker and consultant for XenoPort Inc, whose gabapentin enacarbil agent, Horizant, is approved by the US Food and Drug Administration for moderate to severe RLS.

American Academy of Neurology (AAN) 66th Annual Meeting. Abstract 13-1.009. Presented April 28, 2014.

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