Experimental Prodrug May Ease Restless Legs, Aid Sleep

CHICAGO – An investigational gabapentin prodrug may be an effective therapy for symptoms and sleep problems associated with restless legs syndrome, Dr. Arthur S. Walters reported at the annual meeting of the American Neurological Association.

The active compound gabapentin has already been shown to improve the sensory and motor symptoms of restless legs syndrome (RLS) and decrease periodic leg movements during sleep, but the drug is approved only for treating epilepsy and postherpetic neuralgia, according to Dr. Walters of the Seton Hall University School of Graduate Medical Education, Edison, N.J.

The gabapentin prodrug XP13512 has several potential advantages over standard gabapentin for treating RLS: The agent has linear pharmacokinetics, doesn't reach a saturation point, and is formulated for sustained release. The capacity for once-daily dosing differentiates gabapentin prodrug XP13512 from the active compound gabapentin (Neurontin), which cannot be manufactured in a sustained-release delivery and must be taken three to four times per day, Dr. Walters discussed on his poster at the meeting.

XenoPort Inc., the drug's manufacturer, has sponsored two phase II, randomized, double-blind trials. One of these trials was a crossover study with 38 patients testing 1,800 mg XP13512 against placebo. The other trial compared XP13512 at 600 mg and 1,200 mg and placebo in 95 patients without any crossover. In both studies, patients had RLS symptoms at least 4 nights during a 7-day baseline period and had a score of at least 15 (out of a possible 40) on the International RLS Study Group rating scale (IRLS). Most patients were white, and mean age was about 50 years.

Compared with patients given placebo, patients treated with the gabapentin prodrug had significantly greater improvement (decreases) in IRLS scores at doses of 1,800 mg (20.4–8.4 vs. 20.4–18.5) and 1,200 mg (22.4–6.3 vs. 22.4–13.5) at the end of the 2-week trial. The patients who received XP13512 at 1,200 mg also had significantly greater improvement than those who received 600 mg. Clinical global impressions of change from both patients and investigators followed the same trend and were significantly in favor of patients who received XP13512, reported Dr. Walters, who received compensation for consulting with XenoPort.

Polysomnographic assessments in the crossover study found that patients had significantly more total sleep time (25 minutes) while receiving the gabapentin prodrug than with placebo. In both studies, patients who received XP13512 had significantly fewer awakenings and spent less time awake per night because of RLS symptoms.

More than 30% of patients who received either 1,200 mg or 1,800 mg of XP13512 experienced somnolence. Dizziness also occurred in 28% of patients at 1,800 mg and in 18% at 1,200 mg. In most cases, the events were transient and mild. Other adverse events occurred at much lower rates, and none were serious.

CHICAGO – An investigational gabapentin prodrug may be an effective therapy for symptoms and sleep problems associated with restless legs syndrome, Dr. Arthur S. Walters reported at the annual meeting of the American Neurological Association.

The active compound gabapentin has already been shown to improve the sensory and motor symptoms of restless legs syndrome (RLS) and decrease periodic leg movements during sleep, but the drug is approved only for treating epilepsy and postherpetic neuralgia, according to Dr. Walters of the Seton Hall University School of Graduate Medical Education, Edison, N.J.

The gabapentin prodrug XP13512 has several potential advantages over standard gabapentin for treating RLS: The agent has linear pharmacokinetics, doesn't reach a saturation point, and is formulated for sustained release. The capacity for once-daily dosing differentiates gabapentin prodrug XP13512 from the active compound gabapentin (Neurontin), which cannot be manufactured in a sustained-release delivery and must be taken three to four times per day, Dr. Walters discussed on his poster at the meeting.

XenoPort Inc., the drug's manufacturer, has sponsored two phase II, randomized, double-blind trials. One of these trials was a crossover study with 38 patients testing 1,800 mg XP13512 against placebo. The other trial compared XP13512 at 600 mg and 1,200 mg and placebo in 95 patients without any crossover. In both studies, patients had RLS symptoms at least 4 nights during a 7-day baseline period and had a score of at least 15 (out of a possible 40) on the International RLS Study Group rating scale (IRLS). Most patients were white, and mean age was about 50 years.

Compared with patients given placebo, patients treated with the gabapentin prodrug had significantly greater improvement (decreases) in IRLS scores at doses of 1,800 mg (20.4–8.4 vs. 20.4–18.5) and 1,200 mg (22.4–6.3 vs. 22.4–13.5) at the end of the 2-week trial. The patients who received XP13512 at 1,200 mg also had significantly greater improvement than those who received 600 mg. Clinical global impressions of change from both patients and investigators followed the same trend and were significantly in favor of patients who received XP13512, reported Dr. Walters, who received compensation for consulting with XenoPort.

Polysomnographic assessments in the crossover study found that patients had significantly more total sleep time (25 minutes) while receiving the gabapentin prodrug than with placebo. In both studies, patients who received XP13512 had significantly fewer awakenings and spent less time awake per night because of RLS symptoms.

More than 30% of patients who received either 1,200 mg or 1,800 mg of XP13512 experienced somnolence. Dizziness also occurred in 28% of patients at 1,800 mg and in 18% at 1,200 mg. In most cases, the events were transient and mild. Other adverse events occurred at much lower rates, and none were serious.

CHICAGO – An investigational gabapentin prodrug may be an effective therapy for symptoms and sleep problems associated with restless legs syndrome, Dr. Arthur S. Walters reported at the annual meeting of the American Neurological Association.

The active compound gabapentin has already been shown to improve the sensory and motor symptoms of restless legs syndrome (RLS) and decrease periodic leg movements during sleep, but the drug is approved only for treating epilepsy and postherpetic neuralgia, according to Dr. Walters of the Seton Hall University School of Graduate Medical Education, Edison, N.J.

The gabapentin prodrug XP13512 has several potential advantages over standard gabapentin for treating RLS: The agent has linear pharmacokinetics, doesn't reach a saturation point, and is formulated for sustained release. The capacity for once-daily dosing differentiates gabapentin prodrug XP13512 from the active compound gabapentin (Neurontin), which cannot be manufactured in a sustained-release delivery and must be taken three to four times per day, Dr. Walters discussed on his poster at the meeting.

XenoPort Inc., the drug's manufacturer, has sponsored two phase II, randomized, double-blind trials. One of these trials was a crossover study with 38 patients testing 1,800 mg XP13512 against placebo. The other trial compared XP13512 at 600 mg and 1,200 mg and placebo in 95 patients without any crossover. In both studies, patients had RLS symptoms at least 4 nights during a 7-day baseline period and had a score of at least 15 (out of a possible 40) on the International RLS Study Group rating scale (IRLS). Most patients were white, and mean age was about 50 years.

Compared with patients given placebo, patients treated with the gabapentin prodrug had significantly greater improvement (decreases) in IRLS scores at doses of 1,800 mg (20.4–8.4 vs. 20.4–18.5) and 1,200 mg (22.4–6.3 vs. 22.4–13.5) at the end of the 2-week trial. The patients who received XP13512 at 1,200 mg also had significantly greater improvement than those who received 600 mg. Clinical global impressions of change from both patients and investigators followed the same trend and were significantly in favor of patients who received XP13512, reported Dr. Walters, who received compensation for consulting with XenoPort.

Polysomnographic assessments in the crossover study found that patients had significantly more total sleep time (25 minutes) while receiving the gabapentin prodrug than with placebo. In both studies, patients who received XP13512 had significantly fewer awakenings and spent less time awake per night because of RLS symptoms.

More than 30% of patients who received either 1,200 mg or 1,800 mg of XP13512 experienced somnolence. Dizziness also occurred in 28% of patients at 1,800 mg and in 18% at 1,200 mg. In most cases, the events were transient and mild. Other adverse events occurred at much lower rates, and none were serious.