Pauline Anderson

December 24, 2013

WASHINGTON, DC — Doctors treating patients with epilepsy should soon have a new extended-release anticonvulsant available to prescribe.

A New Drug Application for extended-release topiramate has been accepted for review by the US Food and Drug Administration, and the agent should have completed the regulatory process in the first half of next year, according to Bill Pullman, MD, PhD, chief scientific officer at Upsher-Smith, the company developing the new drug.

This agent, along with another of the company's investigational drugs, intranasal midazolam, was showcased in numerous posters and a scientific session during the American Epilepsy Society (AES) 67th Annual Meeting.

Achilles Heel

While immediate-release topiramate has a proven track record in terms of efficacy, patients taking this version of the drug can experience fluctuations in plasma concentration throughout the day, which can increase the risk for breakthrough seizures, and its adverse effect profile, particularly with respect to somnolence, attention, and other cognitive effects, has been something of an "Achilles heel" for the drug, Dr. Pullman told Medscape Medical News.

"We have selectively engineered a new formulation of topiramate with extended-release characteristics that reduce the fluctuation index, or the peak concentrations, that are felt to be responsible for the side effect profile, but at the same time maintaining the minimum concentrations required for efficacy."

Reducing the number of doses is the "holy grail" for drug development, and extended-release topiramate gives patients the freedom to take it when they want during the day, with or without food, Dr. Pullman added.

Much of the research highlighted at the AES meeting focused on findings from the phase 3 PREVAIL trial, which included 249 patients with partial-onset seizures with 8 or more seizures and 21 or fewer seizure-free days during an 8-week baseline phase.

Patients, who were taking 1 to 3 other antiepileptic drugs (AEDs), were randomly assigned to also receive the active drug or placebo.

Results showed that at 11 weeks (3-week titration plus 8-week maintenance), the active treatment was associated with a significantly greater median percentage reduction in seizure frequency compared with placebo (39.5% vs 21.6%; P < .001.) The 50% responder rate was also significantly greater (37.9% vs 23.2%; P = .013).

Subgroup analysis revealed that the drug was effective in patients with all types of partial-onset seizures with a variety of concomitant AEDs, and in the most refractory of patients.

Few Adverse Events

Other trial findings revealed that extended-release topiramate was effective as early as the first week of treatment, with significant seizure reduction sustained throughout the remaining weeks of study. In addition, it was safe and well tolerated, with a low incidence of adverse neurocognitive events and high treatment adherence.

Both clinicians and patients reported improved functional status with no adverse effect on quality of life.

The company reports that to date, 96.8% of patients who completed the double-blind portion of PREVAIL elected to continue in a year-long open-label extension study of the drug. While that study is ongoing, interim exposure and safety data suggest that the agent, at dosages up to 400 mg/d, is generally well tolerated as an adjunctive treatment.

Another study, a phase 1, open-label, single-center, single-dose, crossover study of 36 healthy participants, showed that ingesting the contents of an extended-release capsule sprinkled on food resulted in the same pharmacokinetic properties as ingesting the capsule whole.

"So you can put it on apple sauce or whatever and not run the risk of adverse events because the concentrations are too high, or because of lack of efficacy," said Dr. Pullman.

Results from studies of another of Upsher-Smith's investigational agents, intranasal midazolam, were also released at the AES meeting. This agent is designed as a rescue treatment of intermittent bouts of increased seizure activity.

The only medication now approved in the United States for such rescue treatment on an outpatient basis is rectal diazepam (Diastat), but many patients find this route inconvenient or are too embarrassed to use it.

Nasal Rescue

Phase 1 data demonstrated that single doses of intranasal midazolam had rapid peak pharmacokinetic and pharmacodynamic effects, with fast return to baseline.

Although it was associated with dose-dependent increases in sedation and psychomotor impairment, these effects were not excessive or prolonged and returned to near baseline values within 4 hours. The agent was safe and generally well tolerated, with no respiratory events.

The intranasal version of midazolam is the subject of an ongoing international phase 3 clinical trial (ARTEMIS1) with an open-label safety extension study.

Control of acute repetitive seizures is particularly problematic in school-aged children, noted Dr. Pullman.

"You want to have an agent that you can administer easily, and you want an agent that is known to have an effect and has a rapid onset, but not to have an overly delayed or negative impact on sedation."

This isn't the only research investigating an alternative route to deliver benzodiazepines, considered effective rescue therapies for seizure emergencies. Other alternatives being developed were also discussed at the AES.

According to Upsher-Smith, seizure emergencies represent about 1% to 2% of all emergency department visits in the United States.

Dr. Pullman is an employee of Upsher-Smith.

American Epilepsy Society (AES) 67th Annual Meeting. Abstracts 1.221, 2.116, 1.222, 1.219, 1.223 2.117.

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