New Safety Data on Lacosamide Reassure, but Questions Remain About Cognitive Effects

Allison Gandey

December 07, 2009

December 7, 2009 (Boston, Massachusetts) — New safety data suggest that adverse events associated with lacosamide at 6 months and 1 year are similar to short-term results reported in clinical trials. Presenting here at the American Epilepsy Society 63rd Annual Scientific Conference, investigators outlined vital signs, body weight, clinical laboratory, and electrocardiography findings.

"This is a clean drug," lead investigator William Rosenfeld, MD, from the Comprehensive Epilepsy Care Center for Children and Adults in Chesterfield, Missouri, said during an interview. "We started studying this therapy 7 years ago, and we are finding that the side effects are quite low."

Dr. William Rosenfeld

Another study presented at the same poster session at the meeting provided a preliminary evaluation of the risk for cognitive adverse events associated with lacosamide. Those results suggest that therapy may prompt cognitive changes in patients.

Lacosamide (Vimpat, UCB Pharma) was approved by the US Food and Drug Administration in October 2008. Formerly known as erlosamide, the product was developed as adjunctive treatment for partial-onset seizures and diabetic neuropathic pain. It is thought to exert its therapeutic effects through a different mechanism of action by enhancing slow inactivation of sodium channels.

The new safety data provided by Dr. Rosenfeld's team include phase 2 and 3 clinical trials and extension studies. There were 4 initial studies and 3 open-label extensions.

More than 1300 patients received one or more doses of lacosamide. This represents more than 2660 patient-years of exposure. At the time of this interim analysis, 526 patients (40%) were still enrolled in lacosamide clinical trials.

Table 1. Status of Patients Enrolled in Lacosamide Long-term Safety Studies

Patients Long-term Safety Pool, No. (%) Open-Label Extension Trials, No. (%)
Treated 1327 (100) 1054 (100)
Completed 37 (2.8) Ongoing
Discontinued 764 (57.6) 528 (50.1)
Ongoing 526 (39.6) 526 (49.9)

 

Most patients (62%) had a modal dose of lacosamide of 400 mg/day or more. Most received the drug for more than 6 months (88%) or a year (76%).

Table 2. Reasons for Discontinuation

Reason Long-term Safety Pool, % Open-Label Extension Trials, %
Adverse event 20.5 10.0
Lack of efficacy 20.7 25.0
Withdrew consent 10.1 9.5
Protocol deviation 1.2 0.5
Unsatisfactory compliance 2.3 1.6
Lost to follow-up 1.1 1.2
Other 3.2 3.3

 

The most common adverse events were dizziness (46%), headache (21%), diplopia (19%), nausea (15%), and nasopharyngitis (14%). Some patients also experienced vomiting, fatigue, abnormal coordination, visual blurriness, tremor, somnolence, convulsion, and contusions.

The investigators also observed a small increase in the mean PR interval on electrocardiograms. Some patients (0.8%) experienced a first-degree atrioventricular block.

We were reassured to see the cardiovascular findings in the range we anticipated.

"We were reassured to see the cardiovascular findings in the range we anticipated," Dr. Rosenfeld said. "We also saw no major changes in body weight for patients taking lacosamide."

Investigators report that they did not observe any pattern of change in the median or mean measurements for hematology, clinical chemistry, or vital signs.

Asked by Medscape Neurology to comment on the study, Patricio Espinosa, MD, from the International Center on Neurosciences in Mandeville, Louisiana, said, "These findings reflect what I would have expected to see with this drug."

Dr. Espinosa says he prescribes lacosamide and has a positive impression of its safety profile. "It is generally well tolerated and is a lot like Keppra," he said. The popular UCB Pharma product is also known as levetiracetam.

Cognitive Adverse Events

A second preliminary study evaluated the risk for cognitive adverse events associated with lacosamide. Investigators led by David Hebert, MD, from Schwarz Biosciences — part of UCB Pharma — conducted a post hoc analysis of the same phase 2 and 3 clinical trials.

Patients were 16 to 70 years of age with partial-onset seizures, and investigators found that some experienced cognitive adverse events with therapy.

They report that 8.5% in the lacosamide, 400 mg/day, group experienced cognitive changes. The rate was higher with increasing doses of the drug. Fewer patients in the placebo group receiving 1 to 3 concomitant therapies experienced cognitive adverse events — just 4.7%.

The adverse events included memory impairment, cognitive disorders, confusion, disruptions in attention, and mental difficulties. Dr. Hebert and his team suggest that formal neuropsychiatric testing is needed to determine the full cognitive profile of the drug.

This study was funded by UCB Pharma. Dr. Rosenfeld has received research support from the company and is on the UCB speaker's bureau.

American Epilepsy Society (AES) 63rd Annual Scientific Conference: Poster 2.231. Presented December 6, 2009.

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