Cenobamate Not Associated With Clinically Significant Weight Change in Epilepsy Treatment

Louis Ferrari, RPh, MBA

Data from the phase 2 and 3 clinical development of cenobamate (Xcopri; SK Life Science) suggest that adjunctive use of the treatment was not associated with clinically significant changes in weight for those treated for 1 and 2 years. Notably, cenobamate exposure was associated with weight reductions among individuals who were overweight and obese, but not in those who were underweight or normal weight.¹

Ultimately, among patients treated with the SK Life Science agent in 3 clinical studies—Study C013 (NCT01397968; n = 39), Study C017 (NCT01866111; n = 206), and Study C021 (NCT02535091; n = 1054)—the median weight changes from baseline to year 1 ranged from –0.2 kg in Study C021 (n = 1054) to –0.9 kg in Study C017(n = 206). From baseline to 2 years, the median weight change ranged from –1.0 kg in Study C017 (n = 176) to 1.0 kg in Study C013 (n = 21).

The data were presented as a poster at the 2022 American Epilepsy Society Annual Meeting, held December 2 to 6, in Nashville, Tennessee, by Louis Ferrari, RPh, MBA, vice president of medical affairs at SK Life Science. “Some ASMs [antiseizure medications], such as valproate, gabapentin, and pregabalin, are associated with weight gain. Treatment-associated weight gain correlates with negative health effects such as cardiac disease, diabetes, high blood pressure, and elevated cholesterol, reduced quality of life and mental health, and reduced compliance,” Ferrari et al wrote.

At baseline in the 3 studies, the mean weight was 73.3 kg (SD, 16.9) in Study C013, 75.9 kg (SD, 18.7) in Study C017, and 77.9 (SD, 18.4) in Study C021. The respective baseline median weights for the trials were 72.1 kg (range, 43.0-119.0), 74.6 kg (range, 41.0-161.0), and 52.1 kg (range, 32.0-167.0). Baseline BMIs were 26.0 (SD, 5.4), 25.9 (SD, 5.3), and 27.0 (SD, 5.9) in Studies C013, C017, and C021, respectively.

Among the subset of patients who were underweight, defined as a BMI of less than 18.5, the median weight changes at 2 years ranged from 0.3 kg in Study C017 (n = 8) to 2.1 kg in Study C013 (n = 1). Among those in the normal (BMI ≤18.5 to <25), overweight (BMI ≤25 to <30), Class 1 obesity (BMI ≤30 to <35), and Class 2 obesity (BMI ≤35 to <40) subsets, median weight change at 2 years ranged from –3.1 kg in Study C017 to 6.0 kg in Study C013.

Patients who were in the Class 3 obesity subgroup (BMI ≥40) experienced a median weight change of –2.9 kg in Study C021 (n = 30) t –14.5 kg in Study C017 (n = 4) at 2 years. “No patients in the Class 2 and Class 3 obesity classifications remained in the C013 [open-label extension] at 2 years,” Ferrari et al noted.

The mean weight changes from baseline for the subsets of individuals who continued concomitant valproate, gabapentin, or pregabalin ranged from –3.1 kg in Study C021 (pregabalin; n = 30) to 2.6 kg in Study C013 (valproate; n = 5) at 1 year. At 2 years, those weight changes ranges from –1.6 kg in Study C021 (pregabalin; n = 22) to 2.7 kg in Study C013 (valproate; n = 5).

In patients who discontinued valproate by the 1-year mark in Study C013 (n = 1) and at the 2-year mark in Study C017 (n = 2), the maximal numerical reductions in median weight were –13.0 kg and –24.5 kg, respectively. In individuals who discontinued gabapentin by the 1-year mark in Study C017 (n = 2) and at the 2-year mark in Study C017 (n = 2), the maximal numerical reductions in median weight were –7.1 kg and –7.0 kg, respectively.

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REFERENCE
1. Ferrari L, Rosenfeld WE. Effects of cenobamate on weight: Post-hoc analyses of global phase 2 and 3 studies. Presented at: AES Annual Meeting; December 2-6, 2022; Nashville, TN, and virtual. Poster 288.