Evaluation of the Acute Anticonvulsant Efficacy of Fenfluramine in Mouse Models of Acute and Chronic Seizures
Abstract number :
2.203
Submission category :
7. Antiepileptic Drugs / 7A. Animal Studies
Year :
2019
Submission ID :
2421648
Source :
www.aesnet.org
Presentation date :
12/8/2019 4:04:48 PM
Published date :
Nov 25, 2019, 12:14 PM
Authors :
Parthena Martin, Zogenix, Inc.; H. Steve S. White, University of Washington; Melissa L. Barker-Haliski, University of Washington
Rationale: In two recently reported Phase 3 clinical trials, fenfluramine (FFA) dramatically reduced convulsive seizure frequency in patients with Dravet syndrome, a treatment-resistant epileptic encephalopathy. Here we report the results of preclinical assessment of the anticonvulsant activity of FFA when administered acutely in three mouse models of acute and chronic seizures. FFA was tested in three models of acute and chronic seizures in naïve male CF-1 mice (Envigo (Indianapolis, IN, USA); 18-35 g): 1) the acute maximal electroshock (MES) test; 2) the acute 44 mA 6 Hz test; and 3) the chronic corneal kindled mouse (CKM) model. Methods: Testing progressed in three phases: identification, time course, and dose response. In the identification phase, mice were administered FFA (3, 10, 30 mg/kg, ip), vehicle, or retigabine (positive control, 20 or 50 mg/kg, ip) 0.5 or 2 hr before testing (n=4/group). The time course of antiseizure activity of the most effective dose without minimal motor impairment (MMI) was determined at 0.25, 0.5, 1, 2, and 4 hr after dosing (n=4/time point). Dose-dependent anticonvulsant activity of FFA was assessed by testing between 0.25 and 120 mg/kg (n=8/dose). The effect of FFA on MMI in the fixed-speed rotarod (FSR) was assessed prior to the MES, 44 mA 6 Hz, and CKM tests. The doses at which 50% of mice were protected from seizures (ED50) or exhibited MMI (TD50) and 95% CI’s were estimated by Probit. Results: The MES test is a model for generalized tonic-clonic seizures, and FFA demonstrated potent anticonvulsant activity in this test with an ED50 at 4 hrs post-dosing of 2.9 mg/kg (95% CI, 1.4 to 5.1 mg/kg). At the doses used in this test, no motor impairment was seen any time post-dosing, although 1 mouse died following administration of 60 mg/kg. The 44 mA 6 Hz test is believed to model focal seizures that secondarily generalize, as seen in humans. The ED50 of FFA in the 44 mA 6 Hz test was 47.0 mg/kg (95% CI, 31.9 to 66.7 mg/kg), with a time of peak activity at 0.5 hrs post-drug administration; the TD50 was 34.6 mg/kg (95% CI, 25.3 to 53.0 mg/kg) in the FSR test at this time post-drug administration. Mortality occurred in 2 of 8 and 6 of 8 mice following administration of 90 and 120 mg/kg, respectively. The CKM test is a model that identifies compounds that may be useful in the treatment of human partial epilepsy (eg, levetiracetam). FFA demonstrated minimal anticonvulsant activity at the doses tested, but an ED50 could not be defined. Conclusions: Acute administration of FFA exerted dose-dependent anticonvulsant effect in the mouse MES test, a model of tonic-clonic seizures in humans, an observation aligning with the clinical experience with FFA in Dravet syndrome. FFA may also have activity against focal seizures that secondarily generalize, but effects in different models were inconsistent, suggesting that further studies are warranted. Funding: This work was supported by a grant from Zogenix, Inc. to the University of Washington (H. Steve White and Melissa Barker-Haliski, PI's).
Antiepileptic Drugs