ADVERSE EVENTS OF NEW AEDS LIONEL CARMANT, MD Professor of Neurosciences and Pediatrics
DISCLOSURE Lionel Carmant: Grants/Research projects: Mettrum/ Zogenix Speakers bureau: UCB, Eisai, Lina Nova Off label use of Rufinamide
INTRODUCTION BRIVARACETAM PERAMPANEL RUFINAMIDE ESLICARBAZEPINE CBD FENFLURAMINE CONCLUSIONS OVERVIEW
INTRODUCTION It is unclear whether the rapid development of new AEDs has actually reduced the number of drug resistant epilepsy patients So the next goal to improve quality of life for these patients is to reduce the number of treatment-emergent adverse events This could lead to rationale polytherapy being eventually reality
BRIVARACETAM
Discovery of Brivaracetam Discovered from a rational drug discovery screening project of racetam derivatives for selective, high-affinity SV2A ligands ~12,000 compounds screened for in vitro interaction with SV2A 1 ~ 900 compounds tested for in vivo activity against audiogenic seizures in mice 1 ~ 30 compounds profiled in a broad range of animal models of seizures and epilepsy 1 Levetiracetam FAMILY LEV-like animal model seizure protection profile 1,2a Inactive in MES and PTZ models 1 Brivaracetam FAMILY LEV non-like animal model seizure protection profile 1 Active in MES and PTZ models 1 The clinical relevance of these findings is unknown a Animal model seizure protection profile is the range of rodent models that all compounds were tested in. LEV=levetiracetam; MES=maximal electroshock; PTZ=pentylenetetrazole; SV2A=synaptic vesicle protein 2A. 1. Matagne A, et al. Br J Pharmacol. 2008;154:1662-1671; 2. Klitgaard H, et al. Eur J Pharmacol. 1998;353:191-206. 6
BRIVARACETAM CLINICAL TRIALS 3 pivotal studies: N01252, N01253, and N01358 % PBO (n=459) BRV 50 mg/day (n=200) BRV 100 mg/day (n=353) BRV 200 mg/day (n=250) BRV Combined (n=803) At least 1 TEAE 62.1 71.0 66.9 67.2 68.0 TEAEs leading to study drug discontinuation 3.9 5.0 7.6 6.8 6.7 Drug-related TEAEs 30.3 47.0 39.9 43.6 42.8 Severe TEAEs 4.1 6.0 4.8 6.4 5.6 Serious TEAEs 2.8 3.0 2.5 3.6 3.0 Deaths 0.2 0.5 0 0.8 0.4 BRV=brivaracetam; PBO=placebo; TEAE=treatment-emergent adverse event. Quarato PP, et al. Presented at the 31st International Epilepsy Congress (IEC): September 5-9, 2015; Istanbul, Turkey. Poster P0851.
BRIVARACETAM Most frequent behavioural AE: Irritability (3.2%) Aggression (0.5%) Agitation (0.5%) Anger (0.2%) Leading to treatment discontinuation (0.9%)
BRIVARACETAM Key results 27/29 (93.1%) patients had physician-assessed clinically meaningful reduction in BAEs at end of treatment (primary safety analysis); no worsening in intensity was reported 18/29 (62.1%) patients had complete abatement from primary BAEs; median time to primary BAE resolution was 15 days after the first BRV dose Intensity of BAEs at baseline, % Intensity of BAEs at end of treatment period, % Resolved Mild Moderate Severe Mild 3.4 3.4 0 0 Moderate 34.5 10.3 3.4 0 Severe 27.6 6.9 10.3 0 Total 65.5 20.7 13.8 0 BAEs=behavioral adverse events; BRV=brivaracetam; LEV=levetiracetam. Yates SL, et al. Epilepsy Behav. 2015;52:165-168.
Experimental data Sanon et al. manuscript in preparation
Summary Table Sanon et al. manuscript submitted
Resident Intruder test: aggressive and social behaviors are affected by LEV, not BRV Sanon et al. manuscript in prep
PERAMPANEL
PERAMPANEL
PERAMPANEL Blockade of AMPA receptors will alter fast synaptic transmission 3 pivotal studies: 304-305- 306 Perampanel Placebo (N=442) 2 mg (N=180) 4 mg (N=172) 8 mg (N=431) 12 mg (N=255) Subjects with any TEAE 66.5 61.7 64.5 81.2 89.0 Dizziness 9.0 10.0 16.3 31.8 42.7 Somnolence 7.2 12.2 9.3 15.5 17.6 Headache 11.3 8.9 11.0 11.4 13.3 Fatigue 4.8 4.4 7.6 8.4 12.2 Irritability 2.9 3.9 4.1 6.7 11.8 Fall 3.4 1.1 1.7 5.1 10.2 Nausea 4.5 2.2 2.9 5.8 7.8 Nasopharyngitis 4.1 3.9 5.2 5.3 4.3 Upper respiratory tract infection 2.7 6.1 3.5 3.2 3.9 Ataxia 0.0 0.0 0.6 3.2 8.2 Balance disorder 0.5 0.0 0.0 5.1 3.1
Alertness / Cognition-Related TEAEs Placebo (n=82) Perampanel (n=81) Patients with any TEAE (narrow and broad SMQ terms) 12 (14.6) 16 (19.8) Somnolence 3 (3.7) 9 (11.1) Hallucination 2 (2.4) 2 (2.5) Mood swings 0 (0.0) 2 (2.5) Mood altered 2 (2.4) 1 (1.2) Abnormal behavior 2 (2.4) 1 (1.2) Affect lability 0 (0.0) 1 (1.2) Aggression 0 (0.0) 1 (1.2) Aphasia 0 (0.0) 1 (1.2) Delusion 0 (0.0) 1 (1.2) Hallucination, visual 0 (0.0) 1 (1.2) Illusion 0 (0.0) 1 (1.2) Speech disorder 0 (0.0) 1 (1.2) Confusional state 2 (2.4) 0 (0.0) Hallucination, auditory 1 (1.2) 0 (0.0) Initial insomnia 1 (1.2) 0 (0.0) All values are n (%).
Psychosis / Psychotic Disorder-Related TEAEs Placebo (n=82) Perampanel (n=81) Patients with any TEAE (narrow and broad SMQ terms) 3 (3.7) 6 (7.4) Hallucination a 2 (2.4) 2 (2.5) Abnormal behavior b 0 (0.0) 1 (1.2) Affect lability b 0 (0.0) 1 (1.2) Delusion a 0 (0.0) 1 (1.2) Hallucination, visual a 0 (0.0) 1 (1.2) Illusion a 0 (0.0) 1 (1.2) Paranoia a 0 (0.0) 1 (1.2) Speech disorder b 0 (0.0) 1 (1.2) Hallucination, auditory a 1 (1.2) 0 (0.0) No TEAEs were considered serious 1 patient in the perampanel group discontinued treatment due to abnormal behavior (severe and treatment-related; resolved after 1 day) a Narrow SMQ term; b broad SMQ term. All values are n (%).
PERAMPANEL Treatment-emergent SAEs occurred in 6 (7.4%) patients receiving perampanel vs 7 (8.5%) patients in the placebo group Discontinuation due to TEAEs occurred in 9 (11.1%) patients receiving perampanel and 5 (6.1%) patients in the placebo group Dose reductions related to TEAEs occurred in 8 (9.9%) patients receiving perampanel and 6 (7.3%) patients in the placebo group Dose interruption or reduction occurred at 8-12 mg per day.
RUFINAMIDE
Bialer & White, Nat Rev Drug Disc 2010
RUFINAMIDE Studied in children/adults with LGS (90 sz/mo) 2 pivotal studies: 022E and 303 81% AE with most frequent Somnolence (33.8%) Vomiting (21.6%) Decreased appetite (9.5%)
RUFINAMIDE SAE rare, similar to placebo <1% Risk of increased major seizure frequency (20.8%)
RUFINAMIDE Post marketing data For LGS 12 studies 23-71% AEs Drowsiness/Fatigue and GI symptoms Non LGS 17 studies 24-96% (most in the 20-40%) Dizziness and fatigue most common Go slow, stay low!
ESLICARBAZEPINE
ESLICARBAZEPINE First approved in Europe in 2009 4 Pivotal studies 301-302-303-304 Special studies in >65 y.o.; hepatic and renal impairment Frequent (>10%) TEAE: Dizziness, somnolence, headache and nausea Dose dependent
ESLICARBAZEPINE SAE: Not dose dependent 1.2% Post-marketing studies: hyponatremia (10.2%) seizure (5.8%) dizziness (4.1%) Sperling M. et al., 2015
ESLICARBAZEPINE Sperling M. et al., 2015
ESLICARBAZEPINE
FENFLURAMINE
FENFLURAMINE 1981 by Douglas et al.: 2 women with symptoms of pulmonary hypertension, including exertional breathlessness and exercise intolerance, while taking fenfluramine at doses of 120 or 160mg/day. Case-control study: 95 patients with PPH compared with a cohort of 355 control patients matched for age and gender The use of dexfenfluramine or fenfluramine, was higher in the case patients (31.6%) compared with the controls (7.3%; adjusted odds ratio for the risk of PPH = 6.3, 95% CI = 3.0 13.2). The use for periods >3 months was associated with an odds ratio of 23.1 (95% CI1 46.9 77.7).
FENFLURAMINE Incidence of at least 1 TEAE: 95% (n=38) of patients in the 0.8mg/kg/day group 94.9% (n=37) of patients in the 0.2 mg/kg/day 65.0% (n=26) of patients in the placebo group. Incidence of SAEs: 12.5% (n=5) of patients in the 0.8 mg/kg/day group 10.3% (n=4) of patients in the 0.2 mg/kg/day group 10.0% (n=4) of patients in the placebo group. AEs leading to discontinuation: Five patients in the 0.8 mg/kg/day group None in the other treatment groups.
CBD/THC
CBD
CBD 100 mg/ml of CBD 5, 10 and 20 mg/kg AE reported in 93% vs 75% SAE in 10 vs 3 children Withdrawal from trial 8 vs 1 child
CBD
CBD Care-E study: Pharmacokinetic study Efficacy study Small number of patients Quebec registry: 32 children and opening to other centres Goal is to study Canadian products: THC- other compounds Open label study to enable physicians to prescribe in a research protocol Looking to recruit 300 children
CBD In our experience: Lower doses than epidiolex are needed to see effect Somnolence is common, interaction with clobazam Tolerance can be seen Dose dependent increase in seizure frequency
CONCLUSIONS Systemic AEs are rare with new molecules but CNS still common Knowledge of drug specific AEs is required Rationale polytherapy for Dravet syndrome: CLB- STP- Fenfluramine With growing list of available seizure medication, early referral to Epilepsy Centre is becoming more and more important