Authors :
Presenting Author: Yong Park, MD, FAASM, FAES, FAAN – Medical College of Georgia at Augusta University
Teresa Greco, PhD – Jazz Pharmaceuticals, Inc.
Kelly Simontacchi, PhD – Jazz Pharmaceuticals, Inc.
Timothy Saurer, PhD – Jazz Pharmaceuticals, Inc.
Elizabeth Thiele, MD, PhD – Massachusetts General Hospital
Rationale:
Five phase 3 randomized controlled trials (RCTs) showed cannabidiol (CBD) reduced seizures associated with three rare epilepsy syndromes–Lennox-Gastaut syndrome (LGS), Dravet syndrome (DS), and tuberous sclerosis complex (TSC). Real-world evidence suggests CBD may have utility in other rare, treatment-resistant epilepsies. This post hoc analysis evaluated seizure and safety outcomes after CBD initiation in patients with severe childhood-onset epilepsies, including developmental and epileptic encephalopathies (DEEs), from an expanded access program (EAP). CBD effectiveness was compared with an external placebo control arm (ECA) from LGS RCTs.
Methods:
Patients received plant-derived, highly purified CBD (Epidiolex®, 100 mg/mL oral solution), increasing from 2 to 10 mg/kg/day as tolerated or a maximum of 25–50 mg/kg/day, based on EAP site. Patients with a DEE, genetic epilepsy, or rare epilepsy syndromes were included; those with LGS, DS, or TSC were excluded from the EAP cohort. CBD effectiveness was assessed as percent reduction from baseline in median 28-day convulsive and total seizure frequency and responder rates (RRs) at Weeks 12 and 48. Effectiveness data (percent reduction) were compared with ECA by applying an inverse probability weighting using propensity score to balance for baseline characteristics. Physician and caregiver Global Impression of Change (GIC) data were reported at Weeks 12 and 48. Safety was reported for the entire treatment period.Results:
Of 135 EAP patients, subgroups included those with Aicardi syndrome (12.6%), CDKL5 mutations (14.8%), epilepsy with myoclonic-atonic seizures (8.1%), Dup15q syndrome (8.1%), early infantile epileptic encephalopathy (4.4%), febrile infection–related epilepsy syndrome (9.6%), myoclonic absence epilepsy (3.7%), SCN2A mutations (3.7%), Sturge-Weber syndrome (3.7%), and other genetic epilepsies (31.1%). At baseline, mean age ranged from 5.0 to 14.4 years and most commonly used antiseizure medications (ASMs) were clobazam (40%) and levetiracetam (33%). Median total daily CBD dose was 25 mg/kg/day. At Week 12, CBD was associated with a median reduction from baseline of 58.1% and 51.8% in convulsive and total seizures, respectively, which was maintained through Week 48 (63.5% and 60.0%). The RRs are shown in Figure 1. Comparative analysis showed 43% greater seizure reduction with CBD vs ECA (P < 0.001; Figure 2). At Weeks 12 and 48, physician-reported GIC improvement was 72.2% and 82.1%, respectively, and caregiver-reported GIC improvement was 73.7% and 82.0%. Treatment-related adverse events occurred in 51.9% of patients; most common (≥ 10%) were diarrhea (18.6%), fatigue (12.8%), and somnolence (12.2%).
Conclusions:
CBD treatment was associated with reductions in convulsive and total seizure frequency in patients with DEEs and rare epilepsies in a cohort that excluded patients with LGS, DS, and TSC. These findings suggest that CBD may be an effective ASM for a broad range of DEEs and other rare epilepsies and warrants further investigation.
Funding:
Jazz Pharmaceuticals, Inc.