Long‐term efficacy and safety of cannabidiol in patients with treatment‐resistant focal epilepsies treated in the Expanded Access Program
Patel et al.
Nationwide Children's Hospital Columbus Ohio USA
University of Alabama at Birmingham Birmingham Alabama USA
Winchester Neurological Consultants Winchester Virginia USA
Jazz Pharmaceuticals, Inc. Palo Alto California USA
Jazz Pharmaceuticals, Inc., Gentium Srl Villa Guardia Italy
Massachusetts General Hospital Boston Massachusetts USA
* CorrespondenceAnup D. Patel, Nationwide Children's Hospital, 700 Children's Drive, Columbus, OH 43205, USA.
Email: anup.patel@nationwidechildrens.org
Abstract
Objective
Cannabidiol (CBD) treatment was associated with long‐term seizure reduction in patients with various treatment‐resistant epilepsies who participated in the CBD Expanded Access Program. A phase 3 trial showed CBD effectively treats tuberous sclerosis complex (TSC)‐associated seizures, which are primarily of focal origin. However, the effectiveness of CBD in non‐TSC focal epilepsies is not well reported. Here, we evaluate CBD treatment outcomes among patients with a variety of focal epilepsies, including TSC.
Methods
Patients received plant‐derived highly purified CBD (Epidiolex; 100 mg/mL oral solution) doses starting at 2–10 mg/kg/day and titrated up to each patient's limit or to a maximum of 25–50 mg/kg/day. CBD effectiveness was assessed by the median percentage change from baseline in monthly frequency of focal and total seizures and by responder rates through 144 weeks of treatment. Safety data were reported for the full follow‐up period.
Results
Of 140 patients with focal epilepsies, 33 (24%) had TSC and 107 (76%) had other focal epilepsies, including cortical dysplasia (14%), frontal lobe epilepsy (10%), and malformation of cortical development (9%). Median age was 11.9 years (range = 2–31) in the TSC group and 17.8 years (range = 2–73) in the non‐TSC group. Median CBD daily dose was comparable between TSC and non‐TSC groups (25 and 23 mg/kg/day, respectively). CBD treatment was associated with a median reduction from baseline of 51%–87% in focal seizures and 44%–87% in total seizures in the TSC group and 46%–75% and 45%–71% in the non‐TSC group, respectively. Responder rates were similar for both groups. Adverse events occurred in 91% of the TSC group and 96% of the non‐TSC group.
Significance
Open‐label CBD treatment was associated with sustained seizure reduction through 144 weeks, with a consistent safety profile in patients with treatment‐resistant focal epilepsies, regardless of epilepsy type.
Graphical
Open‐label CBD treatment was associated with sustained seizure reduction through 144 weeks, with a consistent safety profile in patients with treatment‐resistant focal epilepsies, regardless of epilepsy type.
Boxed Text
Article notes
Patel AD , Szaflarski JP , Lyons PD , Boffa M , Greco T , Saurer TB , et al. Long‐term efficacy and safety of cannabidiol in patients with treatment‐resistant focal epilepsies treated in the Expanded Access Program. Epilepsia. 2025;66:3730–3740. 10.1111/epi.18496 40673944 PMC12605695
Boxed Text
- Effectiveness (n = 140) and safety (n = 148) of adjunctive CBD were evaluated prospectively in patients with treatment‐resistant focal epilepsy who participated in the CBD EAP.
- CBD treatment resulted in a comparable reduction in focal seizure frequency of 51%–87% in the TSC group and 46–75% in the non‐TSC group.
- Reduction in the median monthly frequency of total seizures was similar between the TSC and non‐TSC groups through 144 weeks of CBD treatment.
- The ≥50, ≥75, and 100% responder rates were notable and similar in both the TSC and non‐TSC groups.
- Treatment‐emergent adverse events with CBD were consistent with those reported previously in EAP analyses and clinical trials.
1INTRODUCTION
A plant‐derived highly purified pharmaceutical formulation of cannabidiol (CBD; Epidiolex in the USA and Epidyolex in the EU and UK) has been approved by the US Food and Drug Administration for the treatment of seizures associated with Dravet syndrome (DS), Lennox–Gastaut syndrome (LGS), and tuberous sclerosis complex (TSC). 1 , 2 , 3 , 4 , 5 , 6 These syndromes are characterized by multiple seizure types, including focal and generalized seizures. 7 , 8 , 9 Patients with LGS present with various seizure types, with tonic and atonic seizures being particularly common. 9 Those with DS may experience myoclonic, atypical absence, atonic, focal (with or without impaired awareness), and tonic seizures and nonconvulsive status epilepticus. 7 , 10 TSC is associated with focal or multifocal epilepsy that often presents during infancy or early childhood with infantile spasms and/or focal onset seizures. 11 Some focal seizures can rapidly evolve to generalized seizures. 8
Approval of Epidiolex for the treatment of TSC‐associated seizures was based on the results of a randomized, placebo‐controlled, phase 3 trial, GWPCARE6. 3 , 12 CBD treatment demonstrated a significant reduction in TSC‐associated seizures, which included countable focal motor seizures without impairment of awareness (previously known as simple partial seizures), focal seizures with impairment of awareness (complex partial seizures), focal to bilateral tonic–clonic seizures (secondarily generalized tonic–clonic seizures), and generalized seizures (tonic–clonic, tonic, clonic, or atonic). 3 , 13 These reductions in the frequency of TSC‐associated seizures were maintained through 3 years of treatment in the open‐label extension of GWPCARE6 with a consistent safety profile. 14
CBD has also been evaluated in patients with other treatment‐resistant epilepsies (TREs) in the CBD Expanded Access Program (EAP). 15 The CBD EAP was a prospective, open‐label study conducted between January 2014 and January 2019 that provided compassionate access to CBD for 892 patients with any type of TRE. 12 , 15 , 16 Data from the EAP suggested a reduction in seizure frequency in patients with various TREs, including DS, LGS, and TSC, who were treated with CBD. 12 , 16 , 17 , 18 , 19 , 20 The effectiveness of CBD treatment was also observed in both convulsive and nonconvulsive seizure types and epileptic spasms. 15 In these analyses, convulsive seizure types included clonic, tonic, tonic–clonic, atonic, and focal to bilateral tonic–clonic, and the nonconvulsive seizure types included focal seizures with and without impaired consciousness, absence (typical and atypical), myoclonic, and myoclonic absence. 15
Whereas CBD has demonstrated efficacy for TSC‐associated seizures, 3 the effectiveness of CBD in non‐TSC focal epilepsies has not been well characterized. In this analysis of pooled data from the CBD EAP, we evaluated the effectiveness and safety of adjunctive CBD treatment in patients with focal epilepsies.
2MATERIALS AND METHODS
2.1Ethical considerations
The study was conducted in accordance with the International Conference on Harmonization, Good Clinical Practice guidelines, and local standard operating procedures. An institutional review board at each participating site approved the study protocol, and patients or parents/caregivers provided written informed consent before any study‐related assessments were conducted.
2.2Patient eligibility and study design
The EAP was conducted at 35 epilepsy centers in the USA and included individual physician‐ or state‐sponsored investigational new drug applications for the use of highly purified CBD in patients with TRE. The study design and patient eligibility criteria have been published previously. 17 Although criteria for inclusion in the EAP and endpoints varied according to site‐specific protocols, all patients had TRE and were receiving stable doses of antiseizure medications (ASMs; commonly referred to as antiepileptic drugs) for ≥4 weeks before enrollment. For this prospective analysis, patients with a diagnosis of focal epilepsy or those with a focal etiology were identified and reviewed by an epileptologist. Patients with a diagnosis of LGS were excluded regardless of etiology. The study included a 4‐week baseline period during which parents/caregivers recorded all countable seizures prospectively in a diary. After the baseline period, all patients received a plant‐derived, highly purified pharmaceutical formulation of CBD (Epidiolex, 100 mg/mL oral solution). Each dose started at 2–10 mg/kg/day and was titrated up to the patient's tolerability limit or a maximum dose of 25–50 mg/kg/day, depending on the study site and institutional review board approval. The currently approved recommended maintenance dosage of CBD for TSC is 25 mg/kg/day. 5 Patient visits were every 2–4 weeks through 16 weeks and every 2–12 weeks thereafter.
2.3Outcome measures
The effectiveness of CBD was evaluated by calculating the median percentage change from baseline in the monthly frequency of focal and total seizures in patients with focal epilepsy, including the subgroups of patients with TSC and those with other focal epilepsies (non‐TSC group). Each site reported the weekly seizure frequency since the previous visit, which was used to calculate the frequency per 28 days (monthly seizure frequency). Responder rates were calculated as the proportion of patients who had a ≥50, ≥75, or 100% reduction from baseline in monthly focal and total seizure frequency.
Subsequently, last observation carried forward (LOCF) analysis was conducted to account for missing data by using data from the last available visit window for all patients with postbaseline seizure frequency information. For patients who withdrew from the study, their most recent reported seizure frequency was carried forward to account for the remainder of the treatment period.
Descriptive statistics were reported to summarize these study findings. Effectiveness outcomes were reported as ranges for each of the 12‐week visit windows through 144 weeks of treatment. Safety data were reported for the complete follow‐up period, up to 240 weeks. The analysis encompassed all adverse events (AEs), whether treatment‐related or not, reported by patients throughout their duration of EAP involvement.
2.4Analysis populations
In this analysis, patients with focal epilepsy who had ≥1 dose of CBD and ≥1 postbaseline evaluation were included in the safety analysis dataset (n = 148). All patients in the safety analysis dataset who had at least one seizure recorded at baseline were included in the efficacy analysis dataset (n = 140).
3RESULTS
3.1Patient disposition and demographics
Overall, 148 of 892 patients (17%) treated in the CBD EAP had either a diagnosis of focal epilepsy or a focal etiology of their seizures and were included in the safety analysis dataset. Efficacy data were available for 140 patients (efficacy analysis dataset); 33 (24%) were diagnosed with TSC (TSC group), and 107 (76%) had other focal epilepsies (non‐TSC group). The most common diagnoses/causes of focal epilepsy in the non‐TSC group were cortical dysplasia, frontal lobe epilepsy, malformation of cortical development, and temporal lobe epilepsy (Table 1). In the efficacy population, 53 patients (38%) discontinued treatment with CBD, with lack of efficacy (18%) and AEs (9%) reported as the most frequent reasons for discontinuation (Figure 1). In the efficacy analysis dataset, eight of 33 patients (24%) with TSC and 45 of 107 patients (42%) with other focal epilepsies withdrew, primarily due to lack of efficacy (12% and 20%, respectively) and AEs (3% and 11%; Figure S1).
| Characteristic | All focal epilepsies, N = 140 | TSC group, n = 33 | Non‐TSC group, n = 107 |
|---|---|---|---|
| Age, years | |||
| Mean (SD) | 19.4 (14.8) | 12.4 (8.5) | 21.5 (15.6) |
| Median (range) | 16.0 (2–73) | 11.9 (2–31) | 17.8 (2–73) |
| Sex, n (%) | |||
| Female | 77 (55) | 18 (55) | 59 (55) |
| Concomitant ASMs at baseline, median (range) | 3 (0–7) | 3 (1–7) | 3 (0–5) |
| Baseline ASMs, ≥10% of patients in any group, n (%) | |||
| Clobazam | 53 (38) | 19 (58) | 34 (32) |
| Lamotrigine | 44 (31) | 14 (42) | 30 (28) |
| Levetiracetam | 49 (35) | 11 (33) | 38 (36) |
| Lacosamide | 45 (32) | 17 (52) | 28 (26) |
| Topiramate | 24 (17) | 2 (6) | 22 (21) |
| Valproate | 21 (15) | 6 (18) | 15 (14) |
| Oxcarbazepine | 21 (15) | 5 (15) | 16 (15) |
| Zonisamide | 22 (16) | 2 (6) | 20 (19) |
| Rufinamide | 14 (10) | 4 (12) | 10 (9) |
| Phenobarbital | 12 (9) | 1 (3) | 11 (10) |
| Vigabatrin | 14 (10) | 8 (24) | 6 (6) |
| Diazepam | 7 (5) | 4 (12) | 3 (3) |
| Epilepsy diagnosis, n (%) | |||
| TSC | 33 (24) | 33 (100) | – |
| Non‐TSC | 107 (76) | – | 107 (100) |
| Not specified a | 27 (19) | – | 27 (25) |
| Cortical dysplasia | 19 (14) | – | 19 (18) |
| Frontal lobe epilepsy | 14 (10) | – | 14 (13) |
| Malformation of cortical development | 13 (9) | – | 13 (12) |
| Temporal lobe epilepsy | 10 (7) | – | 10 (9) |
| Stroke‐related | 9 (6) | – | 9 (8) |
| Other focal epilepsy b | 7 (5) | – | 7 (7) |
| Sturge–Weber syndrome | 5 (4) | – | 5 (5) |
| Tumor‐related | 3 (2) | – | 3 (3) |
| Seizure frequency per 28 days, median (Q1, Q3) [n] | |||
| Focal | 26 (9–93) [94] | 37 (24–84) [26] | 20 (8–104) [68] |
| Total | 52 (14–151) [140] | 64 (31–148) [33] | 47 (9–151) [107] |
Patient demographics and baseline characteristics are shown in Table 1. The median age (range) of patients at baseline was 16.0 years (2–73; 11.9 years [2–31] in the TSC group and 17.8 years [2–73] in the non‐TSC group). Patients were taking a median of 3 ASMs; clobazam, lacosamide, and levetiracetam were the most used ASMs in the overall population, and clobazam, lamotrigine, and levetiracetam were the most used ASMs in patients with non‐TSC focal epilepsies, whereas clobazam, lamotrigine, and lacosamide were the most common ASMs used by patients with TSC. At baseline, the median (first quartile [Q1], third quartile [Q3]) monthly focal seizure frequency was 26 (9, 93) for the overall population, 37 (24, 84) for the TSC group, and 20 (8, 104) for the non‐TSC group. The median (Q1, Q3) monthly total seizure frequencies were 52 (14, 151), 64 (31, 148), and 47 (9, 151) for the overall population, the TSC group, and the non‐TSC group, respectively.
3.2Drug exposure
In the efficacy analysis dataset (n = 140), the median time on CBD treatment was 896 days (range = 15–1655), and the median (Q1, Q3) CBD dose was 24 mg/kg/day (15, 30). For the TSC group, the median time on CBD treatment was 1116 days (range = 85–1631), and it was 807 days (range = 15–1655) in the non‐TSC group; median (Q1, Q3) CBD dose was 25 mg/kg/day (18, 35) and 23 mg/kg/day (15, 27), respectively.
3.3Effectiveness
3.3.1All patients with focal epilepsies
After CBD initiation, there was a median reduction of 54%–77% in the monthly frequency of focal seizures and 49%–75% in total seizures, observed across 12‐week visit windows through 144 weeks of treatment (Figure 2A). For patients taking CBD doses of ≤25 mg/kg/day, the median monthly reduction in seizure frequency was 43%–78% for focal seizures and 41%–76% for total seizures (Figure S2A). A ≥50% response rate was observed in 51%–72% of patients for focal seizures and 50%–64% for total seizures; ≥75% responder rates were 28%–54% for focal seizures and 24%–50% for total seizures (Figure 2B). Seizure freedom (100% response rate) was reported in 11%–20% and 5%–14% of patients for focal and total seizures, respectively. In patients taking CBD doses of ≤25 mg/kg/day, the ≥50%, ≥75%, and 100% response rates were 46%–81%, 28%–59%, and 11%–29% for focal seizures and 45%–66%, 24%–51%, and 6%–20% for total seizures, respectively (Figure S2B). The LOCF analysis demonstrated a 47%–59% and 41%–53% median percentage reduction in the frequency of focal and total seizures, respectively (Figure S3). In the overall population taking CBD doses of ≤25 mg/kg/day, an LOCF analysis showed a 40%–56% and 34%–51% decrease in focal and total seizure frequency, respectively.
3.3.2 TSC group
Analysis of the TSC group showed the median percentage reduction from baseline in focal and total seizures was 51%–87% and 44%–87%, respectively (Figure 3A). Among patients taking CBD doses of ≤25 mg/kg/day, the median reductions in focal and total seizure frequency were 44%–100% and 34%–87%, respectively (Figure S4A). The ≥50% response rates for focal and total seizures were 52%–75% and 46%–79%, respectively (Figure 4A). A reduction of at least 75% from baseline was observed in focal seizures in 35%–60% of patients and in total seizures in 26%–65% of patients. In the TSC group, 7%–32% of patients experienced no focal seizures (100% response rate), and 0–13% experienced seizure freedom across 12‐week visit windows. For patients taking CBD ≤25 mg/kg/day, ≥50%, ≥75%, and 100% responder rates were 50%–100%, 29%–67%, and 8%–67% for focal seizures and 41%–100%, 21%–83%, and 0–25% for total seizures, respectively (Figure S5A). LOCF analysis in the TSC group showed reductions of 33%–66% in focal seizures and 36%–74% in total seizures. LOCF evaluation of patients taking CBD doses of ≤25 mg/kg/day showed reductions of 34%–71% and 33%–79% in focal and total seizures, respectively.
3.3.3Non‐TSC group
In the non‐TSC group, the median percentage reduction from baseline was 46%–75% for focal seizures and 45%–71% for total seizures (Figure 3B). In patients taking CBD doses of ≤25 mg/kg/day, the median reductions in focal and total seizure frequency were 43%–78% and 41%–74%, respectively (Figure S4B). The ≥50% response rates were 47%–72% for focal seizures and 47%–68% for total seizures (Figure 4B). A ≥75% reduction from baseline was observed in 26%–51% for focal seizures and 24%–48% for total seizures. In this non‐TSC group, seizure freedom from focal seizures was reported in 7%–19% of patients, and seizure freedom from all seizures was reported in 4%–17% of patients. For patients taking CBD ≤25 mg/kg/day, ≥50%, ≥75%, and 100% responder rates were 45%–77%, 26%–59%, and 7%–27% for focal seizures and 44%–62%, 25%–49%, and 4%–21% for total seizures, respectively (Figure S5B). LOCF analysis showed 44%–58% reductions for focal seizures and 41%–53% for total seizures. Patients taking CBD ≤25 mg/kg/day in the LOCF analysis had 40%–56% reductions in focal seizures and 34%–51% reductions in total seizures.
3.4Safety
In the safety analysis dataset (n = 148), treatment‐emergent AEs (TEAEs) were reported up to 240 weeks by 140 patients (95%), which included 32 patients with TSC and 108 patients with other focal epilepsies (Table 2). The most common TEAEs, occurring in ≥20% of patients, were diarrhea (n = 71 [48%]), convulsion (n = 37 [25%]), and somnolence (n = 32 [22%]). In the TSC group, the most frequently reported TEAEs were diarrhea (n = 10 [29%]) and somnolence (n = 11 [31%]), whereas those in the non‐TSC group experienced diarrhea (n = 61 [54%]) and convulsions (n = 31 [27%]) most frequently.
| AE | All focal epilepsies, N = 148 | TSC group, n = 35 | Non‐TSC group, n = 113 |
|---|---|---|---|
| Patients, n (%) | |||
| Any TEAEs | 140 (95) | 32 (91) | 108 (96) |
| Any TRAEs | 113 (76) | 23 (66) | 90 (80) |
| TEAEs leading to CBD discontinuation | 12 (8) | 2 (6) | 10 (9) |
| Serious TEAEs | 59 (40) | 16 (46) | 43 (38) |
| Treatment‐related serious AEs | 3 (2) | 0 | 3 (3) |
| Deaths a | 4 (3) | 0 | 4 (4) |
| TEAEs reported in ≥10% of patients in any group by preferred term, n (%) | |||
| Diarrhea | 71 (48) | 10 (29) | 61 (54) |
| Convulsion | 37 (25) | 6 (17) | 31 (27) |
| Somnolence | 32 (22) | 11 (31) | 21 (19) |
| Vomiting | 27 (18) | 6 (17) | 21 (19) |
| URTI | 24 (16) | 4 (11) | 20 (18) |
| Headache | 20 (14) | 4 (11) | 16 (14) |
| Decreased appetite | 18 (12) | 5 (14) | 13 (12) |
| Gastroenteritis, viral | 17 (12) | 5 (14) | 12 (11) |
| Nasopharyngitis | 15 (10) | 3 (9) | 12 (11) |
| Dizziness | 13 (9) | 1 (3) | 12 (11) |
| Fall | 13 (9) | 0 | 13 (12) |
| Influenza | 14 (10) | 2 (6) | 12 (11) |
| UTI | 14 (10) | 2 (6) | 12 (11) |
| Nausea | 12 (8) | 0 | 12 (11) |
| Pyrexia | 12 (8) | 4 (11) | 8 (7) |
| Abnormal behavior | 10 (7) | 4 (11) | 6 (5) |
| Ataxia | 7 (5) | 5 (14) | 2 (2) |
| Sleep disorder | 8 (5) | 5 (14) | 3 (3) |
| TRAEs reported in ≥5% of patients in any group by preferred term, n (%) | |||
| Diarrhea | 62 (42) | 5 (14) | 57 (50) |
| Somnolence | 29 (20) | 11 (31) | 18 (16) |
| Dizziness | 10 (7) | 0 | 10 (9) |
| Decreased appetite | 10 (7) | 3 (9) | 7 (6) |
| Vomiting | 9 (6) | 1 (3) | 8 (7) |
| Decreased weight | 8 (5) | 1 (3) | 7 (6) |
| Ataxia | 7 (5) | 5 (14) | 2 (2) |
| Sedation | 8 (5) | 4 (11) | 4 (4) |
| Convulsion | 6 (4) | 0 | 6 (5) |
| Headache | 6 (4) | 0 | 6 (5) |
| Abnormal behavior | 4 (3) | 2 (6) | 2 (2) |
| Agitation | 4 (3) | 3 (9) | 1 (1) |
| Irritability | 3 (2) | 3 (9) | 0 |
| Poor‐quality sleep | 2 (1) | 2 (6) | 0 |
Diarrhea was the most common treatment‐related AE (TRAE) in all patients with focal epilepsy (n = 62 [42%]) and in the non‐TSC group (n = 57 [50%]), whereas somnolence was the most common TRAE in the TSC group (n = 11 [31%]). Liver‐related AEs included abnormal liver function test in seven patients (n = 1 [3%] in the TSC group and n = 6 [5%] in the non‐TSC group), increased alanine aminotransferase in four patients (4%; all in the non‐TSC group), and increased aspartate aminotransferase in three patients (3%; all in the non‐TSC group).
Twelve patients (8%) discontinued CBD treatment due to TEAEs, including two patients in the TSC group and 10 in the non‐TSC group. The most commonly reported TEAEs leading to treatment discontinuation in the overall population and the non‐TSC group were diarrhea (n = 3), constipation (n = 2), and lethargy (n = 2). Among members of the TSC group who discontinued CBD treatment, cardiomyopathy (n = 1), fatigue (n = 1), decreased weight (n = 1), abnormal behavior (n = 1), and hypertension (n = 1) were reported as reasons. Serious TEAEs were reported in 59 patients (40%) in the overall population, 16 (46%) in the TSC group, and 43 (38%) in the non‐TSC group. The most common serious TEAEs reported in the overall population were convulsion (n = 23 [15.5%]), status epilepticus (n = 8 [5.4%]), and vomiting (n = 6 [4.1%]). In the TSC group, serious TEAEs reported were viral infection (n = 3 [8.6%]), status epilepticus (n = 3 [8.6%]), convulsion (n = 3 [8.6%]), and vomiting (n = 3 [8.6%]). In the non‐TSC group, serious TEAES reported were convulsion (n = 20 [17.7%]), status epilepticus (n = 5 [4.4%]), and pneumonia (n = 4 [3.5%]). The TEAEs were considered treatment‐related in three patients (rash, n = 2; convulsion, n = 1), all of whom were in the non‐TSC group. There were four deaths overall, all deemed unrelated to the treatment by the investigator. During the analysis, nine AEs were reported among patients who died: respiratory arrest (n = 1), respiratory failure (n = 1), diarrhea (n = 1), vomiting (n = 1), pneumonia (n = 1), hyponatremia (n = 1), foot deformity (n = 1), pyrexia (n = 1), and death (n = 1).
4DISCUSSION
This open‐label study provides support for the use of CBD in treatment‐resistant focal epilepsies. Focal seizures are the most common seizure type observed in patients with TSC, occurring in 68%–82% of individuals. 8 , 21 To investigate whether the effectiveness of CBD in TSC may be generalizable to other focal epilepsies, we separately evaluated the outcomes in patients with TSC and those with other focal epilepsies (non‐TSC). CBD treatment was associated with a similar reduction in the frequencies of focal and total seizures in both the TSC group and the non‐TSC group, suggesting similar effectiveness across a variety of focal epilepsies. The LOCF analysis yielded similar results, indicating that the seizure reductions were not attributable to patient withdrawals, mitigating potential bias in patients who derived greater benefit.
Focal epilepsies are the most common type of epilepsy and focal seizures the most common seizure type in both children and adults. 22 , 23 In the present study, patients with non‐TSC focal epilepsies were identified based on focal etiologies or the presence of diagnostic terms such as partial epilepsy, intractable localization‐related epilepsy, and multifocal epilepsy. The most commonly reported causes of focal epilepsy in these patients were cortical dysplasia, frontal lobe epilepsy, malformation of cortical development, and temporal lobe epilepsy; these are also reported as the most common causes or forms of treatment‐resistant focal epilepsy in the literature. 24 , 25 , 26 , 27
In the EAP, patients at some sites could receive CBD doses up to 50 mg/kg/day, depending on tolerability and response. However, the maximum approved dosage for patients with TSC is 25 mg/kg/day; therefore, we evaluated the effectiveness in patients who received CBD doses within the approved dose range (≤25 mg/kg/day). Seizure reductions in these patients were similar to the overall population. These results are consistent with data from the randomized clinical trial GWPCARE6, in which no difference was observed in efficacy between CBD doses of 25 and 50 mg/kg/day, although the higher dose was associated with a greater incidence of AEs. The safety profile of CBD in patients with focal epilepsy was consistent with that reported in previous studies, 3 , 12 , 14 , 15 and no new safety concerns were identified in this patient population.
Previous studies of CBD have mainly focused on assessing either the effect on seizures associated with specific syndromes—DS, LGS, and TSC—in randomized controlled trials 1 , 2 , 3 , 4 , 28 or the effect on specific seizure types associated with TREs. 12 , 15 , 17 , 18 Studies of the potential effectiveness of CBD for the treatment of focal epilepsies other than TSC are sparse. 29 , 30 , 31 , 32 Results of this long‐term, open‐label study build upon these previous reports and provide additional evidence for the effectiveness of CBD in the treatment of a variety of focal epilepsies.
Limitations of this study are that the EAP was not controlled or blinded, the patient eligibility criteria and methods for seizure reporting varied across study sites, and not all information was uniformly collected. The study did not use the Epilepsy Study Consortium to validate or confirm seizure type or epilepsy classification, which may have led to some intersite variability in the classification of seizure types. Importantly, there is some evidence that higher CBD exposures may be linked to better seizure control 6 ; however, our analyses did not monitor for CBD levels or timing of CBD administration with respect to meals, which is an important factor affecting CBD exposure. 33 Lastly, all patients in the EAP were taking multiple medications, and the impact of these medications on effectiveness and safety outcomes was not considered in this evaluation.
5CONCLUSIONS
These results from the open‐label, prospective EAP reveal that CBD treatment was effective in reducing seizures in patients with focal epilepsy through 144 weeks. Our findings extend the previously reported literature from the EAP, providing insight into the sustained effectiveness and safety of CBD treatment in patients with focal epilepsy. The reduction in focal and total seizure frequencies was similar for patients with TSC and those with other focal epilepsies. The overall safety profile was consistent with that observed in previously reported EAP analyses and clinical trials. Taken together with prior studies, these findings suggest that CBD may have potential utility in the treatment of various TREs, including focal epilepsies. Further evaluation of CBD treatment for focal epilepsies in randomized controlled trials is needed.
FUNDING INFORMATION
This study was sponsored by Jazz Pharmaceuticals.
CONFLICT OF INTEREST STATEMENT
A.D.P., J.P.S., P.D.L., and E.A.T. have consulted for, conducted studies funded by, or received honoraria for services provided to Jazz Pharmaceuticals, Inc. M.B., T.G., T.B.S., K.R., and K.C.S. are employees of Jazz Pharmaceuticals, Inc. We confirm that we have read the Journal's position on issues involved in ethical publication and affirm that this report is consistent with those guidelines.
Supporting information
ACKNOWLEDGMENTS
The authors would like to thank the patients, their families, and the staff at sites that participated in this study. Medical writing support was provided to the authors by Ritu Pathak, PhD, and editing support by Celia Nelson, both of Ashfield MedComms, an Inizio company, with additional writing support by Damanjeet Ghai, PhD, and Judy Eun, PharmD, both of Syneos Health, which was funded by Jazz Pharmaceuticals.
DATA AVAILABILITY STATEMENT
The data that support the findings of this study are available on request from the corresponding author. The data are not publicly available due to privacy or ethical restrictions.