Phase 4 EpiCom Study Highlights Potential of CBD in Neuropsychiatric Disorders of Tuberous Sclerosis Complex

Newly presented findings from EpiCom, a phase 3/4 study (NCT05864846) of cannabidiol (CBD; Epidiolex; Jazz Pharmaceuticals), revealed that treatment with the cannabis-derived therapy has positive impacts on in the severity of psychiatric and behavioral problems in patients with tuberous sclerosis complex (TSC), a rare epileptic disorder.¹

The trial featured participants with TSC (ages 1-65) experiencing moderate to severe behavioral changes, as assessed by the Caregiver Global Impression of Severity (CareGI-S) scale, received CBD (100 mg/mL oral solution) at doses up to 25 mg/kg/day (adjusted based on response and tolerability) alongside standard of care (SOC) for 26 weeks. After this period, they were given the option to continue CBD with SOC or SOC alone for up to 52 weeks.

Presented at the 2024 American Epilepsy Society (AES) Annual Meeting, held December 6-10 in Los Angeles, California, TSC-associated neuropsychiatric disorders (TAND) were evaluated as change in the most problematic behavior (MPB) on TAND Self-Report Quantified Checklist (TAND-SQ) and Aberrant Behavior Checklist (ABC) at week 13 and CareSI-C and Clinician Clinician Global Impression of Severity (CGI-S) scales at week 4 and 13. Overall, the trial featured 24 enrolled patients, 19 of which who started CBD, and 4 who discontinued. Five of these participants completed assessments within the 13-week window.

Led by Agnies van Eeghen, MD, PhD, an intellectual disability physician at the Amsterdam University Medical Center, patients who completed the 13-week trial reported a change of –4.6 (95% CI, –8.1 to –1.1) in MPB numerical rating scale (NRS) following CBD treatment. Of the 7 TAND-SQ clusters, the greatest changes observed were in dysregulated behavior (change, –3.5; 95% CI, –6.5 to –0.5) and overactive/impulsive scores (change, –2.9; 95% CI, –7.1 to 1.3). All the TAND-SQ clusters were impacted somewhat by CBD treatment, with the least pronounced effects observed in the scholastic cluster (change, 0.3; 95% CI, –6.2 to 6.7).

At baseline, the mean MPB numerical NRS value was 8.8 (SD, 1.01), with mood swings (24%; n = 4) and aggressive outbursts (18%; n = 3) as the most common manifestations. Additional baseline data revealed that 47% of participants experienced seizures (mean 4 per 28 days), with participants using a median of 3 antiseizure medications (range 1–5). Of them, lamotrigine, topiramate, and everolimus were the most common.

In terms of efficacy, the greatest changes in the ABC at week 13 were related to irritability (change, –12.2; 95% CI, –22.3 to –2.1) and hyperactive noncompliance (–11.0; 95% CI, –25.1 to 3.1). Lesser pronounced—but still relevant—effects were seen on other subscales of social withdrawal (change, –4.2; 95% CI, –10.4 to 2.0), stereotypic behavior (change, –4.8; 95% CI, –9.0 to –0.6), and inappropriate speech (change, –2.2; 95% CI, –4.9 to 0.5). In addition, at weeks 4 and 13, less caregivers and clinicians rated behavioral problems as severe/very severe on CareGI-S and CGI-S.

CBD, which was approved for TSC in 2020, maintained its safety profile within the analysis. Adverse events (AEs) occurred in 12 of 19 (63%) participants, with complications that included diarrhea (42%; n = 8), vomiting (11%; n = 2), decreased appetite (11%; n = 2), and lethargy (11%; n = 2). Of note, 4 patients in the study discontinued because of AEs, which included diarrhea, hypersomnia, increased transaminase, and rash.

Epidiolex was first approved in June 2018 for the treatment of seizures associated with Lennox-Gastaut syndrome and Dravet syndrome, 2 rare, treatment refractory types of epilepsy in patients aged 2 and older. When its indication was expanded to include TSC, the drug’s label was updated to include patients in these groups who are age 1 and older. The efficacy of CBD in TSC was demonstrated in the phase 3 GWPCARE6 trial (NCT02544763), a randomized, double-blind, placebo-controlled study of 224 patients who had previous tried and discontinued a number of antiepileptic drugs with no success.^2,3

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REFERENCES
1. Eeghen A, Wilson SM, Smith DM, et al. Tuberous Sclerosis Complex (TSC)–Associated Neuropsychiatric Disorders (TAND) Outcomes Following Add-on Cannabidiol (CBD) Treatment: 3-month Analysis of Open-label Phase 3b/4 Trial Epicom. Presented at: 2024 AES Annual Meeting; December 6-10; Los Angeles, CA. ABSTRACT 2.377
2. FDA approves Epidiolex (cannabidiol) oral solution to treat seizures associated with tuberous sclerosis complex. News release. GW Pharmaceuticals. August 3, 2020. Accessed December 4, 2024. https://www.globenewswire.com/news-release/2020/08/03/2071601/0/en/FDA-Approves-EPIDIOLEX-cannabidiol-Oral-Solution-to-Treat-Seizures-Associated-with-Tuberous-Sclerosis-Complex.html
3. Thiele EA, Bebin ME, Bhathal H, et al. Add-on Cannabidiol Treatment for Drug-Resistant Seizures in Tuberous Sclerosis Complex: A Placebo-Controlled Randomized Clinical Trial. JAMA Neurol. 2021;78(3):285-292. doi:10.1001/jamaneurol.2020.4607