Examining Benefits of Cannabidiol for Patients With Seizures

According to the US Food & Drug Administration (FDA), cannabis is a plant of the Cannabaceae family and contains more than eighty biologically active chemical compounds. The most commonly known compounds are delta-9-tetrahydrocannabinol (THC) and cannabidiol (CBD).¹ CBD does not produce the same “high” that is associated with THC usage and has been found to be associated with various health benefits, prompting increased need for research and improved education for patients, clinicians, and payers covering patient populations where CBD has proven beneficial.

On July 31, 2020, the FDA approved² the first CBD oral solution (Epidiolex) for the treatment of seizures associated with tuberous sclerosis complex (TSC) in patients one year of age or older. Epidiolex was previously approved for the treatment of seizures associated with two rare and severe forms of epilepsy, Lennox-Gastaut syndrome, and Dravet syndrome. As of June 2021, Epidiolex is the only FDA-approved drug containing a purified drug substance derived from cannabis.³

For the purpose of this literature review, we examine the latest data presented at the American Academy of Neurology’s (AAN) 2021 Virtual Annual Meeting regarding the use of CBD for patients with seizure disorders including TSC.  

Understanding Burden of TSC

According to the Genetic and Rare Diseases Information Center,⁴ a program National Center for Advancing Translational Sciences through the National Institutes of Health, TSC is a rare genetic disease caused by the TSC1 or TSC2 gene working incorrectly and is characterized by the growth of benign tumors throughout the body, including the heart, brain, and kidneys.

TSC primarily affects the central nervous system and includes symptoms such as seizures, developmental delay, and behavioral problems.² An estimated 1 in 6000 people are affected.²

Treatment for TSC is highly individualized and based on managing symptoms. Certain medications can be used to slow or stop the growth of the associated tumors but surgical intervention is sometimes needed.⁴

Two orphan products, everoloumus (Afinitor, Novartis) and vigabatrin (Sabril, Lundbeck) are approved by the FDA for the managing treatment of TSC,⁴ but no cure currently exists. Most treatments are used to control symptoms like seizures.

A rare genetic disease like TSC can have significant impact on the daily life of patients and families and symptoms like seizures have an enormous effect on the quality of life of patients attempting to manage the disease. Add-on CBD treatment has shown to be safe and effective at reducing seizures, improving quality of life of patients.

Benefits of Add-on CBD Treatment

According to a recent poster presentation at AAN 2021 Virtual Annual Meeting, add-on CBD resulted in sustained seizure reduction in patients with TSC for up to 192 weeks with an acceptable safety profile.⁵

Weinstock and colleagues evaluated the long-term efficacy and safety of add-on CBD for patients with TSC in the expanded access program (EAP) final analysis through the FDA. Expanded access, which is sometimes referred to as compassionate use, is a potential pathway for patients with an immediately life-threatening condition or serious disease or condition to gain access to an investigational medical product (drug, biologic, or medical device) for treatment outside of clinical trials when no comparable or satisfactory alternative therapy options are available.⁶

Through the EAP, patients at 35 US epilepsy centers with treatment-resistant epilepsies were provided with open-label CBD between January 2014 and January 2019. Weinstock and colleagues report that included patients received plant-derived highly purified CBD (100 mg/mL oral solution) increasing from 2 mg to 10 mg/kg/d to tolerance or maximum 25 mg to 50 mg/kg/d dose, depending on the study site.⁵ Primary outcomes measured included percentage change from baseline in convulsive, focal, and total seizure frequency, and responder rates at 12-week windows for a total of 192 weeks.

Thirty-four of the 892 patients included in the safety analysis reported having TSC and 8 withdrew from the study. Participants’ mean age was 12.4 years. Patients reported taking a median of 3 concomitant antiepileptic drugs with the most reported being: clobazam (59%), lamotrigine (41%), levetiracetam (32%), and valproate (18%). The top median CBD dose was 40 mg/kg/day.⁵  

Seizure frequency reductions during first 48 weeks ranged from 48% to 55% for convulsive, 61% to 75% for focal, and 44% to 56% for total seizures; and the overall pattern of response was maintained through 192 weeks.⁵ Weinstock and colleagues noted that responder rates (≥50%) were also maintained through 192 weeks for all seizure types.

Mostly commonly reported adverse events included somnolence (32%), diarrhea (29%), convulsion (18%), and vomiting (18%). Only 1 patient experience a liver-related adverse event. No deaths were reported.⁵

Long-term Safety, Efficacy of CBD

In a similar study presented at AAN 2021 Virtual Annual Meeting, Wheless and colleagues⁷ shared data from a second interim analysis of an open-label extension (OLE) trial in which the long-term safety and efficacy of add-on CBD for the treatment of seizures associated with TSC was evaluated.

In this 72-week study, patients who completed the randomized clinical trial received 100 mg/mL CBS oral solution in the OLE with titration to 25mg/kg/day or up to 50mg/kg/day. The OLE trial included 199 patients with a median age of 10.7 years, median seizure frequency of 57 seizures in a 28-day period.⁷

Wheless and colleagues reported that 12% of patients completed treatment, 31% withdrew, and 57% were ongoing. Reported median OLE treatment range was 372 days with a median dosage of 28 mg/kg/day. Notable outcomes from the trial include:

• Median percentage reductions in TSC-associated seizures (12-week windows through 72 weeks): 53% to 75%.⁷
• Seizure reductions were 54% to 80% for patients with a modal dose ≤25 mg/kg/day (n=145), ≥50%, ≥75%, and 100% responder rates were maintained up to 72 weeks, ranging from 52%–63%, 29% to 51%, and 6% to 19%, across 12-week windows.⁷
• Improvement on S/CGIC was reported by 85% and 89% of subjects/caregivers at 26 and 52 weeks.⁷

Most commonly reported adverse events were diarrhea (45%), seizure (28%), decreased appetite (23%), pyrexia (21%), and vomiting (20%). Nine percent of patients (n=17) experienced liver-related adverse events; 12 on concomitant valproate. No patient met Hy’s law criteria. There was 1 death due to cardiopulmonary failure, deemed not treatment-related by the investigator.⁷

Overall, Wheless and colleagues reported that add-on CBD treatment is well-tolerated and produced sustained reductions in TSC-associated seizures.

Background of FDA Approval of Cannabis Products

“The Agriculture Improvement Act of 2018 (also known as the 2018 Farm Bill) removed hemp from the definition of marijuana in the Controlled Substance Act (CSA),” explained Stephen M Hahn, MD, commissioner of food and drugs and Amy Abernethy, MD, PhD, principal deputy commissioner, of the FDA in an FDA Voices news article.³ “This means that cannabis plants and derivatives that contain no more than 0.3% THC on a dry weight basis are no longer controlled substances under the CSA.”

The FDA notes that there is significant interest in developing and producing CBD-based therapies and other consumer products and is actively taking steps to improve the efficiency of regulatory pathways for the lawful marketing of said products.³

“The FDA continues to believe the drug approval process represents the best way to make new medicines, including any drugs derived from cannabis, available to patients in need of appropriate medical therapy such as the treatment of seizures associated with these rare conditions. This paradigm ensures new therapies are safe, effective, and manufactured to a high quality that provides uniform and reliable dosing for patients,” said Douglas Throckmorton, MD, deputy center director for regulatory programs in the FDA’s Center for Drug Evaluation and Research, in a press release.² 

References:

1. What you need to know (and what we’re working to find out) about products containing cannabis or cannabis-derived compounds, including CBD. Updated March 5, 2020. https://www.fda.gov/consumers/consumer-updates/what-you-need-know-and-what-were-working-find-out-about-products-containing-cannabis-or-cannabis
2. FDA Approves new Indication for drug containing an active ingredient derived from cannabis to treat seizures in rare genetic disease [press release published July 31, 2021]. Accessed June 14, 2012. https://www.fda.gov/news-events/press-announcements/fda-approves-new-indication-drug-containing-active-ingredient-derived-cannabis-treat-seizures-rare
3. Hahn SM, Abernathy A. Better data for a better understanding of the use and safety profile of cannabidiol (CBD) products. Published January 8, 2021. Accessed June 14, 2021. https://www.fda.gov/news-events/fda-voices/better-data-better-understanding-use-and-safety-profile-cannabidiol-cbd-products
4. US Department of Health & Human Services. Genetic and Rare Diseases Information Center. Tuberous sclerosis complex. 2020. Updated May 2021. Accessed June 14, 2021. https://rarediseases.info.nih.gov/diseases/7830/tuberous-sclerosis-complex
5. Weinstock A, Bebin EM, Checketts D, et al. Long-term efficacy and safety of cannabidiol (CBD) in patients with tuberous sclerosis complex (TSC): 4-year results from the expanded access program (EAP). Presented at: AAN Virtual Annual Meeting 2021; April 17-22, 2021; virtual.
6. US Food & Drug Administration. Expanded access. Updated March 23, 2021. Accessed June 14, 2021. https://www.fda.gov/news-events/public-health-focus/expanded-access
7. Long-term safety and efficacy of add-on cannabidiol (CBD) for treatment of seizures associated with tuberous sclerosis complex (TSC) in an open-label extension (OLE) Trial (GWPCARE6). Presented at: AAN Virtual Annual Meeting 2021; April 17-22, 2021; virtual.