Neurological

Cannabis-based drug for pediatric epilepsy

While an increasing number of states have legalized the use of marijuana for medical or recreational purposes, the United States Drug Enforcement Administration (DEA) must change its designation as a List I substance under the Controlled Substances Act1, still largely preventing it from conducting adequate studies on its use of cannabis-derived products for the treatment of various diseases.

In 2018, however, the U.S. Food and Drug Administration (FDA) approved the cannabis-based drug Epidiolex (GW Pharmaceuticals) for treating seizures in patients 2 years old and older with Dravet syndrome and Lennox-Gastaut syndrome (LGS). Epidiolex, which contains only cannabidiol (CBD), the non-psychoactive compound found in the cannabis sativa plant, is “the first FDA-approved drug that contains a purified active ingredient derived from marijuana,” according to the company the press release announcing its approval 2

The DEA then changed the name of Epidiolex from a List I substance to a List V substance, before reporting such prescriptions to the DEA in 2020, which was finally removed from the List of Controlled Substances

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The FDA approval was based on the results of randomized controlled trials (RCTs) showing the effectiveness of Epidiolex (CBD) compared to placebo in treating drug-resistant seizures in Dravet syndrome and LGS. Following promising results from a number of non-randomized studies, several multinational, double-blind, placebo-controlled studies have further confirmed the effectiveness of CBD for this indication.

In a 2017 study published in the New England Journal of Medicine (NEJM), researchers compared the effectiveness of CBD (20 mg per kilogram of body weight daily) with that of placebo along with standard anti-epileptic (AED) therapy in children and young adults using Dravet Syndrome. The sample consisted of 120 patients aged 2 to 18 years (boys, 52%) who had previously tried a median of 4 antiepileptic drugs

Over the 14-week treatment period, the median monthly seizure frequency decreased from 12.4 to 5.9 in the CBD compared to a decrease from 14.9 to 14.1 in the placebo group (adjusted median difference in change the seizure frequency -22.8 percentage points.). ; 95% CI, -41.1 to -5.4; P = 0.01).

The results further showed that 43% of the patients in the CBD group had at least a 50% reduction in the frequency of seizures compared to 27% in the placebo group (odds ratio 2.00; 95% CI 0.93- 4.30; P =). .08).

Patients who received CBD compared to placebo experienced a greater number of side effects, including “diarrhea, vomiting, tiredness, fever, drowsiness and abnormal liver function test results”.

In a study published in NEJM in 2018, children and adults aged 2 to 55 years with Lennox-Gastaut syndrome were given a 20 mg CBD group (n = 76), a 10 mg CBD group (n = 73 ) or placebo (n = 76), in addition to standard AED therapy.5 Compared to a 28-day baseline period in which patients experienced 2 or more seizures per week, the median seizure frequency decreased by 41.9 %, 37.2% and 17.2% in each group during the 14-week treatment period (P = 0.005 for 20 mg CBD vs. placebo and P = 0.002 for 10 mg CBD vs. placebo).

Common side effects in the CBD groups were drowsiness, decreased appetite, and diarrhea, with greater frequency in the 20 mg group. Elevated liver aminotransferase concentrations were observed in 14 patients in the CBD groups. In 6 patients in the 20 mg CBD group and 1 patient in the 10 mg CBD group, the study medication was discontinued due to side effects.

A study published in the Lancet in 2018 also looked at the use of supplemental CBD to treat drop attacks in patients aged 2 to 55 years with LGS who had had at least 2 drop attacks per week for a 4-week baseline period. Participants received either 20 mg / kg oral CBD (n = 86) or placebo (n = 85) for 14 weeks

During the treatment period, the CBD group showed an average percentage decrease in monthly seizure frequency from baseline of 43.9% (IQR, -69.6 to -1.9) compared to 21.8% (IQR, -45.7) to 1.7) in the placebo group. with an estimated median difference between groups of -17.21 (95% CI, -30.32 to -4.09; P = 0.0135).

Adverse events similar to those seen in the other LGS study included 86% of patients in the CBD group and 69% of patients in the placebo group, and 14% and 1% of patients in these respective groups dropped out due to adverse events.

In a systematic review of 35 studies published in February 2020, Elliott et al. concluded that data from both randomized and non-randomized studies “suggest that cannabidiol reduces seizure frequency and increases response to treatment; However, there is an increased risk of gastrointestinal side effects. ”7

In 2020, Epidiolex was also approved for the treatment of tuberous sclerosis complex (TSC) seizures. Studies are currently underway to assess the drug’s effectiveness in patients with infantile convulsions, Rett syndrome, and other conditions

To get a clinician’s perspective on the matter, we interviewed Charuta Joshi, MBBS, Professor of Pediatric Neurology and Regional Director of Neurological Services at Colorado Children’s Hospital, Anschutz Medical Campus, Aurora.

Since Epidiolex was approved for the treatment of seizures associated with Dravet Syndrome, LGS, and TSC, what has been seen to date regarding its effects on these patients?

We have not conducted a systematic study to determine how many patients with Dravet, LGS, and TSC responded to Epidiolex in our clinic. However, this is certainly a welcome addition to the arsenal of drugs available to these patients with difficult-to-treat seizures. Since we do not know which of these patients will respond to Epidiolex, we offer it to anyone who can make use of it. GW Company is also very helpful to patients and doctors in navigating the needs of the specialty pharmacy to get the drugs to the patients.

What are important considerations for clinicians regarding the use of this drug?

We offer it to patients aged 2 and over with Dravet syndrome, LGS or TSC. It is important to note that Epidiolex, while “natural”, has many interactions with various anti-epileptic drugs – not just clobazam.9 It can reduce levels of commonly used drugs such as topiramate, oxcarbazepine, zonisamide, etc. However, with drugs such as stiripentol, Clobazam, valproic acid, everolimus have major interactions and therefore dose adjustments may be required.

In addition, co-medication with valproic acid requires monitoring of liver function as this can lead to increases in enzyme levels aspartate aminotransferase (AST) and alanine aminotransferase (ALT). Changes in the complete blood count (CBC) have also been reported with the combined use of valproic acid and Epidiolex. 9

What are other emerging areas of research related to the use of cannabis-based therapies for epilepsy or other neurological disorders?

We have a study at Children’s Hospital Colorado using Epidiolex in people with autism. Dr. Nicole Tartaglia is leading this study. 10

What are remaining concerns or questions regarding the use of such therapies for these disorders?

I think the remaining concerns are the same with most new anti-epileptic drugs, such as the fact that many are not “anti-epileptogenic”. They target broad mechanisms and are therefore not precisely selective for the disease state or do not prevent seizures. Therefore, it becomes easier to understand why they are not always 100% effective in treating seizures and why some patients do not get any benefit from their use.

References

1. Drug Enforcement Administration. Drug fact sheet: marijuana / cannabis. April 2020. Accessed online May 31, 2021. https://www.dea.gov/sites/default/files/2020-06/Marijuana-Cannabis-2020.pdf

2. US Food and Drug Administration. FDA approves first drug with an active ingredient derived from marijuana for the treatment of rare, severe forms of epilepsy. Published online on June 25, 2018. Accessed online on May 31, 2021. https://www.fda.gov/news-events/press-announcements/fda-approves-first-drug-comprised-active-ingredient-derived- marijuana-treat-rare-severe-forms

3. MJBizDaily. DEA removes the cannabis drug Epidiolex from the list of controlled substances. Published online April 7, 2020. Accessed online May 31, 2021. https://mjbizdaily.com/dea-removes-cannabis-drug-epidiolex-from-controled-substances-list/

4. Devinsky O, Cross JH, Laux L, et al. Cannabidiol study in drug-resistant seizures in Dravet syndrome. N Engl J Med. 2017; 376 (21): 2011-2020. doi: 10.1056 / NEJMoa1611618

5. Devinsky O, Patel AD, Cross JH et al. Effect of cannabidiol on drop attacks in Lennox-Gastaut syndrome. N Engl J Med. 2018; 378 (20) :: 1888-1897. doi: 10.1056 / NEJMoa1714631

6. Thiele EA, Marsh ED, French JA, et al. Cannabidiol in patients with seizures associated with Lennox-Gastaut syndrome (GWPCARE4): a randomized, double-blind, placebo-controlled phase 3 study. Lancet. 2018; 391 (10125): 1085-1096. doi: 10.1016 / S0140-6736 (18) 30136-3

7. Elliott J, DeJean D, Clifford T, et al. Cannabis-Based Products for Pediatric Epilepsy: An Updated Systematic Review. Seizure 2020; 75: 18-22. doi: 10.1016 / j.seizure.2019.12.06

8. Golub V, Reddy DS. Cannabidiol therapy for refractory epilepsy and seizure disorders. Adv Exp Med Biol. 2021; 1264: 93-110. doi: 10.1007 / 978-3-030-57369-0_7

9. Gaston TE, Szaflarski JP. Cannabis used to treat epilepsy: an update. Curr Neurol Neurosci Rep. 2018; 18 (11): 73. doi: 10.1007 / s11910-018-0882-y

10. McNamara NA, Dang LT, Sturza J, et al. Thrombocytopenia in pediatric patients taking cannabidiol and valproic acid concomitantly. Epilepsy. 2020; 61 (8): e85-e89. doi: 10.1111 / epi.16596

11. Cannabidiol Study in Children with Autism Spectrum Disorder (CASCADE). ClinicalTrials.gov ID: NCT01550003. Accessed online May 31, 2021 https://clinicaltrials.gov/ct2/show/NCT04520685

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