Epidiolex: Marijuana-derived drug to treat rare forms of epilepsy

June 26, 2018 – The American Food and Drug Administration (FDA) just approved Cannabidiol (Epidiolex), for the treatment of seizures associated with Lennox-Gastaut syndrome and Dravet syndrome, two rare and severe forms of epilepsy, in patients two years of age and older. Lennox-Gastaut syndrome begins in childhood. It is characterized by multiple types of seizures. People with Lennox-Gastaut syndrome begin having frequent seizures in early childhood, usually between ages 3 and 5. More than three-quarters of affected individuals have tonic seizures, which cause the muscles to contract uncontrollably. Almost all children with Lennox-Gastaut syndrome develop learning problems and intellectual disability. Many also have delayed development of motor skills such as sitting and crawling. Most people with Lennox-Gastaut syndrome require help with usual activities of daily living. Dravet syndrome is a rare genetic condition that appears during the first year of life with frequent fever-related seizures (febrile seizures). Later, other types of seizures typically arise, including myoclonic seizures (involuntary muscle spasms). Additionally, status epilepticus, a potentially life-threatening state of continuous seizure activity requiring emergency medical care, may occur. Children with Dravet syndrome typically experience poor development of language and motor skills, hyperactivity and difficulty relating to others.

Cannabidiol (Epidiolex) is the first FDA-approved drug that contains a purified drug substance derived from marijuana. Cannabidiol (CBD) is one of many chemical components of the Cannabis Sativa plant, commonly known as marijuana. However, CBD does not cause intoxication or euphoria (the “high”) that comes from tetrahydrocannabinol (THC). It is THC (and not CBD) that is the primary psychoactive component of marijuana. The effectiveness of Cannabidiol (Epidiolex) was studied in three randomized, double-blind, placebo-controlled clinical trials involving 516 patients with either Lennox-Gastaut syndrome or Dravet syndrome. Cannabidiol (Epidiolex), taken along with other medications, was shown to be effective in reducing the frequency of seizures when compared with placebo. The most common side effects that occurred in Epidiolex-treated patients in the clinical trials were: sleepiness, sedation and lethargy; elevated liver enzymes; decreased appetite; diarrhea; rash; fatigue, malaise and weakness; insomnia, sleep disorder and poor quality sleep; and infections.

The actual genetic basis of Lennox-Gastaut syndrome (LGS) appears rather complex. Recent progress in genome and exome sequencing is revealing that some individuals diagnosed with Lennox Gastaut Syndrome have de novo mutations in a variety of genes, including CHD2, GABRB3, ALG13 and SCN2A, The Epi4K study consortium (2013) observed de novo mutations in at least 15% of a study cohort of 165 patients with LGS and infantile spasms using whole exome sequencing.  A 2013 study by Lund and colleagues found a high frequency of rare copy-number variation (CNV’s) in adult patients with LGS or LGS-like epilepsy begins in childhood. For Dravet syndrome, the genotypic basis of the disorder has been located on the specific voltage-gated sodium channel genes SCN1A and SCN2A. The SCN1A gene is clinically more relevant; the largest number of epilepsy related mutations characterized thus far occur in this gene. Typically, a missense mutation in either the S5 or S6 segment of the sodium channel pore results in a loss of channel function and the development of Dravet syndrome. A heterozygous inheritance of an SCN1A mutation is all that is necessary to develop a defective sodium channel; patients with Dravet syndrome will still have one normal copy of the gene. Cannabidiol (Epidiolex) will provide much needed treatment options for the difficult-to-control seizures that patients with Dravet syndrome and Lennox-Gastaut syndrome experience, and which have a profound impact on these patients’ quality of life.

Cannabidiol (Epidiolex) must be dispensed with a patient Medication Guide that describes important information about the drug’s uses and risks. As is true for all drugs that treat epilepsy, the most serious risks include thoughts about suicide, attempts to commit suicide, feelings of agitation, new or worsening depression, aggression and panic attacks. Epidiolex also caused liver injury, generally mild, but raising the possibility of rare, but more severe injury. More severe liver injury can cause nausea, vomiting, abdominal pain, fatigue, anorexia, jaundice and/or dark urine.

In addition, under the Controlled Substances Act (CSA), CBD is currently a Schedule I substance because it is a chemical component of the cannabis plant. In support of this application, the company conducted nonclinical and clinical studies to assess the abuse potential of CBD. The FDA prepares and transmits, through the U.S. Department of Health and Human Services, a medical and scientific analysis of substances subject to scheduling, like CBD, and provides recommendations to the Drug Enforcement Administration (DEA) regarding controls under the CSA. DEA is required to make a scheduling determination.

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About the Author
thassodotcom Ph.D.; Professor in Pharmacology and Toxicology. Senior expert in theragenomic and personalized medicine and individualized drug safety. Senior expert in pharmaco- and toxicogenetics. Senior expert in human safety of drugs, chemicals, environmental pollutants, and dietary ingredients.

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