United States: Ground Breaking: First Marijuana Based Drug Product Nearing US FDA Approval

An experimental drug derived from cannabis is well poised to become the first of its kind drug to win approval from the United States Food and Drug Administration (USFDA). The drug in question is being developed by GW Pharmaceuticals and is currently known as Epidiolex. Epidiolex is GW's lead cannabinoid product candidate and is a proprietary oral solution of pure plant-derived cannabidiol, or CBD. GW's Epidiolex development is initially concentrating on severe, orphan, early-onset, treatment-resistant epilepsy syndromes including Dravet syndrome, Lennox-Gastaut syndrome (LGS), Tuberous Sclerosis Complex (TSC) and Infantile Spasms (IS)28.

Cannabidiol (CBD) is a cannabinoid prepared from the Cannabis sativa L. plant and is a new molecular entity. It is structurally unrelated to other drugs approved for the treatment of seizures. CBD is currently a Schedule I drug. The exact mechanism of the anticonvulsant effect of CBD is unknown but does not appear to involve an interaction with cannabinoid receptors.

During the initial review with the US FDA's internal review team, the experimental drug scored a favorable review29. The review concluded that the company has provided "substantial evidence" of the drug's effectiveness in treating two rare forms of epilepsy, which are Lennox-Gastaut syndrome (LGS), and Dravet syndrome (DS) in patients 2 years of age and older.

Subsequently, on April 19, 2018, the Peripheral and Central Nervous System Drugs Advisory Committee of the USFDA unanimously recommended supporting the approval of the New Drug Application (NDA) for the investigational cannabidiol oral solution (CBD), also known as Epidiolex®, for the adjunctive treatment of seizures associated with Lennox-Gastaut syndrome (LGS) and Dravet syndrome in patients two years of age and older30. The FDA Advisory Committee is an independent expert panel and even though their votes are not binding on the agency but are considered by the agency when deciding whether to approve or not to approve a new medicine. The PDUFA (Prescription Drug User Fee Act) goal date for completion of the NDA review of the cannabidiol oral solution is currently set at June 27, 2018.

Both LGS and DS are rare, severe, refractory epilepsy syndromes with onset in early childhood. The syndromes are categorized as developmental and epileptic encephalopathies, in which the epileptic activity is thought to contribute to developmental delay and behavioral abnormalities beyond the pathology of the underlying disease. The syndromes are characterized by multiple seizure types that are generally refractory to many of the drugs typically used for the treatment of seizures. Both syndromes are associated with higher rates of mortality than in the general epilepsy population, primarily due to status epilepticus and sudden unexpected death in epilepsy patients (SUDEP).

Efficacy and Safety Data

The efficacy and safety data was assessed from the following three randomized, double-blind, placebo-controlled trials:

  • Study 1414 and Study 1423 – two 14-week, multicenter, randomized, double-blind, placebo-controlled trials in patients with LGS;
  • Study 1332B – a 14-week, multicenter, randomized, double-blind, placebo-controlled trial in patients with DS

For Efficacy

The agency's preliminary review concluded that the applicant has provided positive results from three randomized, double-blind, placebo-controlled trials conducted in patients with LGS and DS. The design of the studies and primary endpoints are consistent with other studies that have been used to support drug approvals for epilepsy indications, including LGS. The studies are adequate and well-controlled. The statistically significant and clinically meaningful results from these three studies provide substantial evidence of the effectiveness of CBD for the treatment of seizures associated with LGS and DS.

For Safety

The agency's preliminary review concluded that in general, the risks associated with cannabidiol appeared to be acceptable. Although the risk of liver injury has the potential to be serious, the observed risk can be appropriately managed with inclusion of relevant language in labeling, education of prescribers regarding the risk of transaminase elevation and need for monitoring of liver enzyme levels, and further characterization of the risk in the post-market setting.

Abuse Potential

Cannabidiol (CBD) is considered to be a new molecular entity for regulatory purposes because there are currently no FDA-approved drug products containing CBD. Under the Controlled Substances Act (CSA), CBD is a Schedule I substance based on its derivation from the plant, Cannabis sativa, also known as marijuana (hereafter, cannabis). Given that CBD is proposed for the treatment of a central nervous system (CNS) condition (epilepsy), it was necessary to evaluate the abuse potential of CBD through both preclinical studies (chemistry, receptor binding, animal behavioral studies) and clinical studies (including a human abuse potential study, as well as analyses of abuse-related adverse events in all clinical studies).

The agency's preliminary review concluded that in general the 750 mg dose of CBD (the low 10 mg/kg therapeutic dose) did not produce abuse potential signals. Although the two higher doses of CBD tested in studies (1500 and 4500 mg, representing the 20 mg/kg therapeutic dose and a supratherapeutic dose) produced some signals of abuse potential, they were small and often inside or just outside the acceptable placebo range. Thus, these data show that although CBD is present in the marijuana plant, it does not produce dronabinol-like responses or depressant-like responses that are indicative of abuse potential.

Overall Conclusion – Safety & Efficacy

The agency's preliminary review overall concluded that clinically meaningful and statistically significant reductions in seizure frequency were demonstrated in three adequate and well-controlled trials in LGS and DS. The results from these three studies provide substantial evidence of the effectiveness of CBD for the treatment of seizures associated with LGS and DS. Though the review is still ongoing, the risk-benefit profile established by the data in the application appears to support approval of cannabidiol for the treatment of seizures associated with LGS and DS.

Marijuana – Medical Usage

In the United States, the use of marijuana for medical purposes is legal in 29 states, In 2017 West Virgina was the latest state to legalize usage of Marijuana for medical purpose31.

Proponents of medical marijuana argue that it can be a safe and effective treatment for the symptoms of cancer, AIDS, multiple sclerosis, pain, glaucoma, epilepsy, and other conditions. Opponents of medical marijuana argue that it is too dangerous to use, lacks FDA-approval, and that various legal drugs make marijuana use unnecessary. They say marijuana is addictive, leads to harder drug use, interferes with fertility, impairs driving ability, and injures the lungs, immune system, and brain.

FDA and Marijuana – Research and Development

The FDA so far has not approved marijuana as a safe and effective drug for any indication. The agency has, however, approved two drugs containing synthetic version of a substance that is present in the marijuana plant and one other drug containing a synthetic substance that acts similarly to compounds from marijuana but is not present in marijuana32. The FDA has approved Marinol and Syndros for therapeutic uses in the United States, including for the treatment of anorexia associated with weight loss in AIDS patients. Marinol and Syndros include the active ingredient dronabinol, a synthetic delta-9- tetrahydrocannabinol (THC) which is considered the psychoactive component of marijuana. Another FDA-approved drug, Cesamet, contains the active ingredient nabilone, which has a chemical structure similar to THC and is synthetically derived.

Although the agency has not yet approved any drug product containing or derived from botanical marijuana, the agency is aware that there is considerable interest in its use to attempt to treat a number of medical conditions, including, for example, glaucoma, AIDS wasting syndrome, neuropathic pain, cancer, multiple sclerosis, chemotherapy-induced nausea, and certain seizure disorders. Therefore, manufacturers may be able to make investigational drugs available to individual patients in certain circumstances through expanded access, as described in the FD&C Act and implementing regulations33. Conducting clinical research using marijuana involves interactions with several federal agencies in the United States. This includes - obtaining the marijuana for research from the National Institute on Drug Abuse (NIDA) within the National Institutes of Health or another Drug Enforcement Administration (DEA)-registered source; review of an investigational new drug (IND) application and the research protocol by the Food and Drug Administration (FDA) and an investigator registration and site licensure by the DEA34.

Conclusion

The United States Food and Drug Administration is expected to decide whether to approve GW Pharma's investigational cannabidiol oral solution (CBD), also known as Epidiolex® by June 27, 2018. If approved, this could help pave the way for other cannabis-based drugs and will mark a sea change in the acceptability of cannabinoids as therapy.

Footnotes

28. http://www.gwpharm.com/epilepsy-patients-caregivers/patients

29. https://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/PeripheralandCentralNervousSystemDrugsAdvisoryCommittee/UCM604736.pdf

30. http://ir.gwpharm.com/news-releases/news-release-details/gw-pharmaceuticals-and-us-subsidiary-greenwich-biosciences-1

31. https://medicalmarijuana.procon.org

32. https://www.fda.gov/NewsEvents/PublicHealthFocus/ucm421163.htm

33. https://www.fda.gov/NewsEvents/PublicHealthFocus/ucm421168.htm

34. https://www.fda.gov/NewsEvents/PublicHealthFocus/ucm421173.htm

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