GW's Epidiolex Approval Encouraging For Pharma-grade Cannabinoid Pipeline

Beyond Epidiolex for severe epilepsy, cannabinoid candidates are in development for a range of diseases, including acute pain, graft-versus-host disease, scleroderma, schizophrenia, pain and substance use disorder.

US FDA approval of GW Pharmaceuticals PLC' marijuana plant-derived product Epidiolex in rare epilepsy disorders sets a regulatory precedent and is encouraging for the large pipeline of cannabinoid candidates in development for various disorders.

The agency cleared Epidiolex (cannabidiol, or CBD) oral solution on June 25 for the treatment of Lennox-Gastaut syndrome (LGS) and Dravet syndrome (DS), noting that this is "the first FDA-approved drug that contains a purified drug substance derived from marijuana." (Also see "Gottlieb: Epidiolex Approval Covers One Specific Cannabidiol Medication, Not Marijuana" - Scrip, 25 Jun, 2018.) In addition to setting a precedent in that the drug is the first plant-derived cannabinoid to win approval, the decision is also ground-breaking because Epidiolex is the first approved for Dravet syndrome.

Importantly, Epidiolex does not include tetrahydrocannabinol (THC), which is associated with the psychoactive effects of marijuana. Synthetic versions of THC that have been approved by FDA include AbbVie Inc.’s Marinol (dronabinol) and Mylan NV's Cesamet (nabilone). GW Pharma markets Sativex (nabiximols) buccal spray, which includes CBD and THC and is derived from cannabis plants, outside the US for spasticity associated with multiple sclerosis.

FDA Commissioner Scott Gottlieb stressed in a statement about the Epidiolex news that this is not a broad approval for marijuana. "This is the approval of one specific CBD medication for a specific use. And it was based on well-controlled clinical trials evaluating the use of this compound in the treatment of a specific condition,” Gottlieb said.

Epidiolex currently has Schedule I status with the US Drug Enforcement Agency, which would severely limit access, but the company believes that it will likely be rescheduled to a very unrestricted level – Schedule IV or V.

The rescheduling of Epidiolex, ensuring wide access, would be an encouraging development for GW in terms of its own further development and the cannabinoid pipeline generally, noted Datamonitor Healthcare analyst Stephanie Yip.

GW Pharma also has Epidiolex in Phase III for tuberous sclerosis complex and Phase II/III for infantile spasms.

Commercial Team Ready, Pricing Still In The Works

The company already has a commercial team in place to market the drug for its initial indications in the US, with 70 reps geared up to reach 4,000 to 5,000 specialist epilepsy prescribers. The patient populations are small – 8,000 people have Dravet Syndrome and 35,000 have Lennox-Gastaut syndrome.

GW has not set a price yet for Epidiolex, but Yip notes that there is no other FDA-approved option for Dravet syndrome so there is high unmet need in a niche space and this is a first-in-class drug, so it could be priced at a premium. Yip points out that Eisai Co. Ltd.'s Banzel (rufinamide), which is FDA-approved for Lennox-Gastaut Syndrome, commands an annual price of about $20,000, whereas the average annual price across other key branded anticonvulsants is approximately $6,500. (Also see "Eisai's Banzel gets US approval and complete response letter for epilepsy" - Scrip, 18 Nov, 2008.)

The market factors will allow GW to maximize the commercial opportunity, Yip told Scrip, and noted that Datamonitor is projecting sales of $822m in 2025.

Although there is nothing else approved for Dravet Syndrome, Epidiolex does have a competitor on the near horizon. Zogenix Inc.'s oral serotonin reuptake inhibitor ZX008 (low-dose fenfluramine) has shown impressive effects in reducing the number of monthly seizures for patients with this condition. (Also see "Stellar Zogenix Phase III Epilepsy Data Lift ZX008's Competitive Position" - Scrip, 29 Sep, 2017.) A filing is expected in the second half.

A Turning Point For Cannabinoids

The development space for cannabinoids has been challenging. Initially, they were developed for obesity. Sanofi withdrew an NDA for Zimulti (rimonabant) in 2007 and took the drug off the market in 2008 in Europe due to the risk of psychiatric side effects. Since then, the field has shifted to development in what is considered more serious conditions, like severe forms of epilepsy. (Also see "Cannabinoid Market Snapshot: GW's Epilepsy Success Bodes Well" - Scrip, 25 Nov, 2016.)

GW sees its plant-based approach as offering advantages over other drugs in the pipeline, which largely consists of synthetic candidates. The company aims to provide a standardized, entirely pure formulation, with no other parts of marijuana aside from CBD, or impurities.

Stephen Schultz, GW's vice president of investor relations, said in an interview that the company has refined the science over 20 years of working in the space and is able to grow plants with a specific cannabinoid profile. Generation after generation, the plants are exactly the same, which is what patients and physicians expect from a medicine, he said.

The cannabinoid pipeline includes at least 27 drugs in clinical development, according to Informa's Pharma Intelligence Biomedtracker database (see chart).

In addition to Epidiolex in tuberculosis sclerosis complex, the late-stage compounds include Insys Therapeutics Inc.'s synthetic formulation of cannabidiol, which is in Phase III for seizure disorders and infantile spasms. Other drugs are in clinical development for a range of conditions, including acute pain, graft-versus-host disease, scleroderma, schizophrenia and substance use disorder.

There also are 49 pipeline products in preclinical development that target the cannabinoid type 1 receptor and these are being tested in 47 different indications spanning neurology, psychiatry, oncology, metabolic diseases, respiratory disease, endocrine and infectious disease, according to Biomedtracker.

"This reflects the excitement surrounding the potential for medical marijuana as companies are willing to invest in testing these products for a wide array of diseases, as they perceive the commercial opportunity for this new drug class," Datamonitor's Yip said.

Over time as clinical data roll in, the field may become more targeted at particular conditions.

Cannabinoid Pipeline
Company	Drug	Development Phase/Indications
Insys Therapeutics	cannabidiol	Phase III: Seizure disorders, infantile spasms. Phase II: Substance use disorder and Prader-Willi Syndrome.
Endo International	DDS-06C	Phase III: Acute pain
Kalytera Therapeutics	cannabidiol	Phase II: Graft-versus-host disease
Corbus Pharmaceuticals	Resunab (ajulemic acid)	Phase III: Scleroderma. Phase II: Cystic fibrosis, dermatomyositis and systemic lupus nephritis.
GW Pharmaceuticals	Epidiolex (cannabidiol)	Phase III: Tuberculosis sclerosis complex. Phase II/III: Infantile spasms.
GW Pharmaceuticals	Sativex (tetrahydrocannabinol and cannabidiol)	Phase III: Neuromuscular pain and spasticity
RespireRX Pharmaceuticals	dronabinol	Phase II: Sleep apnea
Echo Pharmaceuticals	Namisol (dronabinol)	Phase II: Multiple sclerosis, Alzheimer's, chronic pain
Axim Biotechnologies	AX-1602	Phase II: Psoriasis, atopic dermatitis
Axim Biotechnologies	CanChew Plus (cannabidiol gum)	Phase II: Irritable bowel syndrome
MMJ PhytoTech	PTL101	Phase II: Seizure disorders
Zynerba Pharmaceuticals	ZYN002	Phase II: Fragile X syndrome and seizure disorders
Zynerba Pharmaceuticals	ZYN001	Phase I: Tourette syndrome
AbbVie	Marinol (dronabinol)	Phase II: Alzheimer's disease
Therapix Biosciences	THX-OSA01	Phase II: Sleep apnea
Therapix Biosciences	THX-TS01	Phase II: Tourette syndrome
Arena Pharmaceuticals	APD371	Phase II: Pain indications
GW Pharmaceuticals	GWP42003	Phase II: Schizophrenia. Phase I/II: brain cancer. Phase I: Neurology.
GW Pharmaceuticals	GWP42002	Phase I/II: Brain cancer
Tetra Bio-Pharma	PPP001	Phase I: Chronic pain
Bird Rock Bio	RYI-018	Phase I: Non-alcoholic steatohepatitis
7TM Pharma	TM38837	Phase I: Obesity
Intec Pharma	AP-CBD/THC	Phase I: Pain indications
Aelis Farma	AEF0117	Phase I: Substance use disorder
Botanix Pharmaceuticals	BTX-1204	Phase I: Atopic dermatitis
Botanix Pharmaceuticals	BTX-1503	Phase I: Acne
Cmxtwenty	CMX-020 (IV)	Phase I: Postsurgical pain
Cmxtwenty	CMX-020 (oral)	Phase I: Neuropathic pain
Source: Biomedtracker