Data from Pharmawand - Curated by EPG Health - Date added 26 June 2018


In the last 30 years or so there has been increased attention on the medical uses of cannabis and its constituent chemicals. Cannabis itself contains at least 60 active cannabinoids, one of which, cannabidiol (CBD), is considered to have a wide scope of medical applications, appearing, for example, to have anti-convulsive action in animal models. Certainly, CBD is thought to be more medically useful than the psychoactive component in cannabis which is tetrahydrocannabinol or THC.

Laws and regulations for the use of cannabis are complex and differ substantially between countries. They tend to distinguish between herbal cannabis, cannabis extracts, and medicines based on synthetic cannabinoids. Neither the EMA and FDA approve the use of herbal cannabis, however the FDA has approved synthetic cannabinoid-based therapeutic agents based on THC for use as antiemetics for instance, as have 23 European countries and Canada. Yet a small number of countries have fully authorised the medical use of herbal cannabis, including Canada, Germany, Israel and the Netherlands, while it can also be prescribed in more than 50% of the states in the United States. Most regulators allow doctors to decide what specific indications they will prescribe herbal cannabis for, but some regulators dictate only specific indications [Ref 1]. Canada in particular remains at the forefront in cannabis regulation and approval [Ref 2]. However, this trend article will not consider herbal cannabis but focus on medical formulations of mainly cannabinoids.

Certainly, the development of cannabinoid-based pharmaceuticals is burgeoning. The estimated medical cannabis market in Europe is 35.7 billion euros annually, according to a 2017 report from analysts Prohibition Partners. Europe will likely be at the forefront for market development with new legislation on medical cannabis formulations currently in preparation in a number of countries. At the same time, doctors hope to identify new approaches to treating pain without fuelling addiction through opioid use - use of older opioid products is in decline, with a market worth $6 billion switching to generics. Not surprisingly, a 2017 report by analysts Cowen & Co. identifies cannabis as a big opportunity, citing data that suggested 64% of medical cannabis patients use the drug to alleviate pain and suggesting that this could be potentially disruptive for both the $5 billion opioid market, and the $2 billion over-the-counter market. With a US National Academy of Sciences study suggesting there is no direct evidence that cannabis is a direct cause of overdose death [Ref 3], it is likely that it will become an increasingly useful alternative to conventional pain relief [Refs 4 and 5].

First approvals

Currently, there are three main therapies amongst the cannabinoid-based medicines approved for marketing. Firstly, Sativex (nabiximol) is an oromucosal spray formula that contains the cannabinoids THC ( tetrahydrocannabinol) and CBD (cannabidiol). Manufactured by GW Pharmaceuticals, its most common indication is multiple sclerosis-associated spasticity, mostly after the failure of previous treatments. Sativex was first indicated in Canada in 2005 to treat neuropathic pain in MS and was then approved in Canada for cancer pain in 2007. It is approved in the EU, though only some countries authorise it, while the drug remains in trials in the US. In two phase III trials for the treatment of pain in patients with advanced cancer, data was consistent with results of an earlier phase III trial, in which Sativex did not meet the primary endpoint. However, a pre-specified pooled analysis of patients across the two trials showed a statistically significant improvement for Sativex compared with placebo, with several secondary efficacy endpoints. Meanwhile, the MOVE2 observational study showed that one month's treatment with Sativex reduces moderate to severe multiple sclerosis spasticity by 20% or more in 4 out of 10 patients previously unresponsive to conventional therapies. After three months, the improvement observed was 30% or more.

Cesamet/Canemes (nabilone) comes in the form of oral capsules containing a synthetic cannabinoid much like THC. The drug originated with Eli Lilly as LY 109514 and Eli Lilly licensed the US rights to Valeant Pharmaceuticals. The UK rights are held by Meda AB and AOP Orphan Pharma sells the drug in Germany and Austria as Canemes. Approved in both the EU and US (Cesamet), the main indication is nausea and vomiting due to chemotherapy treatments, mostly after the failure of previous treatments.

Marinol/Syndros (dronabinol) also comes in oral capsules or solution form  containing  synthetic THC. Marinol was originally approved in the US on 31 May 1985 and is marketed and manufactured by AbbVie while Syndros (a liquid form of synthetic marijuana) was approved  in April 2016 and is manufactured by Insys Therapeutics. Approved in both the US and the EU, the primary indications for use are anorexia associated with weight loss in patients with AIDS and in nausea and vomiting associated with cancer chemotherapy, mostly after the failure of previous treatments.

The main players

As well as making Syndros, Insys Therapeutic's oral CBD cannabidiol (which is over 99.5% pure cannabidiol) is in early studies, phase II and III trials for infant, paediatric and other forms of epilepsy including Lennox-Gastaut and Dravet Syndrome, as well as Prader–Willi syndrome and cocaine dependence. The company has started trials of CBD for Infantile Spasms and childhood absence epilepsy. The company also has an inhalation form of dronabinol in early trials for anorexia in cancer patients and for agitation in Alzheimer’s disease. In April 2018 Insys Therapeutics announced plans to combine this with a breath-actuated device licensed from UK-based Senzer, and accepted by the FDA under an investigational new drug filing, in the second half of 2018.

Also pursuing cannabis-based therapy is GW Pharmaceuticals. Along with Sativex, its lead cannabinoid product candidate is Epidiolex, a liquid formulation of pure plant-derived cannabidiol, which is in development for a number of rare childhood-onset epilepsy disorders. Epidiolex has been accepted for the FDA’s fast-track approval process and was filed in 2017 in both the EU and US for Lennox Gastaut and Dravet Syndrome. In pivotal phase III studies in Dravet syndrome and Lennox-Gastaut syndrome, each trial achieved the primary endpoint demonstrating a statistically significant difference between Epidiolex and placebo in seizure frequency reduction during the 14-week treatment period. The Lennox-Gastaut study was published in NEJM. Prospects seem positive: In April 2018 the FDA Peripheral and Central Nervous System Drugs Advisory Committee recommended supporting the approval of Epidiolex in adjunctive treatment of seizures associated with Lennox-Gastaut syndrome and Dravet syndrome in patients two years of age and older. The PDUFA date is 27 July 2018.

Epidiolex is also in ongoing phase III trials for the treatment of seizures associated with Tuberous Sclerosis Complex (for which it has orphan designation) and in phase II trials for infantile spasms. Epidiolex is expected to become a blockbuster if approved for its three major indications. Sativex failed in a phase III cancer pain trial two years ago, leaving the company’s main hopes for this indication resting on Epidiolex.

GW Pharma is also testing an oral tetrahydrocannabivarin called GWP 42003 which is in early trials for schizophrenia, glioblastoma and neonatal hypoxic-ischemic encephalopathy. It also has GWP 42004 in the pipeline, which is an orally administered product featuring plant-derived tetrahydrocannabivarin (THCV) as its active ingredient, which is in phase II trials as an add on to metformin in the treatment of type 2 diabetes. Another GW Pharma candidate is GWP 42006, which features cannabidivarin (CBDV) as the primary cannabinoid. CBDV has shown anti-epileptic properties across a range of in vitro and in vivo models of epilepsy, especially focal seizures. This is in phase III trials for epilepsy and phase II trials for autism disorders, though it failed in a Phase IIa proof of concept study for focal seizures. GW Pharma has also been working on bringing the first whole-plant-derived cannabis-based medication to the U.S. market. It also has a combination of THC and CBD in an early Phase II trial for Glioblastoma.

Tetra Bio-Pharma is a Canadian based company developing PPP 001 (delta-9-tetrahydrocannabinol 9.5% and cannabidiol 2.5%), which aims to be the first smokable marijuana for advanced cancer pain under prescription. It is a dried cannabis pellet designed to be smoked in an inhalation device specifically developed for this product. PPP 001 is a unique blend of 3 strains of standardized dried cannabis, creating a drug substance with 9.5% THC and 2.5% CBD. PPP 001 is currently in phase II in the US. It also has PPP 002 (dronabinol), a muco adhesive wafer, in phase I for chronic pain and chemotherapy induced nausea and vomiting. PPP 005 (cannabis oil oral capsule) is in phase I trials for chronic pain. The company is also developing cannabis-based treatments for ocular and neuropathic pain. It has also applied for marketing approval in North America for its Rx Princeps medical cannabis and inhalation device and is aiming, through its EU marketing partner PS Innovations, for CE mark approval in the EU for the inhalation device. Tetra has applied  to the FDA with a request to initiate a Phase I trial of topical PPP 004 to treat neuropathic pain. PPP 003 is a combination product targeting chronic pain, PTSD and other conditions.

Other players

Zynerba Pharma is investigating ZYN 002 (synthetic cannabidiol) which is a permeation-enhanced gel for transdermal delivery and which is in phase II trials for treating epilepsy. Most recent data from the Phase II STAR 1 and ongoing STAR 2 study shows that patients who received ZYN 002 for a total of nine months achieved a median reduction in seizures of 65% while those who received it for three months in STAR 1 and six months in STAR 2 achieved a 48% median reduction in seizures. Preclinical results show the effect of transdermally-delivered ZYN002 in an animal model of drug relapse and extended its therapeutic potential to relapse prevention in substance-use disorders.

Centrexion has developed CNTX 6016, the first of a new generation of selective cannabinoid CB2 agonists which the company hopes to test in trials for neuropathic pain alleviation in 2018. Meanwhile Canadian company Harvest One Cannabis is working with Satipharm to develop microgel capsules of cannabidiol. This oral form is in US phase II trials for children with treatment-resistant epilepsy. 

US company Vitality Biopharma has VITA 100 which is a THC cannabinoid drug formulation due to enter phase II trials in 2018 for inflammatory bowel disease, irritable bowel syndrome, and narcotic bowel syndrome, a severe form of opiate-induced abdominal pain. It is looking at more than 20 novel cannabinoid glycoside prodrugs (including prodrug versions of CBD, THC and CBDV). Vitality has developed a new class of cannabinoid pro drugs known as cannabasides which enable delivery of THC to the large intestine.

US-based Phytecs Inc has a number of fluorinated cannabidiol-based derivatives (PECS-101, PECS-111 and PECS-112) in its pipeline, which it believes will increase the drug's bioavailability and is using them in preclinical studies. 

Finally, in April, Israel-based Therapix Biosciences, announced topline results from its phase IIa study suggesting that its combination of dronabinol and palmitoylethanolamide called THX 110 significantly improved symptoms over time in adults with Tourette syndrome. The company has also started a Phase IIa trial for Obstructive Sleep Apnea.

Over the horizon

Founded in 2017, UK-based Oxford Cannabinoid Technologies is studying the potential of cannabinoid-based compounds for treating inflammatory disease (arthritis, auto-immune inflammatory diseases, inflammatory eye diseases), as well as for the more familiar indications in oncology, neurological disorders (addiction, Alzheimer’s, depression, epilepsy, Parkinson’s) and for pain management. This broad approach likely typifies the way cannabis-based formulations will be investigated in future trials. In addition, a number of companies including Kalytera Therapeutics are in the early stages of investigating a combination of cannabinoids with conventional formulations to enhance pain relief.

References

1) Medical use of cannabis and cannabinoids containing products – Regulations in Europe and North America. Ran Abuhasira et al. European Journal of Internal Medicine Volume 49, March 2018, Pages 2–6.

2) The Canadian Cannabis Act legalizes and regulates recreational cannabis use in 2018. ChelseaCox Health Policy, Volume 122, Issue 3, March 2018, Pages 205–209. https://doi.org/10.1016/j.healthpol.2018.01.009.

3) The Health Effects of Cannabis and Cannabinoids: The Current State of Evidence and Recommendations for Research, January 12, 2017, The US National Academies of Sciences Engineering and Medicine. http://nationalacademies.org/hmd/~/media/Files/Report%20Files/2017/Cannabis-Health-Effects/Cannabis-report-highlights.pdf.

4) Cannabis as medicine. BMJ 2017; 357 doi: https://doi.org/10.1136/bmj.j2130 (Published 16 May 2017).

5) Prospective analysis of safety and efficacy of medical cannabis in large unselected population of patients with cancer LihiBar-Lev Schleider et al. European Journal of Internal Medicine, Volume 49, March 2018, Pages 37–43. https://doi.org/10.1016/j.ejim.2018.01.023.

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