High hopes for cannabis

Cannabis has a long history of therapeutic as well as recreational use. Dr Sarah Houlton considers the properties that are making it increasingly attractive to pharma companies now that its legalisation is accelerating

Almost half of the states of the US now permit cannabis to be used for medical purposes; the first, California, legalised it almost 20 years ago. The most recent additions, Maryland, Minnesota and New York, joined the roster last year.

Colorado went a step further in 2012, and legalised marijuana for recreational purposes, too, netting an astonishing US$44m in tax – when medical marijuana is added this comes to a total of about $76m. Recreational marijuana is now also legal in Alaska, Oregon and Washington. Numerous other states are also debating legalisation – and even in those states where it is illegal, the herbal scent of marijuana smoke is a common occurrence in public places, as marijuana is often the drug of choice in the light of the legal drinking age of 21.

Cannabis is first known to be have been used for its psychotropic properties in China 6,000 years ago

Cannabis is first known to be have been used for its psychotropic properties in China 6,000 years ago. Several species of the plant are used as drugs, with the most familiar, Cannabis sativa, happily growing in both temperate and tropical climates. Cannabis indica is also common; another strain, Cannabis ruderalis, has few of the psychogenic properties of C. sativa and C. indica.

There is evidence of modern therapeutic use back in Victorian times, when a British doctor working in India, William O’Shaughnessy, documented his observations on the plant’s use for purposes as diverse as pain relief and muscle relaxation, as well as its application as an anticonvulsant, appetite stimulant and antiemetic. These uses mirror many of those for which the drug is being employed medically today.

While cannabis was initially licensed in the US in 1851 for medical use, its use was banned in 1937 (although the product was not removed from the USP until five years later), despite the protests of the American Medical Association.

Tetrahydrocannabinol

Unsurprisingly, the plant contains many active ingredients – as many as 100 have already been identified. Δ-9 Tetrahydrocannabinol, or THC, is the main psychoactive component, but there are many others, including THC’s Δ-8 isomer, and cannabidiol, which is more abundant in C. indica than C. sativa. The actives act on one, or both, of the cannabinoid receptors CB-1 and CB-2. These receptors were identified in the 1990s. CB-1 receptors are found in various parts of the brain, while CB-2 receptors predominate on cells and tissues involved in the immune system.

Cannabis’s medical effects have attracted pharma companies, too, with the development and clinical testing of products that can be prescribed by physicians. Given the natural variability of the identity and concentrations of cannabinoids within plant extracts, there are distinct advantages in isolating or synthesising individual active ingredients, which ensures the patient knows exactly what they are getting.

Several licensed medicines based on cannabis are already marketed. Dronabinol, another name given to THC, is sold in North America under the trade name Marinol by AbbVie to treat chemotherapy-induced nausea and vomiting (CINV) that does not respond well to normal antiemetic treatment. This is also the indication for nabilone (Cesamet, Valeant), which is a derivative of THC. Both of these products are synthetic.

Nabilone

The two drugs are useful in preventing CINV in patients who do not respond either to 5-HT3 antagonists such as ondansetron and palonosetron, or the newer NK-1 receptor agonist drugs such as aprepitant and netupitant, and the cannabinoid drugs’ sedative and euphoria-inducing effects can also be beneficial. However, there can be notable limiting side-effects such as dysphoria, hallucinations and dizziness.

The potential of these products, and cannabis itself, has also been evaluated in reducing anorexia and weight loss in HIV/AIDS patients, by improving appetite. However, a Cochrane review of seven studies in the area concluded that there was insufficient evidence for its efficacy and safety in this setting, or its ability to improve the morbidity and mortality of AIDS patients.

The only other cannabis-based licensed medicine is GW Pharma’s Sativex, which is a mixture of THC and cannabidiol derived from cannabis plants that is given the generic name nabiximols. This is dosed via a mouth spray where it is delivered via the oral mucosa. Its initial indication when it was first launched in the UK in 2010 was in spasticity caused by multiple sclerosis. In some countries, Sativex also has a licence for neuropathic pain and cancer pain.

Unsurprisingly, as one of the earliest players in the field, GW is investigating a variety of other potential cannabis products for a range of indications. Epidiolex, a formulation of cannabidiol, is being studied in childhood epilepsy, with an initial focus on two orphan indications. The first of these, Lennox-Gastaut Syndrome, is a form of epilepsy that begins in childhood, commonly between the ages of two and six. Children with the disease have frequent seizures of different types, and often experience developmental delays, and problems of a psychological and behavioural nature. The second orphan designation is for Dravet syndrome, otherwise known as severe myoclonic epilepsy of infancy. This extreme form of epilepsy begins in infancy, and causes prolonged seizures; as the infant ages other types of seizure occur. Phase III trials are underway and planned in both of these indications.

Cannabidivarin

A second product for the treatment of epilepsy, GWP42006, has a different primary cannabinoid – cannabidivarin. It has already been shown to have antiepileptic activity in preclinical studies, and Phase I studies have been carried out. A Phase II trial is planned.

Tetrahydrocannabivarin, meanwhile, is the major active in GWP42004, which is in Phase II trials for Type II diabetes and metabolic syndrome. Early studies showed it had positive effects on fasting plasma glucose, fasting insulin, adiponectin, beta-cell function, inflammatory cytokines and systolic blood pressure. Initial trials in patients with normal HbA1c levels were promising, leading on to further studies being carried out in patients whose HbA1c levels were uncontrolled.

Cannabidiol is again the main active in GWP42003, which is being evaluated in Phase II clinical trials for its anti-inflammatory properties in ulcerative colitis. Other trials are underway in the cancer field, notably in patients with glioma. Cannabinoids have been shown in the lab to induce apoptosis in glioma cells, both in vitro and in vivo. They may also have an impact on angiogenesis and inhibit tumour growth.

Finally, cannabidiol is also being investigated by GW in psychiatric conditions such as schizophrenia, depression and anxiety. In particular, the company has started a Phase IIa trial to see whether there is clinical evidence to back up suggestions that the product could alleviate the metabolic and inflammatory problems that schizophrenia patients can suffer from, in addition to its potential antipsychotic effects.

Tetrahydrocannabivarin

Arizona-based Insys Therapeutics is working on an oral cannabidiol formulation, in solution form, and the FDA has granted the product orphan status for the same two rare forms of childhood epilepsy as Epidiolex. Phase III trials are already underway, and the product has been given fast track status by the FDA in Dravet syndrome.

The company also has three other orphan designations for the product, in glioma, glioblastoma multiforme, and schizophrenia in children, for which development is at an earlier stage. Dosing in multiple ascending dose Phase I/II trials also began in April for children with treatment-resistant seizures.

Products are being manufactured in the company’s new facility in Round Rock, Texas – the scheduled nature of cannabis meant inspection by the Drug Enforcement Agency was required. It already markets generic dronabinol for CINV, and last year the company submitted an NDA to the FDA for an oral solution formulation of the drug for the same indication, and also for anorexia and weight loss in AIDS patients. The Phase III trials that supported the submission showed bioequivalence at a lower dose than Marinol capsules, and that the oral solution had a much faster onset of action. There was also significantly less variability between patients in terms of total patient exposure to THC.

Canadian company InMed Pharmaceuticals, based in Vancouver, is investigating the potential of other actives found in cannabis in medical applications. It takes advantage of bioinformatics tools based on genomics and metabolomics to pinpoint chemicals in the plants that might be active as therapies in a range of conditions.

By delivering the formulation topically the aim is to create a product without the systemic side-effects engendered by the cannabinoids

It has yet to get a product into the clinic, but two are currently in preclinical development. CTI-085 is a proprietary topical formulation that contains both cannabinoids and non-cannabis-based actives to treat glaucoma. In animal models, the composition was efficacious in lowering intra-ocular pressure, and by delivering the formulation topically the aim is to create a product without the systemic side-effects engendered by the cannabinoids.

The second product in preclinical development, CTI-091, is also a mixture of cannabinoids and non-cannabis actives, which was designed to give relief from joint pain and swelling caused by arthritis and other joint diseases. Early work in the lab showed that it suppressed the human macrophage interleukin-6, which is a major biomarker for inflammation. A novel delivery system is being created with the aim of enhancing retention and absorption of the actives around the target site, in the hope that this will optimise relief of joint pain and swelling.

Cannabidiol

A third product, INM-750, is in an earlier stage of development for epidermolysis bullosa simplex. This rare, inherited keratin-related skin disorder currently has no approved treatment, and the formulation is designed to suppress the inflammation and pathological skin growth and differentiation that are caused by the disease.

Cannabis Science, based in Colorado, has several products in development for a variety of indications. It is also looking to breed cannabis strains with increased levels of cannabidiol but reduced amounts of THC. CS-TATI-1 is a whole plant extract designed to treat Kaposi’s sarcoma, the otherwise rare skin cancer that is much more common in AIDS patients. The cancer is thought to result from exposure to the HHV8 herpes virus that normally lies dormant in the body, but causes problems in those with greatly weakened immune systems. The idea is that cannabinoids inhibit TAT-induced migration to TAT via the CB2 receptors. This product has initially been formulated for topical administration in Phase I, with a plan to investigate an oral delivery route in the longer term.

Also under investigation is another topical formulation of cannabinoid-based extracts, CS-S/BCC-1, in basal and squamous cell carcinomas. The company claims that four skin cancer patients have seen shrinking and apparent eradication of their skin cancer lesions – reports backed up by their doctors – when self-administering the product topically to affected areas. Talks are underway with the FDA about plans for an IND to carry out formal clinical trials.

A third investigational project, CS-NEURO-1, results from a patent submitted in Europe in 2013 on the development of cannabinoid-based formulations for the treatment of various neurobehavioural disorders. These include ADHD and anxiety. The first formulation in the series is now in preclinical development, and the company plans to use the product in foods as well as pharmaceutical products.

The idea is to encapsulate cells within shells of a bio-inert cellulose-based polymer, allowing the cells to be implanted in the body while shielding them from the immune system

PharmaCyte Biotech is working with scientists at the University of Northern Colorado to create cannabinoid-based therapies for cancer. The university team is looking for a type of cell that can convert cannabinoid-like prodrugs into forms that can be used to kill cancer cells. These cells will then be transformed via Cell-in-a-Box technology into an encapsulated form, a technology that has been licensed from Singapore-headquartered Austrianova. The idea is to encapsulate cells within shells of a bio-inert cellulose-based polymer, allowing the cells to be implanted in the body while shielding them from the immune system, and thus enabling them to produce therapeutic molecules without being destroyed.

If such a cell proves elusive, the plan is for Austrianova to use gene transfection to create one that is suitable. PharmaCyte has already used this strategy to create a potential therapy for pancreatic cancer, using the prodrug ifosfamide. Clearly, this strategy is still in the very early stages of development, having not even reached animal models, but it could prove to be a useful way of delivering cannabinoid drugs directly to the site of the cancer.

Nemus Bioscience, based in Costa Mesa, California, is also collaborating with scientists in the academic world to create cannabis-based therapeutics, in this case with the National Center for Natural Products Research at the University of Mississippi, from whom they have licensed technology. They are looking to develop novel delivery methods for cannabis-based products that optimise their clinical effects while reducing the incidence of side-effects. The company has two products in preclinical development, and more still in the discovery lab. NB1111 is being investigated as a treatment for glaucoma, and NB2221 for spasticity in multiple sclerosis. Its other projects include treatments for anxiety, epilepsy and MRSA infection.

NB1111 is a pro-drug formulation of THC. In studies in rabbits with a-chymotrypsin-induced glaucoma, topical administration of the drug to the eyes resulted in a greater decline in intra-ocular pressure than was observed with either of the existing drugs timolol or pilocarpine. The pro-drug is more hydrophilic than THC itself, and gives better tissue penetration into multiple chambers of the animals’ eyes. Nanoemulsion and micellar solution formulations were used. The company is now looking at modified formulations that extend the drug’s half-life.

The hope is that the cannabinoids will be able to prevent systemic infection among patients colonised with MRSA

The MRSA programme, meanwhile, has recently started, and once in vitro tests are complete they hope to move on to formulation work and animal studies. The hope is that the cannabinoids will be able to prevent systemic infection among patients colonised with these antibiotic-resistant bacteria.

The growth in acceptance of medical marijuana in North America has led to a number of companies springing up that specialise in standardised herbal products that are designed to be less variable in terms of their cannabinoid content. These include Winnipeg, Canada-based Delta 9 Bio-Tech, which sells its own strains and those of two other companies, both Dutch – Serious Seeds and Green House Seed Co. While many of the varieties do not have very medical-sounding names – examples include Train Wreck, Warlock, AK47 and Super Silver Haze – all are bred to produce high quantities of THC, cannabidiol, or both. Delta 9 now has an 80,000ft2 facility where it grows plants under controlled conditions to facilitate the production of standardised extracts so patients know exactly what actives they are getting, and how much of them.

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