Novel drugs: the next generation of medical cannabis

Cannabis has been progressively decriminalised around the world since the early 2000s, starting with Canada granting legal access for medical purposes in 2001 and several other countries following suit.

It has taken Australia 15 years to catch on with the government giving medicinal cannabis the ‘green light’ in 2016. Just two months ago, the Australian Capital Territory also became the first region in the country to legalise recreational use of the drug.

While it seems like the world has had a fair bit of time to evaluate the medical efficacy of cannabis, research is still somewhat wrapped in red tape.

But medical cannabis industry expert Dr Sud Agarwal believes Australia could be the best place to develop the next generation of cannabinoids.

Speaking with Small Caps, he explained how novel drug development can improve on the drawbacks of cannabis in its current form and why it is the future of medicine.

Dr Agarwal is the co-founder and chief executive officer of Australian medicinal cannabis distribution and research company Cannvalate. He is also the chief medical officer of novel medical cannabinoid drug discovery company, Impression Healthcare (ASX: IHL).

The shortcomings of generic cannabis

Despite the many recognised benefits of medical cannabis, Dr Agarwal said a big weakness is the fact that most cannabinoids are currently sold as “general, all-purpose, unapproved” drugs.

These generic cannabis drugs available today do not have clearly defined receptor targets, are not precisely dosed, nor are they scientifically validated for specific therapeutic claims.

“For every other pharmaceutical drug in Australia and the western world, we prescribe a specific dose of a specific drug, which hits a known target to cause effects on a disease that we’re trying to improve, be it cure or manage,” Dr Agarwal said.

With cannabis, a patient will just keep taking it and increasing the dose until they get a desired effect and hope they do not get any adverse effects at this therapeutic level.

“No one knows exactly what the target is and what organs are being affected because it’s possibly affecting multiple receptors in multiple organs,” he added.

When it comes to dosing cannabis accurately, Dr Agarwal said two difficulties are “intra-patient variability and inter-patient variability”.

Intra-patient variability means the same dose of the same drug in the same patient can cause different effects, depending on factors such as the timing and content of recent meals.

Inter-patient variability refers to the different effects occurring in different patients given the same dose of the same drug.

In addition, one drop of cannabis oil from a bottle may differ from another drop in the same bottle, since the majority of the bottle contents are made up of coconut or olive oil with some ground cannabis suspended in it.

“It’s never been measured to be standardised so we know every drop can faithfully give us the same amount of the active pharmaceutical ingredient,” he said.

The development of novel cannabinoid drugs, a concept Dr Agarwal calls ‘Cannabis 3.0’, involves targeting a known receptor with a fixed dose at specified time intervals. For example, scientific experiments might confirm that Drug X will last eight hours, so a patient would take a prescribed milligram dosage of this product three times a day.

Synthetic manufacturing

Another issue highlighted by Dr Agarwal is that standardising a botanically-derived product is “incredibly hard”.

“Today’s harvest might be different to next month’s harvest, meaning the product could have a different potency and will lead to a different effect,” he said.

This is why he believes it is likely the next generation of cannabinoids will be synthetically or biosynthetically manufactured.

This is a controversial topic given cannabis’ appeal partially stems from the perception that it is more natural than other medications.

However, Dr Agarwal argues that hundreds of pharmaceutical products have their origins in plants, including aspirin, which used to be derived from the scraping of willow bark.

“Today, 99.9% of aspirin is made from synthetic chemistry but it acts on the same target as the willow bark extract, so it has the same effect,” he said.

Another example is digoxin, one of the world’s most common cardiac rhythm controlling drugs, which used to be derived from the purple foxglove plant and is now synthetically manufactured.

Dr Agarwal said now that synthetic active pharmaceutical ingredients of common cannabinoids are easily available, novel cannabinoid research can be driven using these as a base ingredient.

Utilising the appropriate format

Interestingly, more than 99% of medicinal cannabis prescribed in Australia is in the form of oil-based products.

This is very different to the US, Canada and Germany, where combustible (i.e. smoked) and vaped cannabis formats are much more commonly used.

Both formats have their pros and cons depending on the targeted disease. While inhaled products are absorbed quickly, their effects also wear off quickly and a patient would require frequent re-dosing every couple of hours.

On the other hand, an oil-based product may take up to four hours to reach its peak effect, which is too slow if a patient suffers from acute pain that comes on suddenly.

The benefit of a novel drug developed for a specific treatment is that the most appropriate format can be determined to achieve the desired effect.

For example, patients suffering chronic pain would benefit from a fast onset delivery system such as an inhaler, while patients needing steady and prolonged treatment might take medical cannabis in an oil, which could last 8-12 hours.

“That’s the idea of this Cannabis 3.0 – it is designed to treat the disease. You’re not just taking the same drug and hoping it works for the disease, which is what is currently happening,” Dr Agarwal said.

Why has it taken so long for novel drug development to start?

There are still a lot of bureaucratic restrictions hindering companies’ abilities to branch into novel drug research.

Dr Agarwal described it as “almost impossible” to perform novel cannabinoid trials in California, despite the US state legalising medical cannabis almost a decade ago.

“If you want to get a cannabis research permit for a novel drug in California, you’ve still got to get an exemption permit from the DEA [Drug Enforcement Agency],” he said.

Likewise, Canadian based companies need an exemption from Health Canada, which can take up to 12 months to be approved.

Dr Agarwal said when testing drugs, researchers “hedge their bets” by evaluating several hundred combinations via high-throughput screening to determine which combination achieves the most effective action.

“If you did that in the US, you’d need an exemption permit for every single permutation of that drug, so the paperwork could take a lifetime,” he said.

However, Dr Agarwal noted that the Medical Cannabis Research Act of 2019 going through US Congress at the moment will “definitely allow things to go faster”.

He added that physician support and patient numbers in the United Kingdom were still too small to get trials up and running.

Australia as the top location for novel cannabinoid research

Until recently, Australia didn’t have the prescriber network support and patient depth to recruit adequate sample sizes for trials.

Although according to Dr Agarwal, the country is “now probably the best place in the world to get cannabis trials up and running and has some of the best pre-clinical and clinical facilities to recruit patients.”

He said in order to undertake cannabis research, a legal framework is required, along with supportive doctors, an adequate patient size and a “cannabis-naïve population”.

“Trials always need a comparison group – a placebo group – who haven’t taken cannabis. It’s much harder to find that in the US and Canada,” Dr Agarwal said.

He said the barriers of access in Australia are still “pretty high”, compared to North America where patients can buy cannabis from a pharmacy without a prescription. In California, you can even buy it from retail shops.

“For example, if you had Crohn’s disease in Canada, the chances are you’ve probably tried some form of cannabis because you can just buy it over the counter,” Dr Agarwal said.

Clinical trials in Australia

Cannvalate and Swinburne University of Technology have a research collaboration in Melbourne named the Medicinal Cannabis Research Collaboration (MCRC), where an experienced team is performing clinical trials on novel cannabinoids  under the supervision of Professor Con Stough and the clinical trial coordinator, Dr Sarah Catchlove.

Dr Agarwal said seven clinical trials are in progress with a further five in the protocol writing stages.

Three of the trials are for Impression Healthcare and concern treatment for sleep apnoea, traumatic brain injury and temporomandibular joint function.

Cannvalate are currently creating a library of novel cannabinoid intellectual property of which the details can’t be disclosed, although Dr Agarwal revealed they involved trials for autism, pancreatic cancer and one, ironically, relates to treating substance addiction.

There has been significant interest in the MCRC internationally. One example involves Cannvalate securing a memorandum of understanding with Israel-based Cannbit to research skin cancer under the supervision of the chairman of Cannbit’s scientific committee, Professor Raphael Mechoulam.

Other companies such as GW Pharmaceuticals and Botanix Pharmaceuticals (ASX: BOT) have used Australian sites for clinical trials of their respective drugs, Epidiolex (for epilepsy) and BTX-1503 (for the treatment of severe acne).