What marihuana teaches us about drug discovery

cannabidiol dravet

There was one clear star at the American Epilepsy Society Annual meeting last week, and that was Epidiolex. Epidiolex is the brand name of cannabidiol, a drug isolated from medicinal cannabis that GW Pharmaceuticals (Greenwich Biosciences in the US) is developing for the treatment of a number of orphan refractory epilepsies.

Epidiolex was featured in multiple talks and posters, the scientific exhibit hosted by GW Pharma was hands down the most popular one during the meeting, and it was also the main conversation topic in the corridors. It was impossible not to hear about it.

Yet four years ago no one would have thought that the cannabis-derived drug would take over the field of epilepsy in such a big way.

The rise of Epidiolex has been spectacular: during 2016 GW Pharma has announced positive results from three different Phase 3 trials with Epidiolex, with ongoing Phase 2 and 3 trials for other rare epilepsies. Analysts predict peak sales of over a billion dollars. Clearly a very useful drug and a successful commercial product.

The reason why I find the success of this drug such an excellent lesson for drug discovery is that it goes against many of the basic requirements to finance a drug development program:

  • Cannabidiol is not a new chemical entity, so GW Pharma doesn’t have a patent on the molecule.
  • As a major medicinal ingredient in marihuana, it is relatively easy for patients to access the plant or extracts without needing to purchase the branded product.
  • Cannabidiol is only expected to have partial efficacy against the main symptom of these orphan refractory epilepsy syndromes, which is seizures. It does not target the disease and is not expected to provide complete symptomatic relief.
  • And on top of all that, the mechanism by which cannabidiol is active in epilepsy is still unclear.

If you had tried to approach venture capital firms with a compound that (1) is derived from a medicinal plant, (2) is relatively easy to source as a plant or extract, (3) is likely to provide moderate symptomatic efficacy, and (4) does not have a defined mechanism of action, you would have come out empty-handed.

I know it because I’ve tried this with another molecule having these characteristics.

Investors (and big pharma) want drugs that target the disease biology, with proprietary chemistry and clearly defined mechanisms of action.

What amazes me is that the same investors that would find all those flaws in the investment proposal that I was supporting would turn around and ask me about Epidiolex and its latest results. When confronted with the observation that the very promising Epidiolex happens to have the same profile as our compound the answer was always the same: true, but they have clinical data.

And that’s what this really all boils down to. We create a number of requirements for drugs candidates as a checklist to minimize risks, but once positive clinical data is available that checklist is no longer necessary. We are not short of drugs that target the disease biology, with proprietary chemistry and clearly defined mechanisms of action, that go on to fail in the clinic. We are short of drugs that actually work in the clinic.

Kudos to the GW Pharma team for understanding this and going straight to generating the early clinical evidence that has taken them to where they are today. 

Clearly not every drug can be fast-forwarded with multiple parallel trials and very aggressive timelines as GW Pharma has done with Epidiolex. But drugs isolated from medicinal plants offer the unique opportunity to be fast-forwarded to generate clinical evidence as GW Pharma did.

In the case of cannabidiol the breakthrough was the extensive availability of safety data that enabled the company to sponsor multiple investigator initiated INDs and obtain early clinical data. In other cases, depending on the nature of the medicinal plant, it might even be possible to run food safety clinical studies to obtain that early clinical data prior to an IND.

For drugs isolated from medicinal plants, where the primary screening was pretty much done in human patients, trying to enforce the IP and mechanistic standards that we apply to hypothesis-driven drug candidates might make us throw away the baby with the water bath. The success of Epidiolex has only been possible because GW Pharma was well-funded and had the vision to ask the right questions.

If clinical data is the main deciding factor, then maybe investors should first ask if a compound has a quick path to be tested in patients. For those compounds where the answer is yes, such as in medicinal plant-derived compounds or repurposed drugs, the priority should be in designing a quick clinical study able to generate that early clinical evidence. For those compounds where the answer is no, then we might continue to use checklists to try and minimize risks prior to any clinical study.

When we ask about the possibility to generate quick clinical data, drugs coming from medicinal plants or repurposed assets, where safety has been established, suddenly become exceptional opportunities. 

I don’t know if investors will be able to look at Epidiolex and reconsider what they ask to early candidate drugs. I, for one, will make sure to tell them the story of what marihuana has taught us about drug discovery and about asking one key question: does this compound offer a possibility to generate quick clinical data.

Let me know what you think about it in the comments.

Ana Mingorance PhD

Originally published in LinkedIn on December 16 2016