Cannabinoids as Pharmaceutical Agents – Overcoming Challenges & Unlocking Potential
TEAM PERSPECTIVES: TU DIEP, Senior Vice President, Development
Skye’s Senior VP, Development, Tu Diep, discusses the untapped potential of cannabinoids and cannabis derivatives as a distinct and important new class of pharmaceutical therapies. Offering additional insights into Skye’s decision to work with THC in the R&D of the company’s prodrug THCVHS focused on glaucoma, Tu explains what makes Skye’s approach unique but also part of the tipping point the industry needs in the ongoing acceptance and advancement of cannabinoids to offer better therapeutic outcomes for patients living with diseases with unmet medical needs.
If cannabinoids work so well, why then do we not have more cannabinoid-derived medicines approved?
The foundational issue to this question is rooted in the legal status of cannabis and cannabinoids, not just in the United States, but globally.
Since the passage of the 1970 Controlled Substance Act, cannabis and its cannabinoids have been classified as Schedule 1 substances. By this definition, the Drug Enforcement Administration (DEA) deems that they provide no medical benefit and have a high potential for abuse. This is the same classification given to substances like heroin.
This continues to be the DEA’s position, despite the fact that researchers, including our collaborators at the University of Mississippi, have continued to uncover the broad therapeutic potential of cannabinoids and published thousands of peer-reviewed papers in support. There have been several attempts to reclassify cannabis and cannabinoids, but they have failed.
As the regulatory climate on cannabis and cannabinoids continues to evolve, there has been some movement from the DEA on non-psychoactive cannabinoids that are derived from the hemp plant, a close cousin to the cannabis plant. The DEA has implemented interim guidance that cannabinoids derived from hemp plants are legal, with the strict requirement that the hemp plant contains less than 0.3% THC. It is important to note that while the DEA has granted this interim approval, the Food and Drug Administration (FDA) has yet to deem any plant-derived cannabinoids other than Epidiolex, a specific pharmaceutical formulation of cannabidiol (CBD), safe for human consumption. In fact, the FDA has increasingly been cracking down on companies making claims regarding cannabinoids, primarily CBD, that have not been validated through the clinical trial process. The bottom line is that on the regulatory front, there is still much to do at the consumer level for cannabis and cannabinoids, however, that is not an impediment to Skye’s strategy as we are taking the traditional pharmaceutical regulatory approach required for any, and all, prescription drugs.
From my perspective, cannabis and derivatives of cannabis have already shown medical benefits and have the potential for many more benefits to be proven, and they should be removed as a Schedule 1 drug by the DEA. This is not a radical statement by any means. The FDA has already approved three cannabis derivatives. The first was dronabinol, a synthetic version of THC for the treatment of chemotherapy-induced nausea and vomiting, approved in 1985. A more potent synthetic analogue of THC called nabilone was re-approved for the same indication in 2013. The third approval was for Epidiolex in 2018 for the treatment of rare childhood epilepsy. This represents only three drug approvals in thirty-four years. In comparison, the first-ever JAK (Janus kinase) inhibitor was approved by the FDA in 2011 for the treatment of myelofibrosis. Since then, seven JAK inhibitors have been approved in the span of eight years for multiple diseases. Why the discrepancy?
In my opinion, a major deterrent for pharmaceutical and biotechnology companies looking to use cannabis or cannabinoids for pharmaceutical development is the restrictions imposed simply because of the Schedule 1 classification. This adds multiple layers of additional regulatory hurdles and challenges that must be overcome by drug developers.
Despite this, a small number of companies, like Skye, are pioneering the research and development of cannabinoids as a medicine because we truly believe that they have the potential to become a new class of drug with broad therapeutic potential across multiple diseases. Although we have witnessed encouraging changes among local and state governments to legalize cannabis, real change cannot be realized until we see the federal government take on this issue.
Skye will continue to advocate for this change, but, until then, our goal remains the same – to unlock the pharmaceutical potential of cannabinoids.
Why THC (Tetrahydrocannabinol)?
THC is one of the major constituents of cannabis and is well known to be the chemical that causes the “high” or psychotropic effects, associated with cannabis. Most of the early research done on the medical benefits of cannabis-focused on THC as the active agent, however, more recent work has demonstrated that CBD also has therapeutic benefits that are unique compared to THC, but without psychotropic effects. As a result, today there is much more interest in CBD than THC as a drug.
So why does THC hold the mantle as the lead drug candidate for Skye? It is a matter of opportunity. We see glaucoma as an indication with significant unmet medical needs. It is the second leading cause of blindness in the United States, and the people most at risk of developing glaucoma are those over the age of sixty, which happens to be one of our largest population groups. Yet, there has been little innovation in this space.
Patients and physicians are using drugs that were approved twenty years ago. They may be cheap, and they may provide symptomatic relief, but they can have significant side effects and most patients will eventually build a tolerance to any single agent and be required to take two or more classes of therapies to control their IOP. More importantly, none of these therapies address the underlying issue of glaucoma, which is the death of the cells that are responsible for vision.
On the other hand, we have THC, a molecule shown to have therapeutic effects in glaucoma by reducing intraocular pressure (IOP). The pharmacology is well known because the eye is one of the organs in the body with the densest population of cannabinoid receptors – THC’s therapeutic target. Cannabinoids have also been shown to be neuroprotective. THC has demonstrated in multiple animal models its ability to protect neuronal cells from damage and ultimately cell death.
The challenge with THC has been the inability to effectively deliver it into the eye, where it can interact with the receptors that mediate IOP at the front of the eye, while also reaching the back of the eye where the retinal ganglion cells (RGCs) of the optic nerve reside. (RGCs are neuronal cells that play the vital role of processing visual information that begins as light entering the eye.) If we can reach the back of the eye and help spare RGCs from apoptosis, or cell death, then we may also have an opportunity to realize the neuroprotective potential of cannabinoids and actually prevent blindness.
We believe that these problems can be solved with our clinical formulation of THCVHS.
What is so special about THCVHS?
THC was shown to have an impact on reducing IOP as early as the 1970s. Since then, multiple clinical trials have been conducted to evaluate if THC could be used to treat glaucoma. Some studies evaluated smoking cannabis, others gave patients THC orally, and others tried to topically apply THC directly into the eye. In fact, many of these studies did show that IOP could be reduced by THC through multiple routes of administration. Unfortunately, the results were short-lived and were often associated with a lot of unwanted side effects. The issue is THC is not easily absorbed by the body when taken orally. It is absorbed better when inhaled but then it has a much shorter half-life or duration of effect. When delivered topically it has almost zero absorption. The bottom line is that previous formulations and delivery methods have been inconsistent and unpredictable. One of the challenges in realizing the potential of cannabinoids like THC as an effective pharmaceutical agent is modifying it so that it has a much higher and more predictable rate of absorption and metabolism.
THC is known as a lipophilic molecule. What this means is the drug prefers oily solutions and does not dissolve well in water. This poses a problem because our bodies are over 50% water, and it poses an even larger problem for delivering drugs into the eye because water makes up over 90% of the eye. This is what makes THCVHS special.
By chemically modifying THC and adding an amino acid, like valine, along with hemisuccinate, we have made THC more soluble in water and changed the physiochemical properties to allow this new molecule to penetrate deeper into the ocular tissue to reach the back of the eye. This was a key step in improving our ability to better deliver THC into the relevant compartments of the eye. Additionally, we developed a proprietary formulation that further improves the penetration of THCVHS into the eye. We did this by evaluating multiple formulation techniques from nanoparticles to basic emulsions.
Molecular Structure of THCVHS
In the end, we landed on a proprietary nanoemulsion formulation that has demonstrated its superior ability to not only deliver THCVHS into the front of the eye where it can exert its effects on improving IOP but to also get it into the back of the eye where it can potentially impact and improve survival of RGCs – which we know are important in preserving sight. Our ability to now easily and reliably deliver THC into the eye through our proprietary prodrug and proprietary nanoemulsion formulation has demonstrated in animal models that our drug is better at reducing IOP than the current standard of care, latanoprost. This is a very exciting result and is one of the reasons we are committed to bringing this technology into the clinic for patients with glaucoma.
What is the outlook for Skye’s THCVHS clinical program for glaucoma?
We are looking forward to initiating our first-in-human clinical trial for THCVHS. The study design is relatively typical for a drug at this stage of development, with its primary purpose to evaluate the safety and tolerability of the drug, and to do this at different dose levels of the drug.
It will first evaluate healthy volunteers segregated into groups or cohorts. The first cohort will be given a single dose of THCVHS or placebo at a dose we believe is safe based on our animal studies. In the next group, each subject will get a single dose of THCVHS at a higher concentration, followed by another group that will get a single dose at an even higher concentration of THCVHS. This is called a single ascending dose, or SAD, design.
Once we can demonstrate that a single dose of THCVHS is safe in healthy volunteers, we will start a second leg of the study using what is called a multiple ascending dose, or MAD design. Like the SAD design, patients will be randomly grouped into cohorts. But instead of each subject receiving just a single dose of the drug, each subject will be exposed to the same dose once per day over multiple days. The purpose of this is to assess whether a more prolonged exposure to the drug creates any undesirable effects. Similar to the SAD leg, the first group will start with a lower dose of the drug and each subsequent group will receive increasing concentrations of the drug.
What makes our Phase 1 study design more notable is that, first, whereas a Phase 1 normally just exposes healthy volunteers to the drug, we are also enrolling patients with glaucoma or elevated intraocular pressure (i.e. ocular hypertension). This gives us the advantage of being able to observe the initial effects of the drug on IOP. This is also a placebo-controlled, randomized, double-masked study, meaning subjects will be randomly assigned to receive either THCVHS or placebo. Both doctors and subjects will be masked and will not know which treatment was given. This type of study design will allow us a greater degree of comparison of the effects of our drug.
The Skye team is hard at work to complete all the necessary steps to initiate this study before the end of the year. That means ensuring that we have enough drug manufactured, the appropriate preclinical safety pharmacology and toxicology studies are completed, and the clinical protocol, investigator brochures, and case report forms are finalized. This is not a small feat, especially for a small team, but we are a group of highly skilled and experienced professionals and I’m confident we will achieve our milestones.
Ultimately, the success of the study would allow us to move on to the next stage of development where we will be able to fully evaluate the potential of THCVHS in glaucoma patients in larger Phase 2 and 3 clinical trials. This is what really excites our team – to be able to offer patients a new class of therapy that can potentially help to better control their glaucoma.
What is the trajectory of Skye’s drug development pipeline?
We view glaucoma as our proof-of-concept indication for THCVHS. If we can demonstrate that this approach is safe and effective at delivering a payload into the eye, then there is potential to broaden the pipeline of indications within the ocular space. Our second molecule, CBDVHS, an analogue of CBD, uses a similar approach to enhance its delivery and bioavailability. It has demonstrated anti-inflammatory properties and could be an ideal candidate for ocular indications such as dry eye and uveitis. Our collaborators at the University of Mississippi have already demonstrated that CBDVHS is effective at entering the eye. We look forward to exploring the possibilities of our cannabinoid drug platform and are eager to expand our reach in the ocular space.
With that said, we know that cannabinoids have a much larger range of potential effects in the human body. We continue to assess how THCVHS and CBDVHS can be deployed through other routes of administration to evaluate their impact beyond the eye. Moreover, our research team continues to look at how additional novel and proprietary cannabinoid molecules with unique properties can also have potential therapeutic benefits. We look forward to sharing these exciting discovery and research projects at the appropriate time. But our focus today is on glaucoma and pioneering the recognition of cannabinoids as pharmaceutical agents through our lead molecule, THCVHS.
Could this represent a new era in drug development?
From the perspective of cannabis and drug development, I think we are still in its infancy. Thirty-six states in America have approved cannabis for medical use. In 2020, it was projected that the US medical cannabis market exceeded $7.2 billion. In addition to that, GW Pharmaceuticals, the company that developed Epidiolex, was sold for $7.2 billion dollars to Jazz Pharmaceuticals. Put this together, and the use of cannabis to treat day-to-day ailments and even serious medical conditions is being legitimized.
This takes me back to the days when Punit and I started OncoSec. In a similar fashion, that was at a time when cancer immunotherapy was still on the fringes of cancer research. Only a few immunotherapy drugs had been approved, both for malignant melanoma – high dose IL-2 and intratumoral injections of Bacille Calmette-Guérin (BCG) vaccine. Both were okay drugs. They were able to control tumor growth but didn’t necessarily extend the life of patients. Then in 2011, just as we were starting up OncoSec, a small company developing an intratumoral immunotherapy for melanoma, Bristol-Myers Squibb (BMS) presented incredible data demonstrating that their anti-CTLA-4 antibody not only reduced the size of tumors in metastatic melanoma but also significantly extended the lives of patients.
I look back on that period fondly because it turned out to be one of those watersheds, “wow this stuff really works” moments, and we were standing in the middle of it all. The following year, there were the breakthrough approvals of Merck’s anti-PD-1 antibody and Genentech’s anti-PD-L1 antibody. Then came the combination therapies and, along with all these exciting drug approvals, incredible in-depth knowledge of how the immune system can impact the development of and treatment against cancer. And most importantly, thousands of lives were saved as a result.
I like to believe that we will soon see that same watershed moment with the development of cannabinoids for the treatment of diseases. Like cancer immunotherapy research did so many years ago, cannabinoid research indicates so much promise for the use of these agents to treat multiple diseases. The wheels are just starting to turn and develop some momentum toward realizing this potential.
Our aim is that Skye and our lead drug, THCVHS, will play an instrumental role in opening the floodgates, much like BMS with the development and approval of their drug. I will still stand with pride knowing that we were one of the pioneers in advancing cannabinoid drug development and be able to see countless people positively affected by the collective work of Skye and others working to realize the benefits of this important area of scientific and medical advancement.