On some indeterminate date this summer, marijuana will become legal across Canada, as it already is in a number of U.S. states. The move is an extension of earlier acceptance of medicinal marijuana for Canadians suffering a variety of ailments.
For some observers, this is proof of the slippery slope. For others, it is a step forward in healthcare and social equalization.
There is yet a third group who see echoes of today’s marijuana industry in the pre-FDA days of tinctures, potions and snake-oil remedies. Rather than shut the industry down, however, they are interested in learning more about the therapeutic potential of the maligned weed. Their goal is to turn a recreational drug into a pharmaceutical therapy.
Thus, if there is an anthem for this group, it might be 1967’s Time Has Come Today:
Time has come today /
Young hearts can go their way /
Can't put it off another day /
I don't care what others say /
They say we don't listen anyway /
Time has come today.
Young hearts can go their way /
Can't put it off another day /
I don't care what others say /
They say we don't listen anyway /
Time has come today.
Despite growing efforts to legalize Cannabis in several jurisdictions and a growing medical literature of legitimate clinical trials that move well past case reports and anecdotal surveys, interest in the medical application of marijuana—and, more precisely, its two key compounds cannabidiol (CBD) and Δ9-tetrahydrocannabinol (THC)—remains controversial.
“I didn’t know anything about cannabinoids a year-and-a-half ago. They are an interesting mixture of folklore, folk medicine and really cool bold science,” enthuses Michael Mendez, founder and CEO of Renew Biopharma. “I was intrigued by the whole self-pharmacy where people were treating themselves for diseases using these molecules and, in some ways, having a lot of success.”
He continues to explain that cannabinoids—the 80 or so naturally occurring compounds from plants (phytocannabinoids), as well as compounds found within human tissues (endocannabinoids)—are interesting because they naturally cross the blood-brain barrier (BBB) and bind receptors, which he says sounds like a trivial feature.
“But you have to understand that medicinal chemists have been trying to make molecules like this for 30, 40 years,” he explains. “And for the most part, they have not been very successful to get molecules across.”
But another feature that drew Mendez’s attention to cannabinoids was the turmoil and politics of the subject.
“What I mean by that is it is not just the federal laws and the legality, but the sense of morality around these molecules,” he continues.
“When I first talked about Renew going after cannabinoids, my colleagues and all the other people that I’ve worked with in biotech were somewhat taken aback,” Mendez recalls. “Come on, Mike, you’re not seriously going to go after cannabinoids, are you?”
He finds a degree of amusement in what he describes as society’s preconditioning with the Reefer Madness style of thinking, referencing the American propaganda film released in 1936 to warn of the dire perils of engaging in marijuana use.
According to Armando Anido, CEO of Zynerba Pharmaceuticals, the social paranoia and need to control the weed has meant that research into possible medicinal opportunities was significantly hampered.
“There has not been a whole lot of basic science that has been done with CBD throughout the years, because at least in the United States, it is very difficult to get hold of any CBD or THC,” he explains. “The University of Mississippi has the exclusive farm that grows it, that is licensed by the Drug Enforcement Agency (DEA) to supply it to investigators.”
“Investigators will tell you that it is near-impossible to get it,” he continues. “One, to get the license from the DEA, but two, to get adequate supplies to do the studies that are necessary.”
Thus, he presses, any knowledge of medicinal efficacy of CBD and THC has come through anecdotal reporting, a catalog that is expanding now as CBD and THC have become more widely available through medical marijuana programs.
But even as social and legal restrictions have started to loosen, the challenges of dealing with a natural product—whether smoking the plant or ingesting extracts—are making it difficult to study possible therapeutic interventions in a truly clinical manner.
Anido hears about the challenges from clinicians with child patients coming into California with severe refractory epilepsy.
“They go one week to the dispensary and get their product for the next month,” he recounts. “It tends to work very well for them. And then they go the following month and think they’re getting the exact same thing. Then all of the sudden, their child experienced more seizures or more safety concerns.”
Recognizing the significant variability both in yields and molecular profiles of farmed Cannabis plants, companies looking to develop pharmaceutical-grade therapeutic molecules have had to move beyond the naturally occurring cultivars to ensure they can produce enough desired product.
In some cases, this has meant leaving the Cannabis plant entirely.
Continuing to see merit in Cannabis, GW Pharmaceuticals has undertaken a proprietary breeding program that has generated a variety of plants that offer specific molecular profiles or, as they describe them, chemotypes.
Steve Schultz, vice president of investor relations at GW, describes this as a continually evolving library that ultimately allows GW to tap into more than a dozen of the phytocannabinoids.
“We believe that GW is in a unique position to develop and manufacture plant-derived cannabinoid formulations worldwide at sufficient quality, uniformity, scale and sophistication for the purposes of pharmaceutical development and to meet international regulatory requirements,” he adds.
Schultz goes on to suggest that complex extracts can be effective if you can ensure consistency throughout production. He points to GW’s original cannabinoid product Sativex, which is approved in several countries but is still investigational in the United States.
“To manufacture this CBD:THC combination product, we employ a range of advanced analytical technologies to demonstrate batch-to-batch uniformity,” he explains. “We standardize the formulation across the extracts as a whole, not simply by reference to their key active components.”
This approach, he continues, offers the prospect of developing a product that enhances the features of one cannabinoid with the complementary features of another cannabinoid, while being viewed as a single pharmaceutical product by regulators.
For its part, Renew Biopharma acknowledges the importance of Cannabis plants as a starting point, but only as a starting point.
“The plant does a lot of interesting things, and again, it’s given us a lot of drug leads,” Mendez allows. “But that’s not the way to develop drug leads. You’ve got to pull it out and command the pathway, which allows you to command the molecules.”
To do that, Renew relies on the emerging approach of synthetic biology.
“How I define that is the ability to synthesize genes cheaply and to sequence genes cheaply, which allows us to explore really broad DNA diversity on a lot of these different enzymes,” he explains.
The beauty of synthetic biology, he presses, is the ability to mismatch, where you can pull in different genes from different organisms.
“I take whatever genes I want; I couldn’t care less if they come from the Cannabis plant,” Mendez enthuses. “If an enzyme performs a task that I need it to perform, it’s showing up. I don’t care if you’re from walrus or wombat or another plant. There are enzymes that have evolved to just do that job better.”
The company then establishes specific metabolic pathways to produce specific compounds in microalgae, offering scale and control that simply is not possible with a farmed plant.
Although the company explored the more traditional microbes E. coli and yeast—Mendez describing himself as microorganism-agnostic—microalgae simply made the most sense.
“The reason for that is, simplistically, it is a plant-based pathway and there are several enzymes in that pathway that prefer to be expressed within a plant,” he explains.
“It would be a daunting effort just to get them to function in [E. coli or yeast], whereas with microalgae, it has no issue expressing those enzymes and they’re highly active.”
The approach, he says, allows the company to produce the naturally less abundant cannabinoids that researchers have traditionally struggled to access.
“I don’t have anything against THC or CBD, but a lot of those molecules are commodities,” he continues. “If they are of interest for drug development, I’ll have no trouble going after either one of those—but Renew is interested in all of the other cannabinoids that are made in such a small amount that researchers haven’t had a chance to get enough of a pure form of them to study them.”
Just as importantly, the synthetic biology route allows the company to engineer the enzymes to explore a broader chemical space than that produced by Cannabis plants.
“The plant molecules are interesting but I don’t think they’re going to be good enough to really come into their own to play as a therapeutic,” Mendez cautions. “So, Renew is very interested in making derivatives.”
“I love the chassis,” he continues. “It gets me across the [blood-brain] barrier and interacts with the receptor, but there is a lot of off-targeting by a lot of those natural molecules. That’s not how you develop a drug.”
But producing non-abundant molecules and derivatives to scale will serve little purpose if they don’t do anything, which is why in January, the company announced a preclinical discovery collaboration with Ken Mackie at Indiana University’s Gill Center for Biomolecular Science.
“Ken and his group really have the expertise, not only from the cell-based assays, but [from] all of the mouse models that they’ve developed over the years to come back and test these molecules for us,” Mendez enthuses. “He’s able to quickly assay which of our molecules he likes, and then go right into a mouse model quickly and try to demonstrate it.”
And Mackie’s response, says Mendez, has been equally effusive.
“He was completely floored and fascinated by the molecules we were showing him,” he laughs. “I love seeing how excited people get just by looking at a structure of a molecule.”
The other advantage the synthetic biology approach offers, Mendez says, is that it establishes a ready production platform that can be scaled should a therapeutic be approved.
“There’s been a lot of great development on finding derivatives, but now no one seems to be able to manufacture these derivatives,” he adds. “I’ve never done synthesis, but my conversation with the chemists is that a lot of people talk about the chemistry of synthesizing cannabinoids, but when you get down into the nitty gritty with the chemists, it is harder than most people think. This is why companies that have gone down that path are still struggling to get products to market.”
Researchers at Zynerba might disagree with this sentiment, however.
“I think it is one thing [to have enough product] to do clinical studies, but it is another thing as you are looking to commercialize a compound and get it approved by the FDA or any regulatory agency,” says Anido. “They are looking for consistency in how you manufacture. They want to know that if you say there is 100 mg of drug in the formulation, it is releasing and giving you 100 mg every single time.”
Despite the best efforts of some of the larger companies that are trying to simulate Mother Nature, he continues, there are a lot of factors that can exacerbate an already difficult process—e.g., plant disease, temperature control, sunlight control, nutrients—and affect the overall yield.
“It’s pretty hard to make sure that every time you are planting and harvesting and extracting and purifying, you are getting the exact same amount and have consistency of dose,” he cautions.
For this reason, the company decided to pursue chemical synthesis in the development of their CBD and THC derivatives, following the model of classical pharmaceutical development.
That approach not only provides the company with consistent yield and product, but also allows it to explore alternative delivery vehicles, choosing transdermal over the more typical oral formulations.
That decision, Anido explains, was the brainchild of pharmacologist Audra Stinchcomb, then at University of Kentucky, who started a spinoff company called AllTranz.
As Anido recounts: “Audra had the idea that 'hey, if I can bypass the GI tract, improve the bioavailability and get more consistent blood levels, you probably have a compound that works as well, if not better, but probably also avoids the peak levels that you get with an oral delivery that will give you the CNS [central nervous system] highs.'”
Having spent a decade working on the formulations and developing intellectual property, Stinchcomb eventually sold the intellectual property to the investment group Broadband Capital, which worked with Anido and Terri Seebree to found Zynerba. Their resulting lead candidates are ZYN001 (transdermal patch THC) and ZYN002 (transdermal gel CBD).
The availability of these many compounds is leading to a rapid influx of clinical studies for a variety of neurological conditions, the predominant target being epilepsy.
Making clinical inroads
“If you go back to what really got companies like GW Pharmaceuticals to focus in epilepsy, it was primarily reports out of Colorado on the use of Charlotte’s Web, which was CBD-enriched medical marijuana, showing that it had a very dramatic effect on kids with Dravet syndrome, a rare childhood refractory epilepsy,” suggests Anido.
GW’s current lead product candidate is Epidiolex, which Schultz explains is an oral formulation of purified CBD for certain severe, early-onset, drug-resistant epilepsy syndromes, with initial focus on two rare and particularly difficult to treat forms: Dravet syndrome and Lennox-Gastaut syndrome (LGS). Both of these conditions, he says, have been granted Orphan Drug designation by the FDA.
“All three Phase 3 pivotal studies met their primary endpoints demonstrating a clinically meaningful reduction in the frequency of seizures compared to placebo,” Schultz adds. “Overall, Epidiolex was generally well tolerated and demonstrated a consistent side effect profile across these studies.”
In a study published early this year in The Lancet, patients with uncontrolled LGS were given Epidiolex or placebo on top of current therapy for 14 weeks. Patients in the treatment group not only experienced a greater reduction in drop seizures, but were also significantly more like to see a reduction in total seizures, as well as experience a 50-percent or more reduction in drop seizures.
“LGS is one of the most difficult types of epilepsy to treat, and the majority of patients do not have an adequate response to existing therapies,” said lead investigator Elizabeth Thiele, director of pediatric epilepsy at Massachusetts General Hospital, in announcing the publication. “These results show that Epidiolex may provide clinically meaningful benefits for patients with LGS.”
Almost a year ago, GW published similarly positive results for Epidiolex in Dravet syndrome in The New England Journal of Medicine.
At the annual meeting of the American Epilepsy Society (AES) last December, Zynerba announced the findings of its efforts with ZYN002 in adults with focal seizures, the Phase 2 STAR 1 study and open-label STAR 2 extension.
Although STAR 1 did not hit its primary endpoint, according to Anido, it and the extension offered a number of insights to the company.
“It appears that in adults with focal seizures, it may take longer for CBD to have its true effect,” he relates. “We’ve had conversations with a number of cannabinoid specialists and neuroscientists who’ve said to us in an adult patient, the neuronal plasticity has been shot, for the most part. It has been hurt and depleted or not very malleable, and therefore it may be that with CBD it just takes a little bit longer.
“And what we have found is that as we’ve followed the patients from STAR 1 into STAR 2, the more time that they were on drug, the better the results were.”
Furthermore, although the overall placebo rate in STAR 1 was within expectations, there were patients within that arm who achieved unexpectedly high improvement in their seizures. Parsing the data further, the clinicians noted that these super-responders tended to have very low baseline seizure rates.
“As we took a look at breaking out those who had high baseline seizure rates and those who had low, ZYN002 did much better in those who had a higher baseline seizure rate,” Anido explains. “Not only did we have better efficacy, but we also saw that the placebo rate went down considerably.”
Thus, he says, the company will change the minimum number of baseline seizures for patients enrolled in their next trial, expected in the second half of 2018.
Also last December, INSYS Therapeutics announced initiation of a Phase 2 trial of its synthetic CBD oral solution in the treatment of refractory childhood absence epilepsy. The new study follows on the heels of success in an earlier Phase 1/2 study—also presented at the AES conference—that demonstrated a reduction in both seizure frequency and intensity in the treatment arm.
“Better treatments with greater efficacy and fewer side effects are needed to improve quality of life and clinical outcomes for these patients,” according to Steven Phillips, study investigator and pediatric neurologist at Mary Bridge Children’s Hospital and Health Center. “CBD holds great promise for this challenging form of epilepsy.”
Slowly but persistently, however, cannabinoids are being tested in an increasingly wider array of neurological conditions.
According to Schultz, GW also is working on various clinical initiatives for CBDV (GWP42006) within the field of autism spectrum disorders (ASD) and received Orphan Drug designation in the treatment of Rett syndrome.
“A physician-led, expanded-access IND to treat seizures associated with autism has been granted by FDA for 10 patients, and a number of patients have commenced treatment,” he says. “In addition, an investigator-led 100-patient placebo-controlled trial in children with ASD is due to commence in the second quarter of 2018.”
In Rett syndrome, he continues, the company expects to commence an open-label study in the second quarter of 2018, with hopes for a Phase 2 placebo-controlled trial in the third quarter of 2018.
Last October, Schultz says, the company presented several abstracts at a symposium hosted by the Italian Society of Pharmacology.
“These abstracts included science that was developed by GW in concert with numerous academic partners and highlighted a range of in-vitro and in-vivo ASD models, including Rett syndrome-like phenotype rodent models and models related to cognitive and social impairment,” he explains. “These data will guide and inform our development program.”
Through their collaboration with Ken Mackie’s group, Renew has partly focused its interests on the opioid crisis.
“Ken is very passionate about Renew going after opioid addiction,” Mendez says. “[So] our first pass will be opioid craving and pain management.”
Initial efforts will likely focus on CBD and its derivatives, but Mendez sees opportunities for other cannabinoids that simply were not previously available.
Also hoping to enter the opioid addiction space is Aphios Pharma, which announced its efforts to raise equity capital in late 2017 to develop its CBD candidate.
Looking to address some of the issues of current therapeutics like methadone, buprenorphine and naltrexone, which are themselves opioids, Aphios is leveraging proprietary SuperFluids extraction technologies to develop cGMP in a DEA Schedule 1 facility.
It is also working to improve delivery of its lead compound by nanoencapsulating the cannabinoids in biodegradable polymer nanospheres, according to the company's president and CEO, Trevor Castor.
Zynerba has also extended its efforts into the exceptionally rare fragile X syndrome, a condition to which they were first introduced by Randi Hagerman of the UC Davis MIND Institute, who was seeing positive results from children using CBD oils.
Working with Hagerman and Nicole Tartaglia of Children’s Hospital Colorado, the company launched a 20-patient open-label Phase 2 study of ZYN002 and were impressed with the results. Once the data were in, says Anido, the company quickly prepared a meeting with the FDA, held earlier this year, and is hoping to move into a larger, well-controlled double-blind study.
On the THC side, Zynerba has also developed an interest in Tourette syndrome. According to Anido, previous double-blind studies with plant-derived oral THC have demonstrated efficacy both in the severity and frequency of tics, as well as obsessive-compulsive behavior.
“Today, the only things that have been approved for Tourette syndrome have been the atypical antipsychotics that are very difficult to tolerate in patients,” he says. “Most patients don’t like taking it. So we think there is a nice opportunity.”
The company, Anido continues, is going into Phase 1, where they hope to find their transdermal ZYN001 can maintain THC in the blood consistently over a 24-hour period, avoiding the peaks and valleys often seen with oral delivery.
Another company pursuing this angle in Tourette is Therapix Biosciences, which in February announced it had completed pre-IND communications with the FDA for its THX-110 lead candidate, a combination of synthetic THC and palmitoylethanolamide (PEA).
“We believe that this enables us to continue our clinical program with minimum risk, which is consistent with our platform of repurposing and reformulating for unmet and underserved needs for Tourette syndrome,” said Therapix CTO Adi Zuloff-Shani in announcing the discussions. “We expect to evaluate THX-110 in a Phase 2b clinical study in the second quarter of 2018."
In December, the company announced it had completed enrollment in its Phase 2a single-arm open-label study being conducted at Yale University.
Meanwhile, Renew is looking beyond simply creating therapeutic compounds and moving into prevention.
Hoping to leverage evidence that certain cannabinoids demonstrate neuroprotective and anti-inflammatory properties, Mendez and Mackie are eyeing traumatic brain injury and concussions.
“There’s a lot of evidence for a lot of these molecules, and definitely derivatives of these molecules, that it slows down the progression,” Mendez explains. “There’s no reason not to believe that if we worked hard on the derivatives, we could stop the progression.”
More importantly, however, he sees opportunities for such compounds to be used for preventative intervention.
“These molecules should be taken before injury to prevent the immune response that happens at the point of injury,” he presses. “We would like to develop these as preventatives, so one would be able to take these before you went in to play a contact sport or before you went out on patrol if you’re military. That’s where I think it’ll have the greatest impact.”
Regardless, the question arises of why there is suddenly so much activity in this space.
“Why hasn’t this been done before?” Mendez asks. “Why now? Why 2018?”
A matter of timing
“We knew these compounds had these great effects 20 years ago, 30 years ago,” he continues, yet no one stepped forward as they have recently to fit this into a traditional pharma model.
“I wouldn’t have been able to start a company like Renew if California didn’t legalize,” Mendez offers. “It doesn’t matter that I am developing these things legally. The stigma would still have prevented anyone from investing in Renew.”
He’s not sure that the stigma has completely disappeared, but at least, he suggests, people don’t have to worry about jail time.
But even as the industry needed to wait for the social and political environment to change, companies like Renew also had to wait for the scientific landscape to change.
“The cannabinoid pathway itself is not particularly a super difficult pathway to deal with, but there are key enzymes in the pathway that present a true problem for molecular biology,” Mendez says. A new approach to the science was going to be necessary.
“[Synthetic biology] allows us for the first time to really modify these enzymes and really get them into the right place for us to use in microorganisms,” he explains. “You probably wouldn’t have been able to do that maybe 10 years ago.”
As society aligns with technology—like Jupiter with Mars—it seems that time has come today for cannabinoids.