How Close Is The First FDA-Approved Full-Spectrum Botanical Drug For Autism?

A conversation with Joel Stanley, CEO, AJNA BioSciences

From corner markets to online marketplaces, CBD has become a widely available and used supplement, chosen by consumers to treat pain, sleep issues, and mood disorders. And in 2018, it became an FDA-approved drug to treat seizures. Since then, only four botanical drugs have been approved by the FDA, though the quest has been quite active.

Born out of CBD supplement giant Charlotte’s Web, Ajna Biosciences has emerged as the latest contender for regulatory approval for a botanical drug. But this time, the Ajna team isn’t studying single-molecule cannabis but, rather, a full-spectrum hemp extract.

In this Q&A, Ajna Biosciences CEO Joel Stanley shares his experience in the CBD supplements market and his transition into the botanical drug market, highlighting the need for rigorous chemistry manufacturing controls, the value of frequent conversations with the FDA, and the importance of building a team of KOLs.

You began filing the pre-IND for what's now DeFloria in Q4 of 2022, and now you're into Phase 2a. When you were first getting started, what were some of your biggest challenges or concerns with the regulatory environment, given your pursuit of a botanical drug?

As far as we're aware, this is the first oral, systemically-absorbed botanical drug to make it into a Phase 2 trial. There are only four FDA-approved botanical drugs; three of those are topical, and one coats the GI tract, but none of them are systemic.

Given that's the case, the most difficult part of a botanical drug is the chemistry manufacturing controls. You have a complex botanical drug substance; you need to characterize the molecules. When we filed our pre-IND package, we showed the FDA the level of characterization, the quality controls, as well as why it's consistent and why it's a botanical drug — because botanically derived does not mean botanical drug. You can't manipulate your extraction method, run through chromatography, or pare back molecules.

Fortunately, a member of our team worked at the FDA for over 15 years and was the primary author on that guidance. He helped us put the package together. You don't know what you don't know until you file it, have the meeting, and they come back with feedback. We initially proposed going directly into Phase 2, but the FDA didn't agree. They wanted to see a juvenile toxicology study and a healthy human Phase 1 before allowing us to go into pediatrics. Given that we're going after autism, the pediatric market is going to be very important.

Why then pursue this as an FDA-approved drug and not a supplement, as you’ve done so well with Charlotte’s Web CBD products? 

I’ve effectively been working on this drug for over 15 years, ever since my brothers and I began breeding plants for high-CBD expression. Charlotte’s Web became the face of that effort and ultimately, the catalyst for the entire CBD industry thanks to the story of Charlotte Figi. The genetics behind Charlotte’s Web were awarded the first-ever plant variety protection patents by the U.S. Patent and Trademark Office for a cannabis strain. Those patented genetics form the foundation of our current drug development efforts.

My first meeting with the FDA was shortly after medical doctor and reporter Sanjay Gupta told Charlotte's story, and the FDA told me I have a botanical drug. Now, here's the catch: As a U.S. company, I could not move through the botanical drug development system because the DEA didn't know what to do with hemp. It wouldn't be until December 2018 that the final passage of the Farm Bill would remove hemp from the Controlled Substances Act. Now that you've got hemp legalized, a U.S. company can work with this without it being controlled inventory, and the DEA has started giving out licenses on a very limited basis, which apply to some of our other drugs.

Since then, one CBD drug, Epidiolex, developed by GW Pharmaceuticals, has been approved for very rare epilepsy diagnoses. A pure CBD drug — very different than our drug AJA001 — made by a U.K. company meant they didn't need a Schedule 1 manufacturing license. Yet for American companies, the DEA considered CBD a Schedule 1 drug up until 2019. So, the U.K. company was able to race through the process .

Their drug was approved in summer 2018 for an indication in fewer than 70,000 people. This drug does over $1 billion annual gross; Charlotte's Web does $55 million to $60 million annually.

But it's not just about the money; it shows physician advocacy, the legal ability for physicians to advocate and prescribe. They can only recommend supplements, and they rarely will because they have no clinical data. Physician advocacy opens the door for all the people a drug could truly help.

You have to realize: For people to go to a supplement for a severe disorder without a doctor's prescription, they're either completely out of options or they're very brave. It's usually both. Most of the people still experiencing success from Charlotte's Web are people who were out of options. To me, our greatest good was moving these efficacious botanicals through the botanical drug guidance.

Tell me a little bit about team building. You mentioned onboarding an expert from the FDA. How did you ensure you had the right people in the right place?

Honestly, we wouldn't have the right people if we hadn't had the credibility from everything we did at Charlotte's Web. On the chemistry side, this is the hardest part. This is what's different about a botanical drug. The rest of the process — Phase 1, 2, 3, and an FDA review —  is the same, but pharmaceutical contract manufacturers are not set up to work with farms, test the soil, and have standardized plant genetics. And we're using some of the latest technology that most pharmaceutical developers don't need because they're working with single molecules, not creating full-spectrum botanical products, and you have to train high-level chemists to use those.

Moving from regulatory to clinical, our chief medical officer is Dr. Orrin Devinsky, who was the lead principal investigator for Epidiolex, a really top-notch KOL who moved a CBD drug through the FDA. For autism spectrum disorder, Dr. Divinsky brought on Dr. Bob Findling. There are only two FDA-approved drugs for autism, and  Dr. Findling was lead principal investigator on one and an investigator on the other.

Without all of those experts, you can't accomplish this. It's too complex.

How did you get in touch with these folks, and then get them interested and onboard?

Charlotte's mom introduced me to Orrin in 2012. Orrin had designed a Phase 2 trial for us to run in Uruguay back then, but we didn't do it because we chose to spend the money scaling our dietary supplement. Then in 2016/2017, I was really hoping to get into it again. The DEA wasn't ready yet and regulations weren't ready, but I was preparing for it. Orrin said he’d love to help but was conflicted because he was working with GW Pharmaceuticals.

So, when I started Ajna, Orrin was one of my first calls. We developed a partnership with Johns Hopkins early on with Charlotte's Web to collect the data from the families that we're using it. And now that is the world's largest observational research registry for cannabis therapies. So, we have the who's who of advisors from Johns Hopkins, Harvard Medical Cannabinoid Research, and NYU. It's a web that's been woven through our story over more than a decade.

Back to the present, tell me about where you are now with the Phase 2a trial.

We have our IND on file and cleared to move into Phase 2 in an adult population and in ages 3 to 13. Because it's a very diverse drug, a lot of people were surprised that we chose autism — which I know fully why we have.  but there's a substantial amount of evidence that it works for things like seizure disorders. And that would be an obvious candidate for a future indication.

To us, autism is one of the clearest examples of unmet need in mental health. Families are often left with few options, most of which treat isolated symptoms and come with side effects that make long-term use difficult. What’s missing is a safe, effective therapy that can address the broader spectrum of challenges these individuals face, like emotional regulation, sleep, sensory processing, anxiety and more. That’s where we believe a well-characterized, full-spectrum botanical drug can make a meaningful difference.

But the main reason we're raising money right now is to complete the studies looking at the primary endpoint of irritability associated with autism. Of course, there's ongoing nonclinical toxicology work. So, as soon as we close this round, we'll move into those Phase 2 trials, and then it'll probably be 14 to 16 months for results. We’ll start looking at future commercialization partners from that point and look at the appropriate ways to finance the larger Phase 3 trials.

As you know, there's been a lot of changes happening with the HHS and the FDA, and so we've got RFK junior at the helm of one, and then recently Marty McCarey has been named commissioner for the FDA. Kennedy's been a supporter of psychedelic medicines and/or cannabis, but McCarey hasn't said too much on the subject. Do you think these changes will impact your trajectory?

It will be either no impact at all, or it'll be positive. These are the first natural pharmaceuticals, and you've got a guy who is head of HHS who's been screaming about autism and finding solutions for it, as well as being a huge supporter of natural options. If anything, that's regulatory tailwinds. I don't necessarily think it is going to make it easier. We have an extraordinarily viable candidate for autism, where the only two that exist have horrific side effect profiles.

What advice do you have for folks pursuing a botanical drug?

You want to pick your botanical wisely, then you have to figure out how to cultivate it so the botanical raw material is the same thing over and over within a very tight spec. Then, you have to figure out how to keep that spec through the manufacturing, through the drug substance, and into the drug product. Then, ask yourself: Do we have the team and relationships to characterize the molecules satisfactorily to the FDA to advance them into Phase 2 and 3 clinical trials?

There are thousands of people self-medicating, trying to get themselves off SSRIs with psilocybin microdoses that they're getting from their friends, neighbors, cousins, and basement growers. There’s no consistency or oversight. It's tough to dose.

These are going to be very popular drugs, and once that's proven out, I expect to see competition come into the space. The number of botanicals out there in nature that are viable and should be developed as drugs is a lot more than my company can certainly get to in my lifetime. I welcome that competition, but it has to be very carefully thought out, and fortunately, that competition will have more and more examples of how to do this.

About The Expert:

Joel Stanley, former CEO and Chairman of Charlotte’s Web™ and now a board member of DeFloria, leads AJNA BioSciences in developing next-generation botanical therapeutics. As one of the eldest of the Stanley Brothers — credited with pioneering Charlotte’s Web™CBD products and featured in outlets such as CNN, Forbes, The New York Times, and The Washington Post — Joel is bringing the legacy and impact of Charlotte’s Web™ full circle. At AJNA, his vision is to expand access to pharmaceutical-grade botanical psychedelics designed to address mental health and neurological disorders. By building an ecosystem of natural wellness solutions, AJNA is unlocking the full potential of botanical compounds through sustainable, FDA-approved formulations that redefine plant-based medicine.