Small Pharma’s Patented Injectable DMT Formulations Could Help Battle Depression

Small Pharma is evaluating the best way to administer N,N-dimethyltryptamine (DMT) in a therapeutic setting for the treatment of depressive disorders. DMT—the primary psychoactive compound in ayahuasca—could show promise in formulations designed to treat major depressive disorder.

DMT is typically used by inhalation via smoking or vaping, or in combination with a monoamine oxidase inhibitor to make it orally active, making it much harder to develop into medicine. But Small Pharma’s formulations are currently in various stages of clinical trials to determine their efficacy in treating the disorder intravenously.

Small Pharma’s patent application was granted on August 9 in the United States under patent no. 11,406,619 for novel injectable formulations of DMT-based compounds.

It’s the company’s tenth patent as well as its first U.S. psychedelic patent grant, including formulations of DMT, the active ingredient in SPL026, and of deuterium-substituted DMT, including the active ingredient in SPL028. The patent will also protect novel injectable formulations of other known psychedelic compounds, including 5-MeO-DMT and psilocybin.

The fast-acting but powerful psychedelic—wearing off in 20-30 minutes—makes it different from compounds like psilocybin and LSD, which last much longer. DMT could provide an alternative to what would be an otherwise lengthy treatment session and make a more useful option for some clinical applications.

Small Pharma will soon present preliminary safety and efficacy results from the company’s Phase IIa study treating major depressive disorder with DMT-assisted psychotherapy.

“There are a lot of different approaches that are being taken to treating mental health disorders, you know, in particular depression, but at Small Pharma, we’re focused on depression and have been since 2016,” says Small Pharma Co-founder and Chief Innovation and Intellectual Property Officer Peter Rands.

After graduating from University of Oxford, Rands became an experienced patent attorney, often working with pharmaceutical formulation teams.

Rands says that by 2018, Small Pharma selected to focus on DMT. There was a solid base of reason to believe that the psychedelic experience was able to deliver a lasting degree of kind of relief, and DMT could show promise with relief from depressive symptoms, in a matter of months.

“And that’s compared to weeks with ketamine, and no rapid acting response whatsoever with existing antidepressants like SSRIs,” Rands says. “And DMT, has had, at the time, a relatively well known profile, so not at all orally active. It is typically used by inhalation, or in combination with a MAO inhibitor.”

Interactions with conventional drugs for depressive disorders are also being examined. On August 15, Small Pharma announced regulatory approval in the U.K. for a DMT-assisted psychotherapy and SSRI drug interaction study.

DMT’s Role in Medicine

One of the peculiar things about the tryptamine DMT is that it’s a naturally occurring psychedelic found both in plants and in the brain of mammals, also being strongly associated with near-death experiences.

Small Pharma intends to show that a short-acting psychedelic 20-minute timeframe can be delivered with psychotherapy and provide significantly better results than therapy alone.

Could the “near-death” compound be useful in jarring people out of depression?

“And so we designed this study to look purely at efficacy,” says Rands. “And to maximize the likelihood of a real efficacious signal, we wanted to ensure there was 100% bioavailability. So we delivered it by IV.

“And that’s been done,” Rands says. “We weren’t the first company to inject DMT into patients. And a number of primarily academic studies have been ongoing over the period with injectable DMT, but the academic studies have been conducted and the formulations are developed in a pharmacy. And that has a limitation on its shelf life. So what we invested into in 2019-2020, was optimizing a formulation that could be held, you know, in a stable environment, ideally, in kind of ambient conditions, rather than storing in the fridge or freezer for a number of years.”

And it, of course, takes some time to get the data to support that kind of shelf life.

Small Pharma filed a priority application back in 2020 regarding its specific formulation—“the crucial feature that gives it the stability is the non-physiological pH range that we’ve established,” Rands explains. “So there are a number of essential features to the patent, the colors are medicine, it’s got to be injectable, suitable for injection. It isn’t an aqueous solution. So it’s dissolved in water. We maintain the pH at a necessary level by adjusting the pH to between 3.75 and 6.5. And the specific pH bar medicine is still not yet disclosed, but it’s just within the range. We maintain that pH with a buffer and we maintain the osmolality which is basically the number of particles in the medicine within a range that’s comparable to the human physiological range. And those are the features.”

Beginning in February 2021, Small Pharma’s program includes a Phase I/IIa trial on the company’s lead candidate while developing a pipeline of proprietary preclinical assets.

“This U.S. patent represents a major milestone in our development strategy,” Chief Executive Officer George Tziras said. It is also timely, as we anticipate dosing completion in our SPL026 Phase IIa trial in patients with major depressive disorder, and prepare for a Phase I study of SPL028 in healthy volunteers in the second half of this year. For Small Pharma’s longer-term vision, the U.S. will be an important market for DMT-assisted therapies as we look to shape the future of mental health treatments.”

The Patent Process

The rigorous patent process requires a range of hurdles to overcome. Small Pharma’s latest patent grant arrives amid 70 other patent applications.

“A patent is granted on an invention,” Rands says. “An invention is a subset of innovation. So it’s an innovation that involves a novelty and an inventive step, which are just kind of legal parameters. So anyone who’s seeking to obtain patent protection on the medicines that are developing, have to bring something and disclose and give a thorough disclosure of something that is both new and non obvious. And in the psychedelic field, where a lot is already known about, about the substances is sometimes a bit of a challenge to find something that’s both new and non-obvious.”

Another challenge, Rands points out, is that even if you get that patent—will it actually functionally cover your product from generic competition?

“So, you know, companies need to think, what are the ways that a generic can design around their patent? So is the patent actually broad enough to cover what they what they have invested in, because there’s a guarantee that patent will actually deliver a return on your investment that comes from marketing or products and selling it to healthcare systems?

Small Pharma chose IV as a delivery route to guarantee 100% bioavailability, and are hopeful that that would allow them to do so.

“And this has now been proven out in the first part of our study, phase one is a week of producing a single dose, which is able to cause a full psychedelic experience in every subject is dose for that, and yet still remains tolerable. And we’ve now identified that dose after dose that we’ve taken into phase two a, we see no reason to believe that anyone is failing to reach the kind of necessary psychedelic threshold and it has continued to be tolerable.”

Choosing the injectable delivery route has provided Small Pharma with a workable window—which they believe gives them an advantage over inhaled-form formulations.

One of Small Pharma’s competitors obtained Proof of Concept data at the end of last year on 5-MeO-DMT via an alternative trial design in which they titrated up to the effective dose, rather than selecting a dose that works for everyone.

“The primary endpoint is to show significant difference between active and placebo,” Rands says. “And that’s, you know, a statistical measure. So, you know, we’ve modeled it based on the results of an Ayahuasca study. And that is the study showed significant improvement across got, I want to say, about 30 patients, something like that, where within 42, so we’ve studied, you know, we’ve added some additional power to the study.”

Once Small Pharma can find a statistically significant difference between active and placebo, then the company will begin looking further into some of the secondary outcomes.

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