Gilgamesh Tweaks Known Psychedelics To Improve Therapies

Many startup companies developing psychedelic therapies work with classic mind-altering substances such as psilocybin, mescaline and LSD. Jonathan Sporn, the founder and chief executive of Gilgamesh Pharmaceutical, has no interest in any of them.

“There’s no way in hell we’re going to develop a generic drug,” Sporn says.

The 64-year-old psychiatrist-turned-entrepreneur disdains the approach taken by other startups for several reasons. First, without intellectual-property protection, he says, companies will find it all but impossible to raise enough money to commercialize a therapy based on an existing psychedelic drug in the public domain. Second, he believes that therapies using classic psychedelics will be expensive and difficult to fit into today’s health-care infrastructure. Finally, he argues, cutting-edge technology can tweak existing substances to make them safer or more effective or easier to administer or, ideally, all of the above.

Gilgamesh is all about drug discovery –and investors are buying the story. Founded in 2019, the company has raised about $74 million. This winter, as other psychedelic startups have struggled to raise small amounts to stay afloat, Gilgamesh closed a $39 million Series B round of financing from eight venture capital firms. Most had invested in Gilgamesh before and their willingness to put more capital into the company signaled satisfaction with its progress. 

That said, Gilgamesh believes that it is at best seven years away from bringing a drug to the market. Of the four psychedelic medicines in its pipeline, two are farthest along. The first is a drug candidate called GM-1020, envisioned as an analog of R-ketamine that can be taken at home as a pill. The second, called GM-2505, is designed to improve the properties of N,N-Dimethyltryptamine, or DMT. Both compounds are about to enter Phase I clinical trials to test their safety and dosage. Two other drug candidates in the pipeline aim to improve the safety or performance of psilocybin and ibogaine.

Having a number of drugs in development gives Gilgamesh “multiple shots on goal,” says Amy Kruse, a venture partner at Prime Movers Lab who recently joined Satori Capital and sits on Gilgamesh’s board. “We’re faced with a pretty wide slate of mental health challenges that will require different approaches,” Kruse says.

Building Tools For Drug Development

To develop a pipeline of novel medicines, Gilgamesh is building a set of tools that will help the company select and optimize drug candidates. The goal is to develop ways to rapidly evaluate tens or hundreds of chemicals to understand precisely how they work. 

Because research into psychedelics was stymied for decades, researchers say there’s lots to learn. 

“There hasn’t been a concerted effort to structurally optimize compounds to be drugs for a particular indication,” says Andrew Kruegel, a medicinal chemist and the co-founder of Gilgamesh. “If any optimization has been done, it’s been done on the gray market and not to generate a therapeutic effect.”

On its website, Gilgamesh says its drug discovery platform uses “complex behavioral assessment, advanced electrophysiology and molecular measures of neuroplasticity” as well as machine learning algorithms to “systematically characterize the multidimensional bioactivity of known and novel psychoactive molecules to improve clinical translation.”

That’s a mouthful. What it means, in practice, can be seen at Harvard University’s Datta Lab, which is led by Sandeep “Bob” Datta, a pioneering professor of neurobiology. There, researchers working with Gilgamesh, administer test drugs to mice and then capture their reactions using video cameras positioned above their cages.

“They rear, they turn, they do all kinds of things,” Sporn says. “They’re tripping.”

These mouse videos are then analyzed by software that uses artificial intelligence to classify the recorded behaviors, thereby providing an indirect window into the mouse brain. According to the researchers, this process is more accurate than relying on human observers who have historically had to rely on less precise measures of rodent behavior such as counting their head twitches or dumping them in water to see how hard they try to swim.

To literally get inside the heads of mice, Gilgamesh also contracts with researchers who use tiny silicon probes known as neuropixels, which only became available in the late 2010s. By implanting neuropixels into rodent brains, researchers can record the electrical activity of hundreds of neurons across multiple brain regions simultaneously and determine how those signaling patterns change in response to drug treatments. 

Using this information, Gilgamesh hopes to better differentiate the effects of closely related drugs, demonstrate effects on neuroplasticity and develop markers of drug response that may ultimately be translatable to human brains. The technologies are new, but the company says they are promising. “If we’re successful,” Sporn says, the drug discovery platform will be “part of the special sauce of the company in the future.”

Track Record at Startups and Big Pharma

Sporn and Kruegel joined forces to launch Gilgamesh after selling their previous startups to atai Life Sciences. Sporn’s first company, Perception Neuroscience, is developing R-ketamine to treat depression, while Kruegel’s startup, Kures, focuses on the therapeutic benefits of kratom, a tropical plant found in Southeast Asia. The two men retain shares in their first startups but are no longer involved in management. 

Kruegel, 34, is a medicinal chemist who has been a researcher at Columbia University since earning his PhD there in 2015. After earning his medical degree, Sporn practiced psychiatry outside of Boston, helped start the mood and anxiety program as a researcher at the National Institutes of Mental Health in the early 2000s, and then worked for nearly 15 years at drug companies Johnson & Johnson and Pfizer.

Sporn learned a lot about drug development while working in Big Pharma, he says. But he grew frustrated by what he calls the “rigidity in decision-making” and “lack of creativity” at Johnson & Johnson. He also came to believe that decision-making at Pfizer was “political and took forever.” 

By contrast, Gilgamesh is a small operation. The company employs 16 people, most of them scattered along the east coast of the U.S. Research and development is outsourced.

“We were built as a pandemic-friendly company from the start,” Kruegel says. Headquarters are “a small closet in New York.”

Senior executives have been drawn from big pharmaceutical and biotech companies. “It’s a small, very tight team,” Sporn says. “Decisions are made rapidly and efficiently, when compared to a big drug company.” 

Investors in Gilgamesh praise the firm’s managers. Venture capitalist Tim Schlidt of Palo Santo says: “They’re an incredibly well pedigreed team. Great pharmaceutical background. We like to see people who have experience taking drugs through development and all the way to approval.”

Kruse agrees, noting in a story about Gilgamesh on Medium that experience matters. “Anybody can have good molecules and good ideas,” says Krause. “But executing on those has been really critical.”

Gilgamesh really got rolling after its executives participated in a virtual program run by Y Combinator, a high-profile incubator for startups that invests in promising companies and helps them raise money. Gilgamesh told its story to Silicon Valley funders, notably Prime Movers Lab, which became its lead investor and put in slightly more than half of the $39 million Series B Round. “That gave the other investors a lot of confidence,” says Sporn who notes that Gilgamesh is now valued at more than $100 million. 

Research Findings

With its drug candidate known as GM-1020, Gilgamesh is stepping into a long-running debate about two isomers of ketamine, known as S-ketamine and R-ketamine. The isomers contain the same molecules, but they are mirror images of one another. Johnson & Johnson developed S-ketamine into a nasal spray, branded as Spravato, that was approved by the FDA in 2019 for patients with treatment-resistant depression. Both Gilgamesh and Perceptual Neurosciences, the company that Sporn sold to atai, are operating on the assumption that R-ketamine will wind up becoming the superior drug.

This month, however, atai reported disappointing results from Perceptual Neurocience’s Phase 2a clinical trial of R-ketamine for depression. R-ketamine did not do significantly better than a placebo in alleviating the symptoms of depression the day after the drug was given–the primary endpoint of the study. That said, the R-ketamine “demonstrated an encouraging safety profile and signals of efficacy” by secondary measures, according to atai .

Sporn concedes that these results could cast a cloud on Gilgamesh’s work with R-ketamine. He argues, however, that a close look at the trial shows that R-ketamine worked well. The problem was that the placebo also had a positive impact. “It swamped the drug effect,” he said. “This is not uncommon in small trials.” 

The other question hanging over Gilgamesh’s bets on GM-1020 is whether ketamine’s dissociative effects contribute to its anti-depressive effects, or whether they are an unwanted side effect. Researchers have found that R-ketamine generally has fewer dissociative effects than S-ketamine. The GM-1020 analog is designed to limit them further allowing the drug to be taken at home without supervision.

“If you’re listening to music, a dissociative dose is probably very enjoyable,” says Sporn. “But for the antidepressant effects, it’s not clear that that matters.” Kruegel goes further, saying that both animal and human trials indicate that “dissociation is not critical.” 

They hope that by limiting dissociation and developing a new R-ketamine analog available as a pill, GM-1020 will be easier to use and less expensive than Spravato, which must be administered in a clinic or doctor’s office.

Gilgamesh is also moving forward with GM-2505, which it sees as a new and improved version of DMT. According to Sporn, the 2505 analog releases more serotonin which may make it a little warmer and empathogenic than DMT. Importantly, Sporn says 2505 lasts longer than a typical DMT experience which can be as short as ten minutes. A duration that is longer than DMT, but shorter than a multi-hour experience with psilocybin, could have a greater therapeutic effect, he says.  

Users of DMT often report intense and mystical experiences which are frequently short in duration depending on the means of ingestion. “It’s not clear how therapeutic that is,” says Sporn, because the experience often passes so quickly.

According to Kruegel, longer-acting drugs like psilocybin and MDMA, which generally produces an experience of six hours or more, are not “scalable in the health system we have today. Patient access is going to be a huge problem.”

Gilgamesh intends for GM-2505 to deliver a psychedelic experience in about an hour. An hour-long experience is not cost-prohibitive but it could well be enough time to explore “the psychedelic headspace,” says Kruegel.

Meanwhile, Gilgamesh is testing new chemical entities that are similar to psilocybin and ibogaine. The analog of psilocybin that the company is developing has been designed to eliminate the hallucinogenic experiences that are often set off by so-called magic mushrooms. The company’s ibogaine-like compound is intended to reduce or eliminate the cardiac risks associated with ibogaine, a psychedelic substance found in a West African shrub.

None of this will be easy. Most biotech startups fail. But Sporn says that, in contrast to many of its peers, Gilgamesh is “very well-funded to weather the winter in the space.” The company has the money and thus the time to do the science that drives innovation. “That’s where we’re a little bit different,” he says.

Correction: The original version of this story incorrectly stated the original compound on which the GM-2505 analog is based. It is N,N-Dimethyltryptamine, widely referred to as DMT, not 5-MeO-DMT (5-methoxy-N,N-dimethyltryptamine).