What if a psychedelic-inspired compound could treat mood disorders without causing users to hallucinate?
Boston-based Onsero is exiting stealth mode, announcing its intent to develop a psychedelic-inspired antidepressant that offer therapeutic benefits without causing hallucinations.
Such a drug would avoid the shadow side of classic psychedelics such as LSD and psilocybin.
Classic psychedelics continue to be Schedule I substances, which the federal government deems as having “no currently accepted medical use and a high potential for abuse.”
Some individuals who try psychedelics can have intense fear-ridden experiences while the drug is in their system. Others can have hallucinogen-persisting perception disorder (HPPD), a condition in which perceptual changes continue after the effects of the drug have worn off.
Finally, a significant number of people continue to view psychedelics with skepticism. A 2020 survey found that four out of ten adults believed treating mental health conditions with psychedelics was unwise. Nearly as many, 37%, believed psychedelics cause mental illness.
Research is ramping up on compounds that target the same receptor as classic psychedelics — 5-HT2A — but without causing hallucinations. A recent study in Nature profiled novel molecules targeting the 5-HT2A receptor with potent durable antidepressant activity in a mouse model. The molecules did not appear to have psychedelic effects.
Striking a chord
The potential to develop novel medicines to treat mood disorders resonated with Meenu Chhabra Karson, a Massachusetts-based pharma and biotech executive who is now the CEO of Onsero. “When you’re based in Boston, you see CRISPR 4.0 before most of the world hears about it. You’re just seeing so much innovation,” Karson said.
“Nothing struck a chord with me until I found Dr. Brian Roth’s science and Tim Piser as a thought partner,” Karson said.
Timothy Piser is a pharma industry veteran who is now Onsero’s chief scientific officer.
Roth is a molecular pharmacologist at the University of North Carolina-Chapel Hill, focusing on serotonin and opioid receptor families. Roth was a coauthor of the aforementioned Nature study.
In 2020, Roth’s research received a four-year, $27 million cooperative agreement from the Defense Advanced Research Project Agency (DARPA) to develop novel therapies for mood disorders and substance abuse with an improved benefit-risk ratio.
Roth has also established a consortium of researchers from other universities to collaborate with him, including from Mount Sinai, UCSF, Stanford and Duke.
Founded in early 2021, Onsero has licensed a patented compound related to the recent Nature research from Yale, UNC-Chapel Hill, and the University of California, San Francisco.
“What was published in Nature last week is setting the stage for where innovation can finally take center stage for developing meaningful drugs or neuropsychiatric indications,” Karson noted. “We felt like that was a massive void that could finally be filled in our sector.”
Working with its collaborators, Onsero has developed a drug discovery engine focused on the neurobiology of the 5-HT2A serotonin receptor, which is implicated in mood disorders such as depression.
The drug discovery engine, which leverages cryogenic electron microscopy (cryo-EM), supports the visualization of the conformation — shape — of the 5-HT2A receptor when it’s actively being docked by a psychedelic like LSD,” Karson said. “You can use that important puzzle piece to do large-scale virtual screening across billions of compounds.”
Out of the dark ages?
While antidepressants remain some of the most widely-prescribed drugs, depression rates worldwide continue to climb.
Conversely, the pharma sector’s innovation prowess is on the upswing. The pandemic has also underscored the pharmaceutical industry’s ability to accelerate R&D timelines. Additionally, cell and gene therapy innovation has gained momentum in recent years. And the industry’s continued focus on oncology has supported improving cancer survival rates.
“When you come to the world of neuropsychiatry, it’s almost like going back to the dark ages,” Karson said. “The stats alone are just so scary. For example, 40% of Americans struggle with mental health or substance abuse disorder.”
Roughly 40% to 60% of people taking antidepressants noticed improvements in their symptoms within six to eight weeks, according to NIH. Conversely, 20% to 40% of those taking placebo reported such improvements.
Only a minority of depressed patients on SSRIs achieve remission.
Compounds such as psilocybin and MDMA could help some patients with mood disorders, but can come with psychological or physiological risks. In any event, the compounds are spurring a wave of research that could hold insights for patients in the coming years. For example, the FDA has given the psilocybin Breakthrough Therapy Designation for major depressive disorder and treatment-resistant depression. In addition, MAPS is pursuing regulatory authorization to use MDMA in PTSD. Within the past month, MindMed and Atai Life Sciences have begun testing MDMA derivatives in Phase 1 studies, while MAPS has completed a Phase 3 study of MDMA.
Big Pharma, where art thou?
While interest in psychedelics — however defined — continues to build, “there’s one fundamental stakeholder that has not arrived yet, and that’s Big Pharma to set up partnerships and to enable not just approval, but access post approval to these medicines,” Karson said. “The risk profile [with psychedelics] is up in the air.”
While classic psychedelics are 5-HT2A receptor agonists, they also activate other receptors. “They touch 5-HT2B, which introduces the burden of cardiovascular liability in the long term,” Karson said.
Onsero believes the current psychedelic renaissance provides an unprecedented opportunity to review historical data on molecules targeting the 5-HT2A receptor as a new target for drug discovery. “You’re working with something that’s validated. You already know that this receptor can drive efficacy, Karson said. “Now, it’s time to interrogate the next layer of scientific discovery and see how you can fine-tune its performance to deliver new therapeutics.”
Imagining the future
While FDA could potentially approve psilocybin and MDMA in the coming years, it remains difficult to forecast how much traction they might have. Such drugs would likely be administered in clinical settings with an educational component before therapy begins and follow-up care afterward.
Onsero is betting on novel medicines that target the 5-HT2A receptor. “It’s the same as an SSRI today, meaning you can take it at home,” Karson said. “You can take it chronically. It’s easy to administer, but it delivers the profound efficacy of these known psychedelics — with rapid onset, great durability in its response but without the hallucinatory component and a cardiovascular liability.”
The promise of such novel compounds is “very transformative,” Karson said.
Onsero’s collaboration with Dr. Roth and other investigators that have secured DARPA backing “opens up a panorama of possibilities across the entire serotonin receptor family.”
DARPA’s funding of novel antidepressants could benefit the military population, which has seen surging suicide rates in recent decades. A Brown study found that 30,177 U.S. service members have died in post-9/11 wars — more than four times more than the 7,052 killed in war operations.