The CNS drug development drum beat is getting louder

The late 1980s and the 1990s were something of a gold rush for pharmaceutical companies focused on CNS drug development — especially those developing psychiatric drugs. In 1988, Eli Lilly introduced the blockbuster SSRI Prozac (fluoxetine), then a new type of antidepressant. Big Pharma companies launched several SSRIs in the years that followed. 

By the end of the 2000s, the rate of development of antidepressants and psychiatric medicines, more broadly, had crawled to a near standstill as Big Pharma companies slashed R&D budgets for CNS drugs and chose to exit the mental health space. “They were facing patent cliffs and had to make some critical decisions,” said Emer Leahy, said CEO of PsychoGenics. 

The tide is now turning. A growing number of well-funded smaller companies with venture backing are emerging in a quest to develop novel psychiatric drugs. “They’re doing some innovative work with biologics and small molecules,” Leahy said. 

PsychoGenics, as a CNS-focused CRO, may be a bellwether for the industry. “We’ve seen a tremendous uptick in interest in our services and a renewed interest in partnering,” Leahy said. 

Another trend driving progress is a renewed interest in phenotypic drug discovery as more pharma companies realize a target-based approach to CNS disorders has been largely disappointing. “Most drugs brought forward in CNS have been found phenotypically,” Leahy said. “There’s a reassessment of how drugs should be discovered in the space.”

Tackling chronic pain

One driver of the opioid crisis is the relative dearth of non-addictive pain medications. The NIH is working to address the problem with the Helping to End Addiction Long-term (HEAL) initiative, which aims to accelerate the development of new technologies to reduce the reliance on opioids. 

In 2019, PsychoGenics received a contract from the National Institute of Neurological Disorders and Stroke (NINDS), an NIH division, to screen experimental agents through the NINDS Preclinical Screening Platform for Pain. The contract will be worth up to $49.9 million over five years. 

“Companies can go to NIH and present their pain treatments, and NIH can decide if they’re interested in profiling those compounds free of charge,” Leahy said. 

NIH then blinds the compounds and shares them with PsychoGenics to screen them in pain models to assess their potential as putative treatments for various types of pain.

Ketamine and psychedelics making a splash

Interest in the off-label use of the dissociative anesthetic ketamine for depression and other mental health disorders is booming. While more data are needed, early signs suggest ketamine has robust antidepressant properties in some patients. “Ketamine has been enormously helpful for a number of people,” Leahy said. 

But ketamine has limitations. The oral bioavailability of ketamine is low, making it more common to administer it intravenously. While the related drug Spravato (esketamine) is available as a nasal spray, patients receiving it require monitoring by a healthcare provider for at least two hours after receiving a dose. 

The popularity of ketamine may inspire further breakthroughs. “We’re seeing tremendous interest in finding the next generation of ketamine — or the next generation of psilocybin, for that matter,” Leahy said, referring to the classic psychedelic. 

Still, intellectual property related to ketamine poses challenges. “You’re dealing with compounds that have been around for a long time,” Leahy said. 

Some companies are experimenting with alternative versions of ketamine and psilocybin. Atai Life Sciences (Nasdaq:ATAI) subsidiary Perception Neuroscience is developing arketamine. Privately held Lennham Pharmaceuticals scored patents for deuterated versions of psilocybin. 

In addition, pharma companies can secure use patents covering specific patient populations, routes of administration or dosage forms. 

Some companies are also working to develop new chemical entities based on classical psychedelics with similar properties but differences in the mechanism of action. 

AI driving a wave of breakthroughs

Hype continues to swirl around the field of AI, but advanced computational power and algorithms continue to offer significant promise to the field of drug discovery. 

PsychoGenics has an in-house team of data scientists to analyze, integrate and sift through disparate data sets. 

“The AI space, in general, is very interesting,” Leahy said. “There are so many areas where that becomes relevant. It’s being employed to find better compounds for testing and identify appropriate patient populations so that we can do better in clinical trials.”

The company also uses computer vision to analyze behavioral testing involving animal models. The company now uses cameras paired with computer vision to provide an objective interpretation of behavioral testing. Collecting about half a million data points from rodent studies, PsychoGenics uses machine learning to extract behavioral signatures and make predictions about novel compounds. The system could predict that a compound may be an antidepressant. It does this by comparing the profiles or signatures to the reference compound database and making predictions. 

PsychoGenics has tested hundreds of reference compounds at multiple doses on its platforms. “We’ve built classifiers that define the broad behavioral signatures for different classes of drugs, antidepressants, mood stabilizers, antipsychotics, etc.,” Leahy said. 

The company has identified numerous companies that are now in clinical trials, including Ulotaront (SEP-363856), which is now in Phase 3 clinical development. PsychoGenics discovered SEP-363856 in collaboration with Sunovion Pharmaceuticals. 

“We’re really excited about this compound’s novel mechanism. It probably could be the first new mechanism of action for schizophrenia in about 65 years,” Leahy said.  

The drug candidate could treat the so-called negative symptoms associated with schizophrenia, including depression-like symptoms such as apathy, flat affect and social withdrawal. 

“There’s a huge unmet need in schizophrenia,” Leahy said. 

Schizophrenia is treatment-resistant in approximately one-third of cases. Many of the available drugs to treat the condition have significant side effects. “So compliance is a big, big problem in schizophrenia,” Leahy said. “And treatments don’t address negative symptoms — or cognitive symptoms — of schizophrenia.” 

“That’s why this drug that we discovered in partnership with Sunovion is so exciting,” Leahy said. “It addresses the negative symptoms as well as other symptoms of schizophrenia, and it has had placebo-like side effects in clinical trials. We’re hopeful that this will be a game changer.”