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When Dr. Husseini Manji was developing the first-in-class depression medication Spravato at Johnson & Johnson he encountered plenty of naysayers.
“A lot of people didn’t think it would work,” the adjunct professor of psychiatry at Yale University and former global therapeutic head of neuroscience at J&J recalled. “I felt confident that if we did it correctly, the efficacy would carry the day.”
Dr. Husseini Manji, adjunct professor of psychiatry, Yale University
The esketamine-based nasal spray ultimately won FDA approval in 2019, delivering the depression space its first new medication in decades. Spravato also offered an option that could provide more rapid treatment than the four to six weeks selective serotonin reuptake inhibitors, depression’s go-to drugs, usually take to kick in. Although Spravato sales got off to a sluggish start, the drug is now poised for blockbuster status.
And the Spravato breakthrough is just the tip of what’s to come, Manji said.
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As the pharma industry stares down a historic patent cliff, macroeconomic headwinds and challenging R&D costs for increasingly complex medicines, nailing the launch of new medicines has become increasingly critical.
After being abandoned by Big Pharma, psychiatric drug development is undergoing a renaissance with researchers throwing scientific weight behind a range of new targets. Over 160 medications for mental health conditions are moving through the clinic, according to a report released by PhRMA last year, including about 50 candidates for depression.
Underscoring these efforts is a shift in mindset that psychiatric conditions should be broken down into precise diagnoses and treated with more nuanced drugs.
“The more we can refine our population and target them with a precise mechanism, that is the best way,” Manji said.
There have been setbacks, however. Alto Neurosciences reported in late October that its precision medicine candidate for major depression disorder failed to beat a placebo in a mid-stage trial. The study included 301 adults divided into cohorts determined by the presence of biomarkers connected to memory loss.
The drug, ALTO-100, is still being tested in bipolar disorder, and data from that phase 2b trial is expected in 2026, Alto’s CEO, Dr. Amit Etkin, told PharmaVoice via email. And the company is still evaluating the results in MDD.
“The Alto team is analyzing the robust data from the trial’s full dataset and plans to share more when this is available,” Etkin said.
Despite those stumbles, Manji is still optimistic about the biomarker approach in depression and maintained that other up-and-coming strategies could deliver the next dogma-smashing drug. Here are some of the precision approaches emerging in the space.
Orexins are busy neurotransmitters in the brain that play a role in a wide range of functions including mood, appetite, the reward system and, importantly, wakefulness. Insufficient orexin has been linked to narcolepsy. But overstimulated orexin receptors can cause insomnia and hyperarousal.