Advisory Panel Recommends FDA Approval of Esketamine, with New Mechanism to Treat Resistant Depression

Advisory Panel Recommends FDA Approval of Esketamine, with New Mechanism to Treat Resistant Depression

Posted: February 14, 2019
Advisory Panel Recommends FDA Approval of Esketamine , with New Mechanism to Treat Resistant Depression & Suicidal Thinking

On February 12th, an FDA advisory panel recommended overwhelmingly that the agency approve a drug called esketamine for the rapid relief of depression in patients who have not been helped by existing therapies.

If the FDA follows the advisory panel’s recommendation in a meeting scheduled for March 4th and gives the go-ahead for marketing of the drug, it will mark a new opportunity for an untold number of patients in great need.

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An FDA advisory panel has recommended that the fast-acting antidepressant esketamine be approved for use in people whose depression has resisted treatment.

Like the closely related experimental drug ketamine, which has been used for years as an anesthetic, esketamine has been shown in multiple clinical trials to dramatically reduce the symptoms of even intractable depression in many patients, often within minutes or hours of its administration. Its effects typically last 1 to 2 weeks, but can be continued in “maintenance” dosing following initial treatment, clinical trials have suggested.

The advisory panel’s recommendation has attracted much media attention, as esketamine would be the first pharmaceutical since the introduction of Prozac in the late 1980s to have a new mechanism of action to treat depression. Although there are many members of the Prozac “class” of drugs—called SSRIs—all of them are thought to exert their effect via the serotonin neurotransmitter system.

Esketamine’s mechanism of action is still being studied, but the drug is thought to act by affecting the function of the brain’s glutamate neurotransmitter system.
 
Esketamine’s approval would be a moment of great satisfaction and achievement for researchers, including dozens of researchers who have received funding from BBRF. Over the last decade, 90 BBRF grantees have received more than $6.5 million in research funding to study ketamine and rapid-acting antidepressants, work which undergirds the development of esketamine and other new potential medicines.

The esketamine product recommended for approval would be marketed under the name Spravato by its developer, Janssen Pharmaceutical/Johnson & Johnson. It would take the form of a nasal spray, packaged in a delivery device that would contain two doses of 14 mg each.

The advisory panel’s recommendations were based on evidence of its effectiveness and safety in 10 clinical studies, including five Phase 3 randomized, placebo-controlled studies in patients with treatment-resistant depression. The FDA defines treatment-resistant patients as those who fail to respond to at least two trials of antidepressant treatment.

The overriding concern about esketamine, like ketamine and other ketamine-related drugs, has been side effects. Ketamine has been misused as a party drug, sometimes called “Special K.” One of its adverse effects is called dissociation, a sensation of great detachment, sometimes described as an “out-of-body” experience. Another important concern centers on ketamine’s addictive potential. These factors and other side effects including dizziness, sedation, and increased blood pressure, were carefully monitored across the clinical trials in which esketamine has been tested. The drug’s developers say that dissociation, when experienced, was usually seen during the hour or so immediately following the drug’s administration, while patients were still under the observation of clinical personnel, and were resolved the same day. The company also says that addictive behavior did not prove to be a serious issue in the trials.

Among the scientists whose research paved the way to esketamine is BBRF Scientific Council member Husseini Manji, M.D., now of Janssen Pharmaceutical/J&J after many years as Chief of the Laboratory of Molecular Pathophysiology & Experimental Therapeutics at the National Institute of Mental Health. Dr. Manji is a 1999 Falcone Prizewinner (now Colvin Prize) for Outstanding Achievement in Affective Disorders Research and a 1998 BBRF Independent Investigator.

A few of the many other BBRF-affiliated researchers who have made major contributions to the search for rapid-acting antidepressants include John H. Krystal, M.D., of Yale University, a BBRF Scientific Council member and a 2006 and 2000 Distinguished Investigator and a 1997 Independent Investigator; BBRF Scientific Council member emeritus Dennis S. Charney, M.D., of Icahn School of Medicine at Mount Sinai; and Carlos A. Zarate, Jr., M.D., of the National Institutes of Health, a 2011 Bipolar Mood Disorders Award Prizewinner (Colvin Prize), 2005 Independent Investigator and 1996 Young Investigator.

CBS News recently featured a story on the Ketamine nasal spray. Watch video

Advisory Panel Recommends FDA Approval of Esketamine , with New Mechanism to Treat Resistant Depression & Suicidal Thinking Thursday, February 14, 2019

On February 12th, an FDA advisory panel recommended overwhelmingly that the agency approve a drug called esketamine for the rapid relief of depression in patients who have not been helped by existing therapies.

If the FDA follows the advisory panel’s recommendation in a meeting scheduled for March 4th and gives the go-ahead for marketing of the drug, it will mark a new opportunity for an untold number of patients in great need.

Like the closely related experimental drug ketamine, which has been used for years as an anesthetic, esketamine has been shown in multiple clinical trials to dramatically reduce the symptoms of even intractable depression in many patients, often within minutes or hours of its administration. Its effects typically last 1 to 2 weeks, but can be continued in “maintenance” dosing following initial treatment, clinical trials have suggested.

The advisory panel’s recommendation has attracted much media attention, as esketamine would be the first pharmaceutical since the introduction of Prozac in the late 1980s to have a new mechanism of action to treat depression. Although there are many members of the Prozac “class” of drugs—called SSRIs—all of them are thought to exert their effect via the serotonin neurotransmitter system.

Esketamine’s mechanism of action is still being studied, but the drug is thought to act by affecting the function of the brain’s glutamate neurotransmitter system.
 
Esketamine’s approval would be a moment of great satisfaction and achievement for researchers, including dozens of researchers who have received funding from BBRF. Over the last decade, 90 BBRF grantees have received more than $6.5 million in research funding to study ketamine and rapid-acting antidepressants, work which undergirds the development of esketamine and other new potential medicines.

The esketamine product recommended for approval would be marketed under the name Spravato by its developer, Janssen Pharmaceutical/Johnson & Johnson. It would take the form of a nasal spray, packaged in a delivery device that would contain two doses of 14 mg each.

The advisory panel’s recommendations were based on evidence of its effectiveness and safety in 10 clinical studies, including five Phase 3 randomized, placebo-controlled studies in patients with treatment-resistant depression. The FDA defines treatment-resistant patients as those who fail to respond to at least two trials of antidepressant treatment.

The overriding concern about esketamine, like ketamine and other ketamine-related drugs, has been side effects. Ketamine has been misused as a party drug, sometimes called “Special K.” One of its adverse effects is called dissociation, a sensation of great detachment, sometimes described as an “out-of-body” experience. Another important concern centers on ketamine’s addictive potential. These factors and other side effects including dizziness, sedation, and increased blood pressure, were carefully monitored across the clinical trials in which esketamine has been tested. The drug’s developers say that dissociation, when experienced, was usually seen during the hour or so immediately following the drug’s administration, while patients were still under the observation of clinical personnel, and were resolved the same day. The company also says that addictive behavior did not prove to be a serious issue in the trials.

Among the scientists whose research paved the way to esketamine is BBRF Scientific Council member Husseini Manji, M.D., now of Janssen Pharmaceutical/J&J after many years as Chief of the Laboratory of Molecular Pathophysiology & Experimental Therapeutics at the National Institute of Mental Health. Dr. Manji is a 1999 Falcone Prizewinner (now Colvin Prize) for Outstanding Achievement in Affective Disorders Research and a 1998 BBRF Independent Investigator.

A few of the many other BBRF-affiliated researchers who have made major contributions to the search for rapid-acting antidepressants include John H. Krystal, M.D., of Yale University, a BBRF Scientific Council member and a 2006 and 2000 Distinguished Investigator and a 1997 Independent Investigator; BBRF Scientific Council member emeritus Dennis S. Charney, M.D., of Icahn School of Medicine at Mount Sinai; and Carlos A. Zarate, Jr., M.D., of the National Institutes of Health, a 2011 Bipolar Mood Disorders Award Prizewinner (Colvin Prize), 2005 Independent Investigator and 1996 Young Investigator.

CBS News recently featured a story on the Ketamine nasal spray. Watch video