Last month, a Food and Drug Administration (FDA) advisory panel decided that esketamine’s benefits outweighed its risks. The drug was formally approved on March 5th, and launch under the brand name Spravato is expected later this month. Esketamine is indicated for patients with major depressive disorder who have not responded to conventional antidepressants. It is the first fast-acting anti-depressant.
Chemically, esketamine is very similar to ketamine, an anesthetic that was developed in the 1960s. Specifically, esketamine is an S(+) enantiomer – essentially a mirror image – of ketamine.
Esketamine’s clinical studies built on prior research regarding ketamine, which produced “initial reductions in depressive symptoms within two hours, with peak effects at 24 hours.”
Esketamine could turn out to be a major breakthrough, in particular, with respect to suicidal depression. And this is very important, given that treatment-resistant depression affects about one third of approximately 16 million adults in the U.S. who have suffered at least one major depressive episode. For this group the risk of suicide is significant. In light of suicide being an ongoing national crisis, having an effective tool to combat this scourge provides hope.
But, the drug faces several significant clinical as well as economic challenges.
The FDA approval process is invariably a balancing act, weighing safety and efficacy while attempting to get potentially life-saving drugs like esketamine to the marketplace as soon as possible. Three Phase III studies which the sponsor Janssen submitted as part of esketamine’s New Drug Application showed “statistically significant, clinically meaningful rapid reduction of depressive symptoms as compared to placebo.” One of the Phase III studies, however, failed to demonstrate statistically significant clinical change. Now that the drug is entering the market clinicians will soon learn about the drug’s real-world effectiveness, but also long-term effects. Concerns have been raised about potentially serious side-effects and the current lack of long-term data on esketamine’s health impact.
The experience with off-label use of ketamine for clinical depression is a sobering reminder of the importance of effective monitoring in order to prevent abuse from occurring with respect to esketamine. As noted in several studies, ketamine “drug-seeking behavior has appeared as a clinical issue, with some patients shopping infusion clinics to obtain repeated injections for mood elevation.” Last year, the American Psychiatric Association issued a consensus statement on ketamine for mood disorders: “Considering the known potential for abuse of ketamine and recent reports of abuse of prescribed ketamine for the treatment of depression, clinicians should be vigilant about assessing the potential for patients to develop ketamine use disorder.”
The FDA has added a boxed warning to the label that which states that esketamine may cause suicidal thoughts and dissociation, and a sense of detachment from one’s memory and identity. As a result, patients must be monitored for at least two hours every time they take the drug. Accordingly, esketamine will not be available as an outpatient drug, and may only be administered under close supervision. The drug will be delivered to patients by way of a nasal spray; a single-use, disposable device in the doctor’s office. Esketamine can only be administered at treatment centers certified in the FDA-mandated Spravato Risk Evaluation Mitigation Strategy program.
Esketamine’s wholesale acquisition cost will be between $590 and $885 per treatment session. That implies the list price of the drug for a month of treatment — which includes two sessions a week — will be between $4,720 and $6,785. This does not include the costs of physician visits and monitoring, which will be substantial given the high degree of monitoring required.
In light of its potential breakthrough status, I suspect the vast majority of payers will place esketamine on formulary. However, faced initially with uncertain outcomes and relatively high drug and delivery costs, payers will likely institute conditions of reimbursement, such as putting esketamine in a specialty tier with high patient cost-sharing, prior authorization, and step therapy, to manage utilization of the drug. Through Janssen’s CarePath program the drug sponsor is offering cost-sharing assistance to commercially insured patients.