Hailing it as the "first new mechanism of action in decades" to treat major depressive disorder (MDD), specifically treatment-resistant depression, Johnson & Johnson's Janssen unit disclosed the FDA's approval of Spravato (esketamine), a drug that works on the N-methyl-D-aspartate (NMDA) receptor. While a win for Janssen, the agency's nod might portend even better for other NMDA-targeting drugs that can be administered without all of Spravato's restrictions.

Formulated as a nasal spray designed for quick absorption by the lining of the nasal passages and into the bloodstream, Spravato is indicated for use in conjunction with an oral antidepressant and will be available only for self-administration under direct observation of a health care provider, who will then go on to observe the patient for at least two hours, on the lookout for treatment-emergent sedation, dissociation and blood pressure changes. Those rigorous criteria, included in the drug's risk valuation and mitigation strategy (REMS), are intended to mitigate the potential psychological manifestations of esketamine, including sedation, dissociation, hallucinations and suicidal thoughts, as well as to prevent the potential for abuse and misuse of the drug.

All patients also will be enrolled in the Spravato REMS registry, aimed at further characterizing risks of serious adverse outcomes.

It was the REMS, at least in part, that resolved many of the concerns raised during last month's joint meeting of the Psychopharmacologic Drugs Advisory Committee and Drug Safety and Risk Management Advisory Committee, which ultimately voted in Janssen's favor. (See BioWorld, Feb. 13, 2019.)

Esketamine, which received FDA breakthrough therapy designation, was tested in multiple trials, including four phase II studies and five phase III studies. The phase III experiments included two short-term, double-blind, placebo-controlled studies in adults under the age of 65; one short-term, double-blind, placebo-controlled, flexible-dose study in geriatric patients, 65 and older; one randomized withdrawal design study; and one-term, open-label safety trial. Patients in all of those studies had failed at least two prior antidepressant trials and, at study entry, had more severe symptoms on average than patients entering antidepressant trials for previously approved drugs.

According to Janssen, the wholesale acquisition cost of Spravato is $590 to $885 per treatment session, based on whether a patient is treated with the 56-mg or 84-mg dose kit. Costs per patient also will vary on how many treatment sessions are needed, which can differ from patient to patient. During the one-month induction phase, costs could range from $4,720 to $6,785. Patients who respond to treatment will go on to the maintenance phase, which involves weekly or biweekly treatments, resulting in a monthly cost ranging from $2,360 to $3,540. Those amounts do not include administration or observation costs associated with treatment.

Spravato's price is generally comparable with other specialty mental health drugs and is not reflective of mandatory discounts or negotiated rebates that may be paid to government and commercial insurers, Janssen said.

While analysts note that Spravato will certainly have a role in treatment-resistant depression – a not-insubstantial market given that an estimated one-third of MDD patients have not responded adequately to at least two different antidepressant regimens – its approval also signals good news for other drugs advancing rapidly in the space. (See BioWorld, Feb. 14, 2019.)

Those include rapastinel from Allergan plc, for which phase III data in MDD are expected in the first half of this year. Also targeting the NMDA pathway, rapastinel is an injectable candidate, but its route of administration might not be a deterrent vs. Spravato given the latter's strict monitoring requirements, according to an expert cited by Piper Jaffray analysts in a Feb. 25 note to investors.

Earlier in development is Vistagen Inc.'s AV-101, an NMDA receptor GlyB antagonist designed to inhibit NMDA receptor function rather than blocking it. It is in an ongoing phase II trial dubbed ELEVATE to test the adjunctive use in MDD patients with inadequate response to standard antidepressant therapy with either an FDA-approved SSRI or SNRI.

Axsome Therapeutics Inc. is advancing ASX-05, an oral candidate that combines dextromethorphan, a combination with NMDA receptor antagonist, sigma-1 receptor agonist and serotonin/norepinephrine transporter inhibitor, with bupropion. Earlier this year, the drug met the primary endpoint in the Ascend phase II trial in MDD.

Biohaven Pharmaceutical Holding Co. Ltd. also has plans in MDD with its NMDA receptor antagonist, BHV-500, an oral prodrug of lanicemine.