First in Class: Spravato

First approved for adults with treatment-resistant depression (TRD) in March of 2019, Spravato (esketamine) is a rapid acting nasal spray formulation of a non-competitive N-methyl D-aspartate (NMDA) receptor antagonist taken in addition to a daily oral antidepressant. Marketed by Janssen Pharmaceuticals, Inc., Spravato is the first medicine in decades approved with a new mechanism of action addressing the traditionally difficult-to-treat symptoms of major depressive disorder (MDD) in adults, one of the most common mental disorders in the US, according to the National Institute of Mental Health.

“Depression is so much more than feeling sad—it’s a debilitating combination of symptoms that are different for each person and can progress to a point where patients start actively considering suicide,” Michelle Kramer, vice president of US neuroscience medical affairs at Janssen, told Pharm Exec. “Patients with such challenging-to-treat depressive symptoms need more options to reduce the depressive symptoms, allowing other care elements to be put in place.”

Just last month, in a new indication, FDA approved Spravato in combination with an oral antidepressant to treat depressive symptoms in adults with MDD with acute suicidal ideation or behavior. The decision made Spravato the first and only glutamate receptor modulator approved by FDA in two MDD subpopulations with high unmet need.

FDA first granted breakthrough therapy designation to esketamine nasal spray for TRD back in November 2013. The designation is intended to accelerate development and review timelines when preliminary clinical evidence indicates a drug may demonstrate substantial improvement on one or more clinically significant endpoints over available therapies for serious or life-threatening conditions.

“To date, we’ve invested more than nine years in a comprehensive development program that includes 31 global clinical trials to bring this generally well-tolerated and effective treatment option to those who need it,” says Kramer. Spravato has been studied in more than 2,200 patients worldwide, including 19 Phase I trials, five Phase II trials, and seven Phase III trials.

The benefits of Spravato, given with an oral antidepressant, were studied in a clinical program involving both short- and long-term trials consisting of patients with TRD. The studies compared Spravato plus an oral antidepressant, to a placebo nasal spray plus an oral antidepressant. The trials evaluated the short- and long-term efficacy and safety of Spravato for a period of up to one year.

During a Phase III TRD short-term study, individuals who took Spravato and an oral antidepressant experienced superior improvement in depression symptoms at four weeks compared to those who received a placebo and an oral antidepressant. And in a long-term study, patients in stable remission taking Spravato who continued treatment with the medicine were 51% less likely to relapse.

The Phase III trials that evaluated patients with MDD and active suicidal ideation with intent, known as ASPIRE I and ASPIRE II, were the first of their kind. According to Janssen, every patient was treated with a comprehensive standard of care in both trials to safely and ethically conduct the studies, which included initial hospitalization, a newly initiated or optimized oral antidepressant, and twice-weekly treatment visits for four weeks.

Those treated with Spravato plus an oral antidepressant showed significantly improved depressive symptoms at 24 hours compared to placebo—with some responding in as early as four hours.

Cost and access

The cost of Spravato varies by patient, as treatment, the frequency of dosing sessions, and duration of therapy is individualized based on the clinical assessment of their symptoms. However, the average annual price for the drug is mostly comparable with other innovative, specialty mental health drugs.

There are a significant number of healthcare plans that have included Spravato on their formularies. “We estimate just over 85% of patients with TRD are covered under a medical benefit and about 50% under a pharmacy benefit,” explains Kramer. “We’re continuing to work with appropriate payers to educate on access challenges, such as the reimbursement of mandated healthcare services required with Spravato, to ensure appropriate patients have the opportunity to benefit from this medicine.” Patients whose insurance companies have not yet made a formulary determination are able to access Spravato through an exception process, says Kramer.

The focus of Janssen regarding the drug has now turned to education. “We are working to educate healthcare providers, payers, patients, and their loved ones on the updated label, so appropriate patients are evaluated, and the full course of treatment is delivered in a safe and controlled manner for patients to receive the maximum treatment benefit,” says Kramer.

Spravato is being evaluated in additional clinical trials, including an ongoing study assessing the drug’s efficacy in rapidly reducing the symptoms of MDD in patients between 12 and 18 years old who are assessed to be at imminent risk for suicide.

Miranda Schmalfuhs is Pharm Exec’s Assistant Editor. She can be reached at mschmalfuhs@mmhgroup.com​