Blog May 6, 2019

Landmark Approvals in Depression

Depression is a challenging condition to treat. Most antidepressants take four to six weeks to take effect, and patient response to such drugs varies widely from person to person. As a result, most patients must try several drugs over a period of months before they can find relief. In March, the U.S. Food and Drug Administration (FDA) approved two new therapies that provide faster relief: Johnson & Johnson’s Spravato (esketamine) for the treatment of major depressive disorder (MDD) and Sage Therapeutics’ Zulresso (brexanolone) for the treatment of post-partum depression. Both have been cautiously applauded by the medical community as they provide the first advances in decades for the treatment of depression. But both come with important concerns over pricing and restrictions that could limit their use.


Spravato for Major Depressive Disorder


spravatoEsketamine is a single stereoisomer version of ketamine, a drug that exists as a mixture of two mirror-image versions of the same molecule. Ketamine has been used legally in anesthesia for over 50 years, but it has also been abused as an illegal street drug (“Special K”) for its ability to provide out-of-the-body feelings and vivid, colorful hallucinations. Ketamine interacts with GABA and glutamine neurotransmitters in the brain, a mechanism different from that of other antidepressants. In recent years, research has shown ketamine’s ability to quickly alleviate depression in about 70% of those treated, sometimes with just a single intravenous (IV) treatment, but generally within six treatments over a period of two weeks. As a result of this rapid action compared to standard antidepressants, hundreds of ketamine clinics have arisen, which typically charge about $500 per IV administration. Because antidepressant treatment with ketamine is an unapproved use, it is not reimbursed and therefore costs must be paid out-of-pocket by patients.


J&J’s Spravato consists of only the right-handed isomer of ketamine, formulated as a nasal spray. Research has shown that it can work as quickly as ketamine, but there is some evidence that the nasal delivery is less efficient than the IV delivery route, leading to Spravato providing relief to about 45% of patients. As an FDA approved drug, Spravato is reimbursable, and as a patented, proprietary molecule, J&J has been able to set its own price.


The FDA approved Spravato as an add-on to oral antidepressants for patients who have tried at least two of the oral drugs without success. To both monitor the drug’s safety and greatly reduce its potential for abuse, patients are required to take the medication in the doctor’s office, be monitored for two hours for any adverse responses before going home, and are prohibited from driving or operating heavy machinery for at least 24 hours. The drug also has a boxed warning of the risks of sedation, difficulty with attention and thinking, and risk of abuse, as well as suicidal thoughts and behaviors. In addition, the long-term effects of repeat dosing for the drug are unknown, although street drug use of ketamine at higher doses is associated with bladder toxicity and cognitive problems. Despite these concerns, the FDA advisory committee voted 14 -2 in favor of Spravato’s approval given the great medical need for a fast-acting antidepressant.


In addition to logistical issues posed by Spravato’s necessary administration under direct medical supervision, its proposed pricing has also posed some concerns. Patients typically require a month of twice-weekly treatments, followed by several weeks of less frequent dosing. For the first month of therapy, the list price for the treatment is estimated at up to $6,785, minus rebates and discounts. After that, the cost is dependent on the dose and frequency required, with an estimated list price of $3,450 for the medication.


Zulresso for Post-Partum Depression


babyPost-partum depression (PPD) is a common but often overlooked complication of childbirth. An estimated 400,000 women in the United States each year experience the condition to some degree, although only about half of these cases are formally diagnosed. PPD has a deeply negative effect on maternal-infant bonding and later infant development. In severe cases, representing about 20-30% of those diagnosed, PPD is considered life-threatening because these women also have a high risk of suicide. Without treatment, PPD can last months to years. Most antidepressants show little efficacy against this condition, and none have been approved to treat it.


That was until the FDA approved Sage Therapeutics’ Zulresso (brexanolone) as the first treatment for moderate to severe PPD. The approval was hailed by many in the medical community as “trail-blazing.” Clinical studies showed that the drug has a positive effect within hours, and among the 75% of patients who responded within 60 hours, 94% did not relapse within the 30-day observation period of the pivotal trial. Sage is expected to launch the drug commercially by late June and has raised $575 million to support its launch.


Despite the excitement, Zulresso’s launch will not be without challenges. The drug must be given via a 60-hour infusion, followed by a 12-hour follow-up period due to the fainting episodes experienced by 6 of the 140 women taking part in the pivotal trial. Thus, Sage is setting up centers for women to be administered the one-time treatment under medical supervision. Zulresso pricing has also raised some concerns, with a projected cost, before discounts and rebates, of $34,000 on average. Hence the drug is likely to be used primarily for the treatment of severe cases of PPD, where its benefits were most dramatic in clinical trials.


Sage also has a second, orally active drug in late-stage clinical trials. This once-daily agent, SAGE-217, performed very well in a Phase 2 study in major depressive disorder (MDD) and will complete Phase 3 testing in 2020. Potential competition is also following in Sage’s footsteps. Marinus Pharmaceuticals is developing ganaxolone, a GABAA-receptor modulating agent, for the treatment of depression, anxiety, and epilepsy. The company has an IV formulation in a Phase 3 trial for severe PPD, as well as an oral agent in Phase 2 for moderate PPD.