On February 22, AbbVie submitted a supplementary new drug application (sNDA) to the FDA for Vraylar (cariprazine) for the adjunctive treatment of major depressive disorder (MDD). If approved, MDD will be Vraylar’s fourth indication, joining approvals for the treatment of adults with schizophrenia, the acute treatment of manic or mixed episodes associated with bipolar I disorder, and the treatment of depressive episodes associated with bipolar I disorder.

The sNDA is supported by data from three clinical trials: RGH-MD-75, 3111-301-001, and RGH-MD-76. The Phase II/III study, RGH-MD-75 (NCT01469377), involved a randomized, double-blind, placebo-controlled, flexible-dose, outpatient, multicenter trial with 808 participants across 72 study locations. Patients treated with Vraylar at 2–4.5mg/day demonstrated a clinically and statistically significant change from baseline to week eight in the Montgomery-Åsberg Depression Rating Scale (MADRS) total score when compared with placebo. Furthermore, in the randomized, double-blind, placebo-controlled, Phase III study, 3111-301-001 (NCT03738215), patients treated with Vraylar at 1.5mg/day showed a clinically and statistically significant change from baseline to week six in the MADRS total score when compared with placebo. This trial involved 759 patients with MDD and was conducted at 124 study locations across the US and Europe. Finally, in the Phase III study, RGH-MD-76 (NCT01838876), Vraylar demonstrated long-term safety and tolerability over 26 weeks.

However, not all trials of Vraylar in MDD have been so positive. In the Phase III 3111-302-001 study, Vraylar dosed at 1.5mg/day and 3.0mg/day failed to significantly improve depressive symptoms from baseline to week six in MADRS total score compared to placebo. Furthermore, in the 3111-301-001 study, patients treated with a higher dose of Vraylar (3.0mg/day) did not show a statistically significant improvement in MADRS total score at week six over placebo. This is surprising, considering the drug showed efficacy at a lower dose in this trial.

Despite some mixed efficacy data, GlobalData anticipates substantial uptake of Vraylar as an adjunctive treatment of MDD. Key opinion leaders (KOLs) interviewed by GlobalData confirmed that some physicians are already using Vraylar off-label as an adjunctive therapy to selective serotonin reuptake inhibitors (SSRIs) or serotonin-norepinephrine reuptake inhibitors (SNRIs) for the treatment of MDD. GlobalData forecasts that by 2029, Vraylar will generate sales of $741.2 million in the MDD market across the US, five major European markets (5EU) (France, Germany, Italy, Spain, and the UK), Japan, and Canada.

However, Vraylar will need to contend with some significant competition. The most successful adjunctive therapies in the MDD market have been the atypical antipsychotics, with Otsuka’s Abilify (aripiprazole), AstraZeneca’s Seroquel (quetiapine), and Otsuka/Lundbeck’s Rexulti (brexpiprazole) all approved for MDD. In particular, pricey Vraylar will have to compete with low-cost aripiprazole and quetiapine generics, with competition becoming even fiercer when generic brexpiprazole enters the market in 2026. This sentiment was shared by KOLs who noted that Vraylar could struggle in the MDD market as a “me-too” atypical antipsychotic drug that would be more expensive than what is already available on the market. Opportunity remains for AbbVie to conduct a head-to-head trial against other atypical antipsychotics to help potentially differentiate Vraylar and promote its uptake, given that the efficacy data for Vraylar has been mixed.

Additionally, there are four other late-stage pipeline products being developed as adjunctive therapies for MDD that are expected to enter the market over the next decade. These products are Sage Therapeutics’/Biogen’s zuranolone, a gamma-aminobutyric acid (GABA) A receptor allosteric modulator; Janssen’s seltorexant, an orexin receptor type 2 antagonist; Intra-Cellular Therapies’ Caplyta (lumateperone), a 5-HT receptor 2A antagonist; and Relmada Therapeutics’ dextromethadone (REL-1017), an N-methyl-D-aspartate (NMDA) receptor antagonist. Many of these pipeline products have novel mechanisms of action that will help them compete in a highly crowded market space.

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By GlobalData