Disease Analysis: Bipolar Disorder

Disease Overview

BD is a multifactorial psychiatric mood disorder influenced by social, environmental, and genetic risk factors underlying its etiology. The disorder is characterized by fluctuating mood states, such as mania and depression, interspersed with periods of wellbeing over days and weeks. BD describes a range of disease subtypes, including BD type I, BD type II, and cyclothymia.

• Datamonitor Healthcare estimates that in 2018, there were 46.2 million prevalent cases of bipolar disorder (BD) worldwide, and forecasts that number to increase to 50.4 million prevalent cases by 2027.
• The BD market is highly genericized, consisting of antipsychotics, anticonvulsants, and mood stabilizers such as lithium. The atypical antipsychotic market is the most dominant of the drug classes indicated for BD, and the oral atypical antipsychotic market is highly competitive with many generic alternatives available. The atypical long-acting injectable (LAI) antipsychotic market currently sees little competition and is therefore one of the key areas to target for growth, along with the development of drugs focusing on other underserved BD patient segments.
• One of the most impactful recent events that has occurred in the BD space is the FDA approval of Alkermes’s Lybalvi (ALKS 3831), despite the complete response letter issued in November 2020. Additionally, Intra-Cellular Therapies’ Caplyta and BioXcel’s BXCL501 have provided positive topline pivotal trial results in BD depression and acutely agitated BD patients, respectively. BioXcel has since initiated a rolling NDA submission for BXCL501.
• As physicians and patients become more accustomed to the dosing regimens of LAIs and their associated benefits, their uptake will increase. Pharmaceutical treatment compliance is a major issue in BD, and physicians will encourage switching to LAI formulations to reduce relapses. There are only two key brands in the BD LAI atypical antipsychotic market: Risperdal Consta, the first of its kind approved for BD, requiring dosing every two weeks; and Abilify Maintena, which only requires once-monthly administration.
• Seroquel/Seroquel XR has a robust clinical profile in BD due to its strong efficacy as both a monotherapy and adjuvant in the treatment of BD mania, as a BD maintenance treatment, and in BD depression. The drug is one of few therapies specifically approved for BD depression. As a monotherapy in trials, treatment in both type I and II BD patients elicited some of the greatest improvements over placebo that have been witnessed in controlled BD studies. As an atypical antipsychotic, Seroquel/Seroquel XR has modest safety/tolerability profiles at best. Nevertheless, both formulations are genericized, and the market share of this brand in BD has been cannibalized and will continue to plummet.
• Abilify Maintena is one of the few approved LAI antipsychotics available for BD, and its increasing uptake means it is likely to dominate the bipolar LAI market. The drug boasts one of the highest rates of relapse reduction over placebo in clinical trials, granting it a position towards the top of the BD maintenance treatment algorithm. Abilify Maintena can be administered once monthly, surpassing Risperdal Consta’s dosing regimen of once every two weeks, and this less frequent dosing provides further aid to the mitigation of compliance issues so often seen with antipsychotics. With the associated benefits of LAIs, and as both physicians and patients become more accustomed to the dosing regimens, the LAI market should see sizable growth.
• Pipeline drug developers are targeting unmet needs in BD for which there are currently limited options available, and consequently these pipeline drugs will act to drive growth in the market, if successfully approved. Intra-Cellular Therapies has gathered encouraging data from trials investigating the adjunctive and monotherapy use of Caplyta in type I and II BD depression patients. Only Latuda is approved as an adjunctive/monotherapy treatment for BD depression, and also has demonstrable efficacy in type II BD depressed patients, specifically. Intra-Cellular would therefore be offering another much-needed option in this subpopulation, and, moreover, Caplyta displayed minimal motor adverse events in pivotal trials, compared to the higher rates witnessed in Latuda’s regulatory studies.
• Recently approved Lybalvi (Alkermes), a distinct formulation of olanzapine and the novel opioid receptor antagonist samidorphan, is an antipsychotic drug candidate designed to provide the efficacy of olanzapine while mitigating olanzapine-associated weight gain, a firmly established side effect of most antipsychotics. In trials, the drug has demonstrated similar efficacy to olanzapine in schizophrenia patients and a statistically significant reduction in weight gain. It is set to be available to adults with bipolar I disorder in Q4 2021.
• Intra-Cellular Therapies submitted a supplemental NDA for Caplyta in the first quarter of 2021 based on a robust safety and tolerability profile along with a positive evidence base demonstrating efficacy in the treatment of BD depression, including type II BD specifically. Similarly, BioXcel’s rolling NDA submission for BXCL501 as a treatment for acute agitation in schizophrenia and BD is complete, and an approval decision is expected in Q4 2021.