The Bipolar Big Three: LAIs, Atypical Antipsychotics And Symptom Specific Drugs

Despite the highly genericized nature of the bipolar disorder market, firms have innovated with long-acting injectables, improved atypical antipsychotics and drugs targeting specific symptoms.

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BD Is Influenced By Social, Environmental And Genetic Factors

The bipolar disorder (BD) market is dominated by generics but a recent Datamonitor Healthcare report highlighted that atypical long-acting injectables (LAIs) show strong growth potential and there are still gaps in the treatment paradigm. Scrip spoke with some of the leading R&D firms about trends and challenges in the space.

“Doctors often assume that patients don’t want injectable treatments but this is not necessarily the case,” said Oliver Howes, head of translational neuropsychiatry at H. Lundbeck A/S. The firm’s Abilify Maintena (aripiprazole), a once-monthly dopamine D2 receptor agonist LAI, showed one of the highest rates of relapse reduction over placebo in clinical studies, setting it up for market domination in the disease maintenance setting. Fourth quarter sales of the drug totaled DKK610m ($92.7m), an increase of 13% from 2020. (Also see "Lundbeck’s Vyepti Sales Disappoint But Lower Costs Boost Profitability" - Scrip, 9 Feb, 2022.)

BD is characterized by fluctuating mood states such as mania and depression, interspersed with periods of wellbeing. The number of people with BD is expected to rise to 50.4 million by 2027.

People with BD struggle to comply with oral treatments and the condition is related to memory problems, so an LAI ensures they do not have to remember to take a pill every day, Howes explained. Abilify Maintena is now under development as a two-month LAI for schizophrenia and BD. “I don’t think long-acting injectables will replace oral treatments completely but they will be an important part of patient choice,” Howes said.

Indeed, the 2021 approval and launch of Alkermes plc's Lybalvi, a combination of atypical antipsychotic olanzapine and novel opioid receptor antagonist samidorphan, for BD and schizophrenia proves oral treatments are here to stay. Lybalvi demonstrated similar efficacy to olanzapine with the side effect benefit of a significant reduction in weight gain. (Also see "Alkermes Expects Gradual Ramp-Up For Lybalvi Launch" - Scrip, 1 Jun, 2021.)

Alkermes' Damon Harrell: Destigmatization Is Key

“BD patients tend to skew younger and are often professionals. Few people at that stage of life would be happy about putting on an extra twenty or thirty pounds, so the weight gain mitigation is important for quality of life,” explained Damon Harrell, head of marketing at Alkermes’ psychiatry franchise.

On average, a BD patient goes through seven different treatments before finding something that works, Harrell said. Alkermes views Lybalvi as a potential solution for patients who are unhappy with their current treatment. “We’re not necessarily trying to move ahead to the front of the line,” he said.

Nonetheless, the Dublin-headquartered firm recently announced positive top-line data from a Phase III Lybalvi trial in schizophrenia and BD patients early in their disease. While the weight gain difference at 12 weeks was significant (4.91% for Lybalvi versus 6.77% for olanzapine), the magnitude may not be sufficient to differentiate Lybalvi from other therapies, H.C. Wainwright analysts commented in a 9 February note. However, uptake will likely be driven by patient and physician experience in practice rather than the data itself, Cantor Fitzgerald analysts said.

While Abilify Maintena and Lybalvi are approved for bipolar disorder I, BioXcel Therapeutics, Inc.’s orally-dissolving film BXCL501 targets the symptom of agitation in bipolar disorders I and II as well as in schizophrenia. Agitation is classed as a feeling of unease accompanied by excessive speaking or movement that can escalate into violent or disruptive behavior. The selective alpha 2 adrenergic receptor agonist is pending US Food and Drug Administration approval with an April prescription drug user fee act date.

“People think about agitation in BD as a feature of mania but in fact, patients who are hypomanic or even depressed have agitation,” BioXcel’s head of clinical development Robert Risinger explained, adding that the symptom is a source of stress for both patients and their caregivers. With the current standard of care (SoC), patients with agitation can end up in the emergency room for 16 hours, so the company has designed BXCL501 to have a faster onset of action, CEO Vimal Mehta said. Agitation SoC usually involves anticonvulsants or mood-stabilizers during a manic phase or atypical antipsychotics during a depressive phase.

Two-thirds of patients experiencing agitation end up in a critical care setting often because they harm themselves or their caregivers. “We want to make this treatment available in this setting where most patients are and then, depending on our label, expand into the community so patients don’t have to go the emergency room in the first place,” Mehta said. BXCL501 is also in a pivotal study for agitation associated with dementia.

Headwinds Must Be Addressed

Despite high hopes, the experts Scrip spoke with highlighted several headwinds starting with early R&D. “There are really no valid models in BD preclinical development, at least none that have proven to be robustly predictive of clinical effects,” Risinger said. “Quite frankly, there are areas of medicine that are easier to invest in because we have a deeper understanding, whereas we are still such a long way from understanding how the brain functions,” Harrell noted, adding that society must make progress on destigmatizing mental health disorders.

“If you look at a field like cancer, there are lots of charities that have financially supported R&D for decades but this is not the case with mental health disorders,” Howes explained, adding that greater investments from governments are also needed. The disease has thus far been conceptualized as mania followed by depression with discrete treatments developed for each phase, but it’s becoming clear in recent years that most patients can present with a mixture of manic and depressive symptoms, Howes concluded.