New Products Shake Up Overlooked Bipolar Disorder Market
Executive Summary
The highly genericized bipolar disorder market is set for change as both new long-acting injectable formulations of older products and novel therapies reach the market, while firms like NRx and BioXcel target major unmet needs in a disease that needs more R&D.
The approval last year of two new products – Alkermes plc’s Lybalvi and Intra-Cellular Therapies, Inc.’s Caplyta – plus an impending US regulatory decision for BioXcel Therapeutics, Inc.’s novel treatment for agitation are shaking up a staid bipolar disorder market. More novel therapies are also in development or approaching the market for various symptoms of the mental illness, despite the many challenges to R&D in the field.
Bipolar disorder is characterized by fluctuating mood states such as mania and depression, interspersed with periods of wellbeing. After the US Food and Drug Administration approval of the mood stabilizer lithium in the 1970s, the treatment of dipolar disorder went on to be dominated by polypharmacy, with physicians prescribing a sometimes-burdensome combination of different treatments such as anticonvulsants, antidepressants and antipsychotics to address a range of symptoms. the condition’s prevalence is also increasing: Datamonitor Healthcare estimates the number of people with bipolar disorder will rise to 50.4 million by 2027 from an estimated 47.2 million prevalent cases worldwide in 2020.
While oral atypical antipsychotics are the most used drug class, and the segment is dominated by generics, 2021 saw the approval of Alkermes’ Lybalvi (olanzapine/samidorphan), an atypical antipsychotic combined with an opioid antagonist that is associated with a significant reduction in the weight gain side effects seen with older atypicals, in bipolar disorder and schizophrenia, showing that there is room to improve upon generics. (Also see "Alkermes Expects Gradual Ramp-Up For Lybalvi Launch" - Scrip, 1 Jun, 2021.) At present, the prescription split between Lybalvi’s two indications is roughly even, although this may change partly due to historically more flexible payer coverage for bipolar branded agents, said J.P. Morgan analysts in a 16 February note. Lybalvi made $8.2m in the fourth quarter of last year following its October launch.
The 2021 expanded FDA approval of Intra-Cellular Therapies’ atypical antipsychotic Caplyta (lumateperone) as a monotherapy or in combination with lithium or valproate for bipolar disorder depression was a major milestone as this was a symptom previously unaddressed by a specifically licensed product (Caplyta was first approved for use in schizophrenia). Lumateperone represented a novel mechanism of action for neuropsychiatric indications as a selective and simultaneous modulator of serotonin, dopamine and glutamate receptors.
Analysts at Datamonitor Healthcare say future efforts in the disease will focus mainly on the development of long-acting injectable (LAI) atypical antipsychotics and drugs targeting underserved bipolar patient segments.
Only two LAI antipsychotics have been launched for bipolar disorder thus far, leaving plenty of room for competition. Johnson & Johnson’s Risperdal Consta (risperidone) was the first and only LAI on the market until the approval of H. Lundbeck A/S’s dopamine D2 receptor agonist Abilify Maintena (aripiprazole) in 2017. Sales of Abilify Maintena, which is also indicated for schizophrenia, rose by 8% in local currencies to DKK2.42bn ($368.8m) last year.
While Abilify Maintena was launched as a once-monthly treatment, Lundbeck is now working on a two-month version which is currently at Phase I. The once-monthly injection 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 if this can be repeated in pivotal trials. There are no other LAI antipsychotics in the clinic according to the Citeline database Pharmaprojects.
LAIs To Help With Compliance
Lundbeck’s head of translational neuropsychiatry Oliver Howes says the company believes there is a need for LAIs in helping improve compliance rates. “Doctors often assume that patients don’t want injectable treatments but this is not necessarily the case,” he told Scrip. Bipolar disorder is associated with memory problems and patients could struggle to remember to take a pill every day, which leads to compliance issues, he explained. In an institutional setting, patients tend to throw away an oral pill once the doctor leaves the room which further exacerbates the issue.
LAIs may be better suited to certain patients’ lifestyles because one treatment can last between one and three months, noted Damon Harrell head of marketing at Alkermes’ physiatry franchise. Lifestyle considerations could prove especially important for bipolar disorder patients because they tend to skew younger than patients for other mental health disorders and are often working professionals.
But LAIs “do not address all the symptoms of bipolar disorder so they are not the be all and end all of treatment,” BioXcel’s head of clinical development, Robert Risinger, told Scrip.
BioXcel’s selective alpha-2a receptor agonist BXCL501 targeting agitation in bipolar disorder and schizophrenia has a prescription drug user fee act date set for 5 April. Agitation is classed as a feeling of unease that can escalate into violent or disruptive behavior and often necessitates admittance and lengthy stays in a critical care setting. BioXcel believes its oral candidate could eventually expand to home use and thereby help reduce hospital admissions. The firm hopes success in bipolar could provide a basis for tackling agitation in other conditions like dementia. (Also see "The Bipolar Big Three: LAIs, Atypical Antipsychotics And Symptom Specific Drugs" - Scrip, 14 Feb, 2022.)
Elsewhere, firms are tackling other bipolar disorder-related symptoms. Data from a Phase III study of NRx Pharmaceuticals, Inc.’s NRX-101, a combination of FDA-approved D-cycloserine and lurasidone, in severe bipolar disorder with acute suicidal ideation will be of much interest. The candidate is designed as an oral, rapid-onset therapy for sustained home use that can extend the anti-suicidal benefit seen with ketamine while reducing its side effects. There is no FDA-approved treatment or suicidal ideation in bipolar disorder and the current standard of care, electroconvulsive therapy, is often stigmatized due to its controversial history. NRX-101 has a 51% likelihood of approval according to Datamonitor Healthcare.
Notably, psychedelic treatments developed for other mental health disorders are also starting to show promise in BD. COMPASS Pathways’s Phase II bipolar depression study of synthetic psilocybin candidate COMP360, which looked promising in treatment-resistant depression last year, is expected to complete in August this year. SC145383
Unmet Need Prevails
However, the experts Scrip spoke with highlighted that diagnosis of bipolar disorder must get better if new therapies are to prove useful. “On average, it takes 10 years from the first development of bipolar disorder symptoms to correct diagnosis and this delay affects long-term outcomes for patients,” said Lundbeck’s Howes. On average, patients taking medication for bipolar disorder will try seven treatments before finding something that actually works, Harrell added.
The big unmet need is bipolar disorder depression, a phase of illness that many patients spend a lot of time in, Howes said, adding that more options are needed here. Research shows that around 36–37% of time spent ill in patients with bipolar disorder types I and II is due to depression, compared with 9.8–11.5% of time spent ill due to hypomania and just 0.2–1.0% of time spent ill due to mania.
In fact, the entire approach to bipolar disorder drug development could shift as understanding of the condition improves. The disease has thus far been conceptualized as instances of mania followed by depression with discrete treatments being developed for each phase, but it is becoming clear in recent years that most patients have a ‘mixed presentation’ with a combination of manic and depressive symptoms, Howes explained. “What we need are treatments that will target the combination of symptoms as best as possible,” he stated.
Overcoming Headwinds To R&D
However, the number of firms involves in bipolar disorder R&D is low relative to the magnitude of challenges. Harrell said part of this was due to stigma surrounding mental health disorders but on a more subtle level, there is generally less investment in broad population disease states. For chronic conditions with large populations, firms need a broad commercial strategy and must be prepared to engage with many healthcare providers, whereas more specialty diseases are associated with smaller patient populations, fewer providers and institutions and higher price points, he explained.
As for difficulties with the science, “there are really no valid models in bipolar disorder preclinical development, at least none that have proven to be robustly predictive of clinical effects,” Risinger noted. Nonetheless, the average probability that bipolar drug advances to Phase III is 65.2%, according to Biomedtracker. On average, it takes a bipolar asset 7.7 years to get from Phase I to approval, which is shorter than the 9.5 years observed in the overall psychiatry space.
“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 more investments from governments are needed.