Disease Analysis: Schizophrenia

Schizophrenia is a serious mental illness characterized by incoherent thoughts, bizarre behavior, and delusions or hallucinations. The American Psychiatric Association (APA) defines schizophrenia as a chronic brain disorder which actively presents with delusions, hallucinations, lack of motivation, and issues with thinking and concentration

Overview

• Datamonitor Healthcare estimates that in 2018, there were 23.6 million 12-month prevalent cases of schizophrenia in those aged 15 years and older worldwide, and forecasts that number to increase to 26.8 million cases by 2027.
• The current dynamics of the antipsychotic market show domination by atypical antipsychotics, mainly oral agents, but there is also increasing uptake of long-acting injectable (LAI) neuroleptics, which will continue. Oral atypical antipsychotics that were historical blockbusters are now facing intense generic erosion. The highest-selling oral antipsychotic is Latuda, one of the newer atypical drugs, but its market exclusivity is only set to last until 2023.
• Other newly marketed and pipeline antipsychotics look likely to maintain growth of the oral antipsychotic segment. Demand for both Rexulti and Vraylar, patent protected until 2029 and 2028, respectively, looks set to continually increase over this decade. Considering the approaching genericization of oral market-leader Latuda, Rexulti and Vraylar are anticipated to take over as key branded products. Vraylar could even become an unprecedented treatment option for the negative symptoms of schizophrenia. Interestingly, the most advanced pipeline neuroleptics, MIN-101 and Nuplazid, as well as recently approved Lybalvi, are all orally administered therapies. However, their respective drug developers differentiate them from the highly genericized oral antipsychotic market by positioning them as drugs directed at the unmet needs of the indication. Alkermes’s Lybalvi, which was approved by the FDA in May 2021, is touted as a better-tolerated formulation of the historical blockbuster antipsychotic olanzapine, reportedly improving tolerability thanks to reduced weight gain. MIN-101 and Nuplazid also aim to satisfy unmet needs by targeting the underserved negative symptom domain.
• Invega Sustenna and Trinza remain highly competitive, with patent expiry and loss of exclusivity not destined to occur for over another decade. In addition to succeeding Invega with a combined wealth of real-world data, these LAI formulations are highly appealing in the schizophrenia market since poor medication compliance rates are seen all too commonly. Furthermore, a longer, six-monthly formulation, Invega Hafyera, was approved by the FDA in August 2021. This is the first – and only – twice-yearly injectable for the treatment of schizophrenia, further tackling non-compliance for longer periods and reducing the burden of frequent healthcare visits for chronic schizophrenia patients. Thanks to this, Johnson & Johnson will likely see its highly lucrative Invega franchise pushed further above the LAI antipsychotic competition.
• Other newer LAIs – Otsuka/Lundbeck’s once-monthly Abilify Maintena, Alkermes’s one-to-two-monthly Aristada, Indivior’s once-monthly Perseris, and potentially Teva’s pipeline product TV-46000 – will strengthen their market positions over the coming years. Abilify Maintena will likely give the Invega franchise the stiffest competition, and Otsuka/Lundbeck benefit from the drug also being indicated for bipolar disorder. On the other hand, treatment initiation of Abilify Maintena requires an oral supplementation of Abilify, unlike Invega Sustenna. To establish more variable dosing options, Lundbeck plans to file an sNDA for a two-monthly Abilify Maintena formulation. In 2018, Alkermes strengthened its position in the LAI market by attaining approval for Aristada Initio, a one-off introductory dose of the drug, mitigating the prior need for three weeks of concomitant oral aripiprazole. Johnson & Johnson’s Risperdal Consta is set to lose market exclusivity in 2023, and Indivior and potentially Teva are looking to capitalize with more appealing, less frequently dosed, subcutaneous LAI risperidone formulations.
• BioXcel’s BXCL501 performs the best clinically in Datamonitor Healthcare’s drug assessment model due to recent pivotal data demonstrating the drug’s superiority over placebo in treating agitation associated with schizophrenia. Treating severe agitation in an acute psychiatric setting is currently typically achieved through invasive administration of antipsychotics or benzodiazepines. This raises ethical dilemmas and, furthermore, these drugs and the doses utilized in this setting are often associated with heavy sedation, among other side effects. The safety and tolerability profile of BXCL501 presented in pivotal trials is comparable to placebo, with the only adverse event experienced to a notably greater degree than with placebo being somnolence, which was generally experienced as mild. Accordingly, BioXcel has recently completed a rolling NDA submission with the FDA, with no further details disclosed as yet.
• SEP-363856 is a novel schizophrenia pipeline candidate from Sunovion, a subsidiary of Sumitomo Dainippon, which has the potential to be a first-in-class trace amine-associated receptor 1 (TAAR1) agonist. Although Phase III data have yet to be released, Phase II results are promising, demonstrating a statistically significant and clinically meaningful improvement in Positive and Negative Syndrome Scale (PANSS) total score compared to placebo at four weeks.
• MIN-101 previously established efficacy in treating negative symptoms in a large, controlled Phase IIb trial. However, more recently, Minerva released Phase III trial results illustrating the drug’s failure to separate from placebo (placebo response was noted as particularly high) on the primary endpoint associated with schizophrenia negative symptoms. This raises uncertainty about the drug’s potential in this indication, which currently has no approved therapies. The company discussed combining the data with the robust Phase IIb data for a potential NDA submission, as previous companies have done; however, the minutes from Minerva’s Type C meeting with the FDA revealed the regulatory body advised Minerva that submitting these data would likely result in an unsuccessful filing. Nonetheless, Minerva seems intent on relying on subgroup analysis to demonstrate efficacy of the drug to the FDA, despite the regulatory body’s initial dissatisfaction with the proposed data. MIN-101 is a potential first-in-class sigma-2 receptor modulator, with research linking the antagonism of this receptor with antipsychotic properties. Moreover, the drug only further targets the 5-HT2A receptor, thus avoiding the direct binding of dopamine receptors which is linked to the troublesome extrapyramidal symptoms associated with the long-term use of dopaminergic antipsychotics.
• Although the current range of antipsychotics may provide some relief from positive symptoms in schizophrenia patients, there are still several large unmet needs that remain. Some of the greatest unmet needs include drugs targeting the negative and cognitive symptoms of schizophrenia, drugs with improved tolerability, therapies encouraging enhanced compliance rates, and more effective treatment options for refractory schizophrenia.
• At least three high-impact upcoming events for schizophrenia drugs are still expected during 2021, including a PDUFA decision and CMHP opinion for Doria. Alkermes’s Lybalvi is also due topline data from a pivotal trial in young adults diagnosed with schizophrenia, schizophreniform, or bipolar I disorder, which will evaluate the effect of Lybalvi on body weight, compared to olanzapine.