Disease Analysis: Schizophrenia

Overview

Schizophrenia is a serious mental illness distinguished 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. The World Health Organization (WHO) states that it is characterized by significant impairments in the way reality is perceived. Schizophrenia is a psychotic disorder that typically first presents in adolescence and young adulthood. The condition is associated with a prodromal period that can last for months or years, during which emotional, behavioral, and attenuated psychotic symptoms first appear. It is frequently associated with significant distress and impairment in personal, family, social, educational, occupational, and other important areas of life.

Latest Key Takeaways

• Datamonitor Healthcare estimates that in 2021, there were 24.7 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, and Indivior’s once-monthly Perseris – 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 is looking to capitalize with a more appealing, less frequently dosed, LAI risperidone formulation.
• Hoping to also make an impact on this crowded LAI market are pipeline drugs TV-46000 (Teva) and Laboratorios Farmacéuticos ROVI’s Risvan, both risperidone formulations. Recently approved for schizophrenia treatment in Europe under the name Okedi, Risvan incorporates ROVI’s in situ microimplants technology, with the aim of overcoming some of the drawbacks associated with risperidone LAIs, such as the use of loading doses or the need for oral risperidone supplementation at the start of treatment, to potentially improve adherence. TV-46000, administered via subcutaneous injection, is a one-to-two monthly dose of extended-release risperidone intended for use as a maintenance treatment for adults and adolescents with schizophrenia.
• 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 completed a rolling NDA submission with the FDA, and the PDUFA action date is now set for April 2022.
• 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.
• Karuna Therapeutics’ KarXT combines xanomeline, a novel muscarinic agonist, with trospium, an approved muscarinic antagonist, and is being primarily developed for the treatment of psychosis in adults with schizophrenia. Five Phase III trials are ongoing and yet to release data, but in the Phase II EMERGENT-1 trial, KarXT met the primary endpoint. Although its twice-daily administration is more inconvenient than available antipsychotics with once-daily or longer dosing schedules, KarXT appears differentiated in its tolerability profile.
• 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.
• 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.
• A number of high-impact upcoming events for schizophrenia drugs are expected during 2022, including PDUFA reviews for TV-46000 and BXCL501, and Phase III trial data for SEP-363856 (evaluating efficacy and safety in acutely psychotic subjects with schizophrenia) and KarXT (evaluating efficacy and safety in acutely psychotic hospitalized adults with DSM-5 schizophrenia).