Schizophrenia Disease Coverage

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.
• There have been a number of recent impactful clinical trial data announcements in the schizophrenia space. One of these was the revival of the Nuplazid’s hopes in schizophrenia with promising results from a Phase II trial focused on the negative symptoms of the disease. Conversely, Minerva released mixed results for its negative symptom prospect, MIN-101, that have plunged the drug’s potential into uncertainty. In addition, impressive pivotal trial results from Alkermes’ ALKS 3831 in late 2018 have provided a strong case for approval of the drug, and the FDA’s advisory committee agreed with these benefits, though the FDA’s issuance of a complete response letter (based on a manufacturing issue) has postponed likely approval.
• The current dynamics of the antipsychotic market show domination by atypical antipsychotics, typically oral agents, but there is an 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. The 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 – ALKS 3831, MIN-101, and Nuplazid – 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, namely increased tolerability (reduced weight gain) and 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, Johnson & Johnson plans to introduce a longer six-monthly formulation to the market next year, which would be a first of its kind in schizophrenia, further tackling non-compliance for longer periods and reducing the burden of frequent healthcare visits for patients.
• Other newer LAIs – Otsuka/Lundbeck’s once-monthly Abilify Maintena, Alkermes’ 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 will 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 that of Invega Sustenna. To establish more variable dosing options, Lundbeck plans to file a supplementary NDA 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 further with its more appealing monthly dosed risperidone formulation, Perseris.
• BioXcel’s BXCL501 performs the best clinically in Datamonitor Healthcare’s drug assessment model due to recent pivotal data exhibiting 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 placebo being somnolence, which was generally experienced as mild. Accordingly, BioXcel plans to file an NDA submission with the FDA in Q1 2021.
• 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 for 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.
• Key upcoming events in the schizophrenia space include the paliperidone palmitate six-month formulation PDUFA deadline, expected in September 2021. If successful, Johnson & Johnson could see its highly lucrative Invega franchise pushed further above the LAI antipsychotic competition, with an unparalleled long-acting dosing regimen to support chronic schizophrenia patients with enhanced treatment outcomes. Alkermes’ ALKS 3831, a distinct formulation of olanzapine and the novel opioid receptor antagonist samidorphan, is due top-line data from a pivotal trial in young adults diagnosed with schizophrenia, schizophreniform, or bipolar I disorder in the first half of 2021. This drug is touted as a better tolerated formulation of the historical blockbuster antipsychotic olanzapine, reportedly inducing less weight gain in patients. Additionally, the company plans to resubmit supporting data in response to a complete response letter received from the FDA, and though this will likely come in 2021, precise timings have not been disclosed.