Despite significant advances in understanding the neurobiology of schizophrenia, treatment options have largely remained limited. But in 2023, four late-stage clinical trial readouts in schizophrenia could offer a new glimmer of hope.
Most currently available treatments for schizophrenia are traditional antipsychotics targeting the dopamine 2 and dopamine 3 receptors, explains Dr. Christopher Correll, psychiatrist at the Zucker School of Medicine at Hofstra/Northwell. However, there is still a huge unmet need for treatments targeting the negative symptoms of schizophrenia that adversely affect functioning.
In 2023, the slate of schizophrenia trial readouts features a variety of novel mechanisms, including two studies focused on subsets of schizophrenia symptoms.
Phase III trials of Reviva Pharmaceuticals’s brilaroxazine, Newron Pharmaceuticals’s evenamide, and Sunovion Pharmaceuticals’s ulotaront are each targeting total symptoms of schizophrenia. Meanwhile, Acadia Pharmaceuticals’s pimavanserin focuses on the negative symptoms of schizophrenia, which include apathy, withdrawal, and blunted effect.
Reviva, Newron, and Sunovion target total symptoms
In mid-2023, Reviva expects topline results for the 402-patient Phase III RECOVER trial of brilaroxazine in schizophrenia (NCT05184335). Brilaroxazine is a dopamine-serotonin stabilizer, meaning it acts on both dopamine and serotonin receptors.
As a primary endpoint, Reviva’s trial measures change versus placebo over four weeks using the Positive and Negative Symptoms Assessment (PANSS). PANSS is a 30-item physician assessment of schizophrenia symptoms, including positive symptoms like hallucination and hostility, negative symptoms like emotional withdrawal and apathy, and general symptoms like anxiety and disorientation.
Meanwhile, Newron expects results in 2023 for a 260-patient Phase II/III trial of evenamide in chronic schizophrenia (EudraCT-2020-006062-36), which also uses a primary endpoint of change in PANSS over four weeks. Evenamide blocks glutamate modulation and voltage-gated sodium channels, which could modulate repetitive neuron firing without impairing normal neuronal excitability.
Newron is also running a Phase II trial of evenamide in treatment resistant schizophrenia (EudraCT-2020-000437-41), which remains an enormous unmet treatment need. The company reported positive interim results earlier this year and plans to present detailed study results in October.
Next, Sunovion expects topline Phase III results for the 525-patient Phase III DIAMOND 1 trial of ulotaront in acutely psychotic people with schizophrenia (NCT04072354). Ulotaront is an agonist of the trace amine-associated receptor 1 (TAAR1) and serotonin 5HT1A receptors, offering a different approach than traditional antipsychotics targeting dopamine receptors. As a primary endpoint, DIAMOND 1 uses PANSS over a slightly longer six-week period.
Acadia targets negative symptoms
Acadia expects results in late 2023 or early 2024 for the 426-patient ADVANCE-2 trial of pimavanserin for the negative symptoms of schizophrenia (NCT04531982). Pimavanserin is a serotonin inverse agonist and antagonist that preferentially targets 5-hydroxytryptamine (5HT2A) receptors, which are thought to play a role in psychosis and schizophrenia.
ADVANCE-2 uses a primary endpoint of the Negative Symptom Assessment-16 (NSA-16) which measures the negative symptoms of schizophrenia along the five domains of communication, emotion/affect, social involvement, motivation, and retardation.
Pimavanserin previously met the primary endpoint of NSA-16 in the Phase II ADVANCE-1 trial, though the drug did not show statistically significant effects across key secondary endpoints. Pimavanserin has FDA approval under the brand name Nuplazid for the treatment of Parkinson’s disease psychosis.
Overall, the negative symptoms of schizophrenia represent an enormous unmet need, says Philip Harvey, PhD, director of the Division of Psychology at the University of Miami Miller School of Medicine, Florida. There are no approved therapies, and around one third of patients with schizophrenia experience negative symptoms, he notes.
Drug development in schizophrenia
Schizophrenia affects approximately 24 million people worldwide, and nearly one third of all cases go undiagnosed. Regulators have pushed strategies to improve clinical trial design and cut costs in schizophrenia, and pharma has followed suit with more drug development investment.
Despite this renewed push for treatments, there has only been a slight increase in trial initiations over the past decade, according to GlobalData’s Clinical Trials Database. There were 121 Phase I–III trial initiations in 2022, which is only a slight uptick on the 117 initiations in 2013. Though the industry experienced a dip in trial activity during the Covid-19 pandemic, trial industry rebounded to its peak in 2022.
Overall, the complexity of schizophrenia makes targeted drug development particularly challenging. “Schizophrenia is an extremely heterogeneous syndrome,” says Dr. Henry Nasrallah, professor of psychiatry, Neurology and Neuroscience, University of Cincinnati College of Medicine. “Patients can share similar clinical symptoms but may be biologically different, as evidenced by the tremendous advances in genetics where over 500 risk genes, copy number variants, and mutations have been identified so far.”
As the search for new schizophrenia treatments and drug mechanisms continues, the four major expected trial readouts from Reviva, Newron, Sunovion, and Acadia could shift the drug development landscape.