''For the treatment of schizophrenia, the use of chlorpromazine in the 1950s as a calming agent for surgical procedures, led to its use for psychosis in patients with schizophrenia. This discovery was followed by the development of haloperidol, a drug that was identified as blocking the hyperlocomotor effects of amphetamine in animals. Since amphetamine abuse in humans can result in symptoms also seen in patients with schizophrenia such as paranoia, hallucinations and delirium, it was correctly postulated that haloperidol could be an effective treatment for psychosis.
These first-generation antipsychotics were subsequently identified as being potent dopamine receptor antagonists and were not without their issues, such as movement disorders. The development of clozapine and related compounds such as D2/5HT2a receptor antagonists heralded the age of ‘atypical antipsychotics’. However, there still remain patients who are unresponsive to therapy, and there are issues such as iatrogenic weight gain. Additionally, even though psychosis (ie, positive symptoms) can be managed, the core underlying cognitive deficits and negative symptoms remain untreated. These challenging areas are bringing exciting developments in new antipsychotic research and development.
Karuna Therapeutics (Nasdaq: KRTX) has recently demonstrated positive efficacy in both positive and negative symptoms in patients with KarXT, which is a combination of xanomeline, a muscarinic mixed MI-M4 agonist combined with trospium (an agent that blocks the peripheral side effects of muscarinic agonist).
A readout on a second Phase III study is expected later this year. Importantly, in the first Phase III study, efficacy of KarXT was observed without either development of movement disorders or weight gain.
Other companies that are working on these targets include Cerevel (Nasdaq: CERE) with emraclidine, a muscarinic M4 positive allosteric modulator (Phase II studies for schizophrenia and Alzheimer’s disease psychosis), and Neurocrine Biosciences (Nasdaq: NBIX) with NBI-1117568, an M4 agonist for schizophrenia.
A non-canonical approach in neuroscience drug discovery is the use of behavioral phenotypic profiling. This approach has resulted in the development of the compound ulotaront (or SEP-363856, Sunovion/PsychoGenics). This compound entered clinical development without an identified mechanism, although it has since been identified as a TAAR1/5HT1A receptor agonist. Initial Phase II results with this compound have shown efficacy against both positive and negative symptoms without movement disorders or weight gain, and a Phase III readout is expected this year.‘’