Neurosterix Initiates Phase 1 Trial of NTX-253, Novel M4 Receptor Modulator for Schizophrenia Treatment
Key Insights
Neurosterix (search) has commenced a Phase 1 clinical study of NTX-253 (search), a selective positive allosteric modulator of the muscarinic M4 receptor for schizophrenia (search) treatment.
The oral drug represents a novel therapeutic approach that could reduce psychosis (search) symptoms while avoiding movement disorders and metabolic complications associated with traditional dopamine antagonists.
Preclinical studies demonstrated robust antipsychotic-like activity and favorable safety profile, supporting advancement into first-in-human clinical trials.
Neurosterix (search), a spin-out company from Addex Therapeutics (search), has initiated a Phase 1 clinical study of NTX-253 (search), a potent, selective, orally available positive allosteric modulator (PAM) of the muscarinic M4 receptor being developed for schizophrenia (search) treatment. The first-in-human study is designed to evaluate the safety, tolerability, pharmacokinetics, and pharmacodynamics of NTX-253 in healthy volunteers.
Novel Therapeutic Approach
"The progression of NTX-253 (search) into clinical studies represents an important milestone for both Neurosterix (search) and Addex," said Tim Dyer, Chief Executive Officer of Addex Therapeutics (search). "Selective modulation of the M4 receptor through a PAM represents a novel therapeutic approach compared to traditional dopamine receptor (search) antagonists and has the potential to provide patients suffering from schizophrenia (search) with a differentiated efficacy and safety profile."
The M4 muscarinic receptor (search) is a validated target for treating schizophrenia (search) and related disorders through indirect modulation of dopamine signaling. NTX-253 (search) fine-tunes muscarinic signaling with the potential to reduce psychosis (search) symptoms while avoiding the movement disorders and metabolic complications associated with traditional dopamine antagonists.
Preclinical Evidence Supporting Clinical Development
The advancement of NTX-253 (search) into Phase 1 first-in-human clinical studies is supported by preclinical studies showing antipsychotic-like activity and a favorable safety profile. These completed studies enabled an Investigational New Drug Application with the US Food and Drug Administration.
Preclinical studies demonstrate robust antipsychotic-like activity and a favorable safety profile. Previous research on this class of drugs has shown that M4 positive allosteric modulators can indirectly affect dopamine levels, providing antipsychotic results without peripheral side effects commonly seen with direct agonists. Studies in rodent models have also shown M4 positive allosteric modulators to reverse in vivo effects of psychomotor stimulants that cause increases in extracellular dopamine.
Addressing Limitations of Current Treatments
Currently available antipsychotics typically target dopamine receptors, providing some success in ameliorating the positive symptoms of schizophrenia (search). However, targeting dopamine can also induce metabolic, cognitive, and motor side effects, limiting their therapeutic utility. Research suggests that M4 PAMs could indirectly modulate dopamine levels and induce antipsychotic activity without peripheral muscarinic side-effects seen with direct agonists.
Highly selective M4 PAMs have been found to have robust antipsychotic-like effects in multiple rodent models and reverse multiple in vivo effects of psychomotor stimulants that induce increases in extracellular dopamine.
Corporate Background
Neurosterix (search) was spun-out of Addex in April 2024, raising $65 million in a Series A financing led by funds affiliated with Perceptive Advisors. Addex retains a 20% equity interest in Neurosterix.
If trials are successful, NTX-253 (search) could join a new class of antipsychotic therapy and contribute to a broader shift in how schizophrenia (search) is treated. Results from the Phase 1 study will inform future clinical development and determine whether the drug advances into trials involving patients with schizophrenia.