First Synaptic Regenerative Therapy for Schizophrenia Under Investigation

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Spinogenix recently announced that multiple sites are now enrolling participants in a phase 2 clinical trial to evaluate SPG302, the first synaptic regenerative therapy for schizophrenia, with the approval of the Australia Human Research Ethics Committee.¹ SPG302 focuses on addressing a key feature of schizophrenia that may contribute to all symptom domains: a loss of glutamatergic synapses.

“Spinogenix’s phase 2 clinical trial in schizophrenia for SPG302 represents a novel therapeutic approach to treat the condition by addressing a key feature of disease pathogenesis—synapse loss—making it the first drug of its kind to apply this therapeutic mechanism to treat this condition,” Peter Vanderklish, PhD, the CSO of Spinogenix, exclusively told Psychiatric Times. “Many lines of evidence support the idea that glutamatergic synapse loss in the frontal cortex and other regions in schizophrenia contributes to all symptom domains, even leading to the hyperactive dopaminergic signaling that drives positive symptoms. SPG302 has the potential to regenerate synapses, in essence reversing a fundamental anatomical deficit in schizophrenia that is germane to all symptoms of the disease. As such, SPG302 may provide a much needed new treatment option in schizophrenia, one that may work as an effective monotherapy or as a regenerative component to standard of care medications.”

This newly-initiated randomized, double-blind, placebo-controlled multicenter phase 2 study will assess the efficacy, safety, and tolerability of once-daily oral tablet SPG302 in adults with schizophrenia. It is believed that SPG302 rapidly regenerates glutamatergic synapses through a novel mechanism of action.

“We are excited to advance the first clinical therapy capable of reversing synapse loss in schizophrenia, which may provide a much-needed advancement in the treatment of multiple symptoms and patients who are treatment resistant,” said Stella Sarraf, PhD, CEO and founder of Spinogenix. “Antipsychotics targeting dopamine signaling have been used since the 1950s to control positive symptoms, but leave psychosis inadequately controlled in many patients and have little benefit on negative and cognitive symptoms. As demonstrated by the expected entry of promising emerging antipsychotics into the schizophrenia treatment landscape, we are at an inflection point where new targets and novel approaches like SPG302 represent our best option to show meaningful improvements for this population.”

Data from varied studies suggest that loss of glutamatergic synapses in the frontal cortex and other regions are a primary feature of schizophrenia that contribute to the onset of psychosis, negative symptoms, and cognitive deficits.²

“SPG302 represents the first opportunity to understand the extent to which clinically targeting synapse loss in schizophrenia can address multiple symptom domains. If it succeeds, it could redefine how we treat the disease by establishing synapse loss as a targetable, key mediator of schizophrenia and other psychiatric diseases—ultimately offering hope for patients whose symptoms go beyond what current medications can address,” Vanderklish told Psychiatric Times.

SPG302 already has US Food and Drug Administration Orphan Drug Designation for the treatment of ALS. It is also under study in Australia for the treatment of Alzheimer disease.

“The synaptic regenerative approach being championed by Spinogenix may add an important new option to the armamentarium of drugs available to those battling schizophrenia,” said Merv Turner, PhD, a member of the Spinogenix board of directors. “While long believed to be of potential benefit, targeting synapse loss in practice represents an entirely new therapeutic strategy. SPG302 has the potential to become another novel and high-value addition to the schizophrenia therapeutics space, following the expected entry of KarXT as the first nondopamine antipsychotic in 70 years.”

References

1. Spinogenix announces launch of a phase 2 clinical trial evaluating SPG302 for the treatment of schizophrenia. News release. Morningstar. September 25, 2024. https://www.morningstar.com/news/globe-newswire/9236143/spinogenix-announces-launch-of-a-phase-2-clinical-trial-evaluating-spg302-for-the-treatment-of-schizophrenia

2. Howes OD, Onwordi EC. The synaptic hypothesis of schizophrenia version III: a master mechanism. Mol Psychiatry. 2023;28(5):1843-1856.