Can evenamide become the first real breakthrough for treatment-resistant schizophrenia?

Newron Pharmaceuticals S.p.A. (SIX: NWRN, XETRA: NP5), the biopharmaceutical company headquartered near Milan, will present pivotal new data this week at the 17th World Congress of Biological Psychiatry (WCBP) in Berlin. The company is scheduled to unveil both oral and poster presentations of its lead investigational drug evenamide, a first-in-class glutamate release modulator being developed as an adjunctive therapy for patients with treatment-resistant schizophrenia (TRS).

Newron’s Phase 2/3 results, especially from the landmark Study 008A, could reshape how physicians approach patients who do not respond to current second-generation antipsychotics (SGAs). According to the company, evenamide demonstrated clinically meaningful and statistically significant efficacy in patients who remained symptomatic on SGAs, including clozapine — the gold standard for TRS. Just as important, the drug also posted a strong tolerability profile, with minimal side effects and low discontinuation rates.

This data is further strengthened by progress in Newron’s ongoing ENIGMA-TRS 1 study, a 600-patient international Phase 3 trial now underway across 20 countries. Combined, these programs position evenamide as a potential first-in-class treatment that could finally address the unmet clinical need in patients with non-dopaminergic schizophrenia pathophysiology.

Why are a third of schizophrenia patients still failing to respond—and can glutamate modulation close that gap?

Roughly one-third of individuals with schizophrenia develop treatment-resistant schizophrenia, a condition marked by poor or absent response to antipsychotics despite adequate dosing and duration. This segment of patients presents a significant burden on healthcare systems and caregivers, with persistent symptoms, frequent hospitalizations, and poor functional outcomes.

Unlike typical and atypical antipsychotics that primarily target dopamine D2 receptors, TRS is increasingly associated with glutamatergic dysfunction — particularly in the cortical and subcortical brain regions. In fact, many TRS patients display normal dopaminergic synthesis capacity, suggesting that dopamine-blocking drugs may never be effective in this subset.

Newron’s approach is built around evenamide, an orally bioavailable small molecule that selectively inhibits voltage-gated sodium channels (VGSCs) and normalizes pathological glutamate release without affecting basal neurotransmission. In essence, it tackles a neurochemical target that current antipsychotics do not reach.

Animal models have shown that combining evenamide with low, ineffective doses of existing antipsychotics (including clozapine) produces therapeutic benefit, pointing to potential mechanism-based synergy. This makes evenamide a compelling candidate for add-on therapy in TRS, rather than a standalone competitor.

What makes Study 008A and ENIGMA-TRS 1 unique in the landscape of schizophrenia trials?

Study 008A, which formed the basis of the oral presentation at WCBP 2025, is a randomized, double-blind, placebo-controlled Phase 2/3 trial designed to assess evenamide as an adjunct to second-generation antipsychotics in patients with schizophrenia who had inadequate symptom control. The trial included individuals already taking SGAs such as risperidone, olanzapine, and notably clozapine, which is often reserved for TRS cases.

For the first time in a large-scale trial, the addition of one antipsychotic to another showed clear efficacy without exacerbating side effects. This is significant in a field where polypharmacy often results in increased adverse events without commensurate benefit. Newron stated that evenamide was “extremely well tolerated”, and dropout rates were notably low — a key signal for long-term adherence.

Meanwhile, ENIGMA-TRS 1, currently enrolling, aims to be the first large, rigorously controlled study to evaluate a glutamate-based mechanism in confirmed TRS patients. It uses strict TRRIP Working Group Consensus Guidelines to ensure that only true TRS patients are included. The study also incorporates SGA plasma monitoring, a feature rarely seen in psychiatric trials, to rule out non-compliance or misclassification of treatment resistance.

Short-term efficacy will be measured at week 12, while durability and functional outcomes will be assessed at weeks 26 and 52 — offering a rare longitudinal look at sustained benefit in this population.

How does evenamide compare to recently approved antipsychotics in terms of safety and mechanism of action?

Beyond efficacy, tolerability remains one of the major barriers to long-term success in schizophrenia treatment. Many newer SGAs and multimodal agents carry burdensome side effects, from metabolic syndrome and weight gain to sedation and extrapyramidal symptoms. These adverse effects contribute heavily to non-adherence rates, which hover around 50% in some cohorts.

At WCBP 2025, Newron will present comparative poster data showing the relative safety profile of evenamide versus three recently approved antipsychotics. While specific comparators were not named, the company is likely referencing SGAs or newer agents such as lumateperone or pimavanserin, based on development timelines.

According to the poster abstract, the analysis compares risk-to-benefit ratios and links those profiles to underlying mechanisms — reinforcing the idea that evenamide’s non-dopaminergic approach sidesteps common liabilities. This safety advantage could give Newron leverage not only in the regulatory arena but also in real-world practice, where psychiatrists must balance efficacy with tolerability.

What is Newron’s commercial pathway for evenamide beyond the European market?

While headquartered in Italy, Newron is aggressively expanding its commercial and regulatory footprint in Asia. The biopharmaceutical company has signed development and licensing agreements with EA Pharma (a subsidiary of Eisai) for Japan and broader Asian territories, and with Myung In Pharm for South Korea. These collaborations provide infrastructure for clinical development, regulatory engagement, and — if successful — eventual commercialization.

The schizophrenia market in Asia is sizable, with Japan alone representing a multi-billion-dollar market for antipsychotics. However, high barriers to entry, cultural differences in prescribing, and payer scrutiny make local partnerships essential. With evenamide now in late-stage trials, these collaborations may soon shift from developmental support to market execution and lifecycle management.

Newron has previously commercialized Xadago® (safinamide), a Parkinson’s disease drug approved across 20+ markets, including the U.S., EU, and Japan. That product was licensed to Zambon and Meiji Seika, offering precedent for successful international out-licensing and cross-border supply chain coordination.

What are investors and institutional analysts saying about Newron’s clinical progress?

Investor sentiment around Newron has trended cautiously optimistic, especially in light of clear unmet need in TRS and clean signals from Study 008A. Given that schizophrenia has seen few meaningful innovations in over a decade — and no approved therapies targeting non-dopaminergic pathways — the market appears open to novel mechanisms like evenamide.

Analysts have noted that if evenamide delivers statistically significant improvements at multiple doses across the ENIGMA-TRS 1 trial’s endpoints, it could set the stage for regulatory filings in 2026, with possible conditional approval pathways in Europe or Asia. The U.S. pathway may be more complex, but a breakthrough designation from the FDA is not off the table depending on Phase 3 data strength.

Newron’s low operating expenses, lean development model, and history of monetizing CNS assets have also made it appealing to small-cap life sciences investors who value pipeline leverage and asset optionality. However, the company’s success will depend on timely enrollment completion, successful long-term readouts, and careful navigation of global pricing and access hurdles.

Can evenamide become the first glutamate-targeted adjunct approved for TRS—and what would that mean for psychiatry?

The stakes are high. If successful, evenamide could become the first approved adjunctive treatment for TRS based on glutamate modulation, introducing a fundamentally new approach to schizophrenia management. This could unlock not only commercial value but also research incentives for other neuropsychiatric conditions where glutamate dysfunction is implicated — such as depression, PTSD, and bipolar disorder.

Newron’s strategy of building rigorous clinical evidence while expanding regionally through licensing is seen by some as a textbook model for small biotech companies seeking global impact without burning excessive capital. The WCBP 2025 presentations may represent a tipping point, as institutional attention shifts from mechanism validation to late-stage clinical execution.

While evenamide still has hurdles to cross — particularly large-scale efficacy in ENIGMA-TRS 1 — the early signals suggest that Newron is no longer just an exploratory player in CNS innovation. It is now part of a select group attempting to redefine pharmacology for patients long underserved by traditional treatments.