Newron's Evenamide Challenges Schizophrenia Treatment Stalemate

MORRISTOWN, N.J. & MILAN – December 08, 2025 – Newron Pharmaceuticals has officially fired the starting gun in the United States for a pivotal Phase III trial of its novel drug, evenamide. This move marks a critical milestone in the journey to commercialize what could be the first significant breakthrough in decades for a particularly challenging and underserved patient population: those with Treatment-Resistant Schizophrenia (TRS). With the first U.S. patient now being enrolled at UCLA’s prestigious Semel Institute, Newron is advancing from promising prototype to the final, high-stakes validation phase before potentially reaching the market.

The Sobering Reality of Treatment Resistance

For millions suffering from schizophrenia, modern antipsychotic medications can be life-altering. However, a staggering portion of this population remains trapped by their symptoms. According to current literature, up to 50% of all individuals with schizophrenia are classified as treatment-resistant, meaning they fail to respond adequately to at least two different antipsychotic drugs. This condition, TRS, is not a rare subset but a common and devastating outcome, with meta-analyses showing a prevalence of nearly 37% across studies.

The current therapeutic landscape for these patients is stark. The only medication specifically approved for TRS is clozapine, a drug developed over 60 years ago. While it can be effective for some, its utility is severely hampered. Studies indicate that 40% to 70% of TRS patients who try clozapine do not achieve a satisfactory response. Furthermore, the drug carries a risk of severe side effects, including a potentially fatal blood disorder called agranulocytosis, which mandates rigorous and burdensome blood monitoring for patients. This creates a vast and urgent unmet medical need for safer, more effective options.

“This study addresses a significant unmet medical need in patients with treatment-resistant schizophrenia who are not responding to their current second-generation antipsychotic medication,” noted Prof. Stephen Marder, the study's principal investigator at UCLA. His statement underscores the clinical desperation for innovation in this space.

Beyond Dopamine: A New Scientific Paradigm

For over half a century, the development of antipsychotics has been dominated by the "dopamine hypothesis," which posits that an overactivity of dopamine pathways in the brain causes psychotic symptoms. Virtually all existing treatments, including clozapine, act primarily on dopamine receptors. Evenamide represents a fundamental departure from this paradigm.

Newron’s drug is a first-in-class glutamate modulator. Emerging evidence points to abnormalities in glutamate—the brain's primary excitatory neurotransmitter—as a key driver of TRS, a dysfunction not targeted by current therapies. Evenamide works by selectively blocking certain voltage-gated sodium channels, which in turn normalizes the excessive release of glutamate without disrupting its essential baseline functions. This unique mechanism of action offers a completely new angle of attack on the disease's underlying biology.

The promise of this approach is not merely theoretical. Earlier Phase II and Phase III studies have already shown that when evenamide is used as an add-on to standard antipsychotics, it is well-tolerated and can lead to clinically meaningful and sustained symptom improvement. This suggests that by targeting glutamate, evenamide may be addressing a core pathological process that dopamine-centric drugs miss, offering hope for patients who have exhausted all other options.

The Gauntlet of a Global Phase III Program

Bringing a first-in-class drug to market is a monumental undertaking, and Newron is now navigating the most critical phase of this journey. The initiation of the ENIGMA-TRS 2 study in the U.S. follows approvals from both the FDA and the Institutional Review Board, clearing a major regulatory hurdle. This 12-week, double-blind, placebo-controlled trial will enroll at least 400 patients across the U.S., Europe, Asia, and Latin America, evaluating a 15 mg twice-daily dose of evenamide as an add-on therapy.

The study’s design reflects the high bar for approval in this complex field. An Independent Eligibility Assessment Committee, comprising leading international experts, will rigorously screen patients to ensure they meet the consensus criteria for TRS. This adds a layer of objectivity and scientific rigor that is crucial for generating convincing data for regulators and, eventually, for prescribers.

This trial runs in parallel with ENIGMA-TRS 1, a larger, one-year study enrolling 600 patients to evaluate two different doses. Together, this pivotal program represents a significant capital investment and the cornerstone of Newron’s global commercialization strategy. The company is betting that the robust data generated will not only secure regulatory approvals but also build a compelling case for market adoption and reimbursement. Their existing commercialization agreements for evenamide in Japan and South Korea with EA Pharma and Myung In Pharm, respectively, demonstrate early confidence from partners in key international markets, a positive signal for investors monitoring Newron's path from R&D to revenue.

With topline results for ENIGMA-TRS 2 expected in the fourth quarter of 2026, all eyes in the neuroscience and investment communities will be on Newron. A positive outcome would not only validate the glutamate hypothesis but would also position evenamide as a transformative add-on therapy, potentially capturing a significant share of a market desperate for innovation. The journey from prototype to profit is fraught with risk, but for Newron and the millions affected by treatment-resistant schizophrenia, the potential reward is immeasurable.