Evenamide Hydrochloride

MILAN & MORRISTOWN, N.J.--(BUSINESS WIRE)--Newron Pharmaceuticals S.p.A. (“Newron”) (SIX: NWRN, XETRA: NP5), a biopharmaceutical company focused on developing novel therapies for patients with diseases of the central and peripheral nervous system, today announced the publication of peer-reviewed data in Therapeutic Advances in Psychopharmacology, co-authored by Newron’s Chief Medical Officer, Ravi Anand, MD, and colleagues1. The publication presents clinical findings showing that evenamide, a novel glutamate modulator, is associated with clinically meaningful and sustained benefits when added to first- or second-generation antipsychotics in patients with schizophrenia who have an inadequate response to existing treatments, including those with TRS. This publication captures more than a decade of scientific and clinical work addressing one of psychiatry’s most difficult challenges. The publication synthesizes results from multiple randomized clinical trials and provides a scientific mechanistic rationale for the use of evenamide as a unique approach that targets disease mechanisms not addressed by existing antipsychotics. Drawing on data and analyses from randomized clinical studies, the publication highlights how modulation of aberrant glutamatergic signaling may deliver clinically meaningful benefits for patients with TRS and for those who continue to struggle despite standard antipsychotic treatment. “This publication captures more than a decade of scientific and clinical work addressing one of psychiatry’s most difficult challenges,” said Ravi Anand, MD, Chief Medical Officer at Newron Pharmaceuticals. “The analyses highlight not only symptom improvement but also real-world functional gains that matter to people living with schizophrenia, particularly those who have exhausted available options.” A Distinct Mechanism Targeting the Site of Dysfunction Unlike currently marketed antipsychotics that act primarily by blocking dopamine receptors in the basal ganglia, evenamide’s primary site of action is the hippocampus, that controls hyperdopaminergic firing in the basal ganglia (a brain region intimately involved in the causation of the core symptoms of schizophrenia). By reducing excessive glutamate activity in the hippocampus, evenamide indirectly rebalances dopamine signaling while preserving normal neuronal function. The hippocampal site of action of evenamide may explain why evenamide has demonstrated improvements not only in positive symptoms but also in negative symptoms, social functioning, and life engagement – domains that together with cognition are controlled by the various nuclei in the hippocampus and remain largely unaddressed by existing therapies. Taken together, the findings support evenamide as a potential first-in-class adjunctive therapy capable of redefining expectations for patients with TRS. Across clinical studies reported to date, evenamide has maintained a favorable safety and tolerability profile, being well-tolerated, with low rates of treatment discontinuation and no consistent pattern of serious safety concerns. “Evenamide represents a fundamentally different treatment approach,” said Anand. “By targeting the hippocampus – the source of the deficit rather than its downstream effects – we believe evenamide has the potential to shift the treatment paradigm, particularly for patients with TRS who urgently need new options.” Clinically Meaningful and Durable Benefits The publication reports analyses from two key clinical programs. In a one-year study of patients with treatment-resistant schizophrenia, more than half of those patients treated with evenamide improved to such an extent that they no longer met the severity criteria for TRS after long-term adjunctive treatment. Approximately one-quarter achieved remission, based on the most stringent criteria for remission. In a separate randomized, double-blind, placebo-controlled trial among patients with inadequate response to antipsychotics, evenamide showed statistically significant improvements over standard of care, regardless of the number of prior failed treatments. Importantly, benefits were observed not only in core symptoms but also in measures of social functioning and life engagement, domains often poorly addressed by existing therapies. “These results are notable because they go beyond symptom reduction,” continued Anand. “With evenamide, we are seeing improvements that translate into patients’ daily lives, including their ability to function, engage socially, and potentially move closer to remission. That is a meaningful outcome for patients, families, and clinicians.” Newron is advancing evenamide through ENIGMA-TRS, an international Phase III clinical program for patients with documented TRS. If successful, these studies could support the use of evenamide as a first-in-class adjunctive therapy, addressing a long-standing gap in the treatment landscape. About ENIGMA-TRS The ENIGMA-TRS pivotal Phase III program consists of ENIGMA-TRS 1 and ENIGMA-TRS 2. ENIGMA-TRS 1, initiated in August 2025, is an international, one-year, double-blind, placebo-controlled study in at least 600 patients to evaluate the efficacy, tolerability, and safety of evenamide 15 mg and 30 mg twice daily as an add-on therapy to current antipsychotics, including clozapine, compared to placebo. ENIGMA-TRS 2, initiated in December 2025, is a Phase III, international, 12-week, randomized, double-blind, placebo-controlled trial evaluating the efficacy, safety, and tolerability of evenamide 15 mg twice daily as an add-on therapy to current antipsychotics, including clozapine, compared to placebo, in patients suffering from TRS. ENIGMA-TRS 2 will enroll at least 400 patients. About evenamide Evenamide is a novel, orally available new chemical entity with a unique mechanism of action distinct from all currently marketed antipsychotics. It acts by selectively blocking voltage-gated sodium channels (VGSCs) and exhibits no biological activity at more than 130 other central nervous system (CNS) targets. It normalizes glutamate release induced by aberrant sodium channel activity (veratridine-stimulated), without affecting basal glutamate levels, due to inhibition of VGSCs. Combinations of subtherapeutic doses of evenamide and other APs, including clozapine, were associated with benefit in animal models of psychosis, suggesting synergies in mechanisms that may provide meaningful benefits for patients who do not adequately respond to current APs, including those on clozapine. Importantly, the benefits seemed to persist for a substantial time after evenamide had been degraded, explaining the long-term effects seen in clinical studies. Through its novel glutamatergic modulation, evenamide represents a first-in-class approach aimed at addressing the unmet needs of patients with schizophrenia who are resistant to existing treatments. About treatment-resistant schizophrenia (TRS) A significant proportion of patients with schizophrenia show virtually little to no beneficial response to currently available antipsychotic (AP) treatments, leading to a diagnosis of treatment-resistant schizophrenia (TRS). TRS is defined as no or inadequate symptom relief despite treatment with therapeutic doses of two APs from two different chemical classes for an adequate period. It is estimated that approximately 15% of patients develop TRS from the onset of illness, and about one-third to 50% of patients with schizophrenia overall. Emerging scientific evidence supports abnormalities in glutamate neurotransmission in TRS, not targeted by current APs, along with normal dopaminergic synthesis, to explain the lack of clinical benefit of most typical and atypical antipsychotics, which act primarily on dopamine receptors. These insights underline the need for novel therapeutic approaches that target the underlying glutamatergic dysfunction in schizophrenia, offering hope for patients who currently have limited or no effective treatment options. About Newron Pharmaceuticals Newron (SIX: NWRN, XETRA: NP5) is a biopharmaceutical company focused on the development of innovative therapies for patients with diseases of the central and peripheral nervous system. Headquartered in Bresso near Milan, Italy, the Company has a strong track record of advancing neuroscience-based treatments from discovery to market. Newron’s lead compound, evenamide, is a first-in-class glutamate modulator and has the potential to be the first add-on therapy for treatment-resistant schizophrenia (TRS) and for poorly responding patients with schizophrenia. Evenamide is currently developed in the global pivotal ENIGMA-TRS Phase III development program. Clinical trial results to date demonstrate the benefits of this drug candidate in the TRS as well as poorly responding patient population, with significant improvements across key efficacy measures increasing over time, as well as a favorable safety profile, which is uncommon for available antipsychotic medications. Newron has signed development and commercialization agreements for evenamide with EA Pharma (a subsidiary of Eisai) for Japan and other Asian territories, as well as Myung In Pharm for South Korea. Newron’s first marketed product, Xadago®/safinamide has received marketing authorization for the treatment of Parkinson’s disease in the European Union, Switzerland, the UK, the USA, Australia, Canada, Latin America, Israel, the United Arab Emirates, Japan and South Korea. The product is commercialized by Newron’s partner Zambon, with Supernus Pharmaceuticals holding marketing rights in the U.S., and Meiji Seika responsible for development and commercialization in Japan and other key Asian territories. For more information, please visit: www.newron.com Important Notices This document contains forward-looking statements, including (without limitation) about (1) Newron’s ability to develop and expand its business, successfully complete development of its current product candidates, the timing of commencement of various clinical trials and receipt of data and current and future collaborations for the development and commercialization of its product candidates, (2) the market for drugs to treat CNS diseases and pain conditions, (3) Newron’s financial resources, and (4) assumptions underlying any such statements. In some cases, these statements and assumptions can be identified by the fact that they use words such as “will”, “anticipate”, “estimate”, “expect”, “project”, “intend”, “plan”, “believe”, “target”, and other words and terms of similar meaning. All statements, other than historical facts, contained herein regarding Newron's strategy, goals, plans, future financial position, projected revenues and costs and prospects are forward-looking statements. By their very nature, such statements and assumptions involve inherent risks and uncertainties, both general and specific, and risks exist that predictions, forecasts, projections and other outcomes described, assumed or implied therein will not be achieved. Future events and actual results could differ materially from those set out in, contemplated by or underlying the forward-looking statements due to a number of important factors. These factors include (without limitation) (1) uncertainties in the discovery, development or marketing of products, including without limitation difficulties in enrolling clinical trials, negative results of clinical trials or research projects or unexpected side effects, (2) delay or inability in obtaining regulatory approvals or bringing products to market, (3) future market acceptance of products, (4) loss of or inability to obtain adequate protection for intellectual property rights, (5) inability to raise additional funds, (6) success of existing and entry into future collaborations and licensing agreements, (7) litigation, (8) loss of key executive or other employees, (9) adverse publicity and news coverage, and (10) competition, regulatory, legislative and judicial developments or changes in market and/or overall economic conditions. Newron may not actually achieve the plans, intentions or expectations disclosed in forward-looking statements and assumptions underlying any such statements may prove wrong. Investors should therefore not place undue reliance on them. There can be no assurance that actual results of Newron's research programs, development activities, commercialization plans, collaborations and operations will not differ materially from the expectations set out in such forward-looking statements or underlying assumptions. Newron does not undertake any obligation to publicly update or revise forward-looking statements except as may be required by applicable regulations of the SIX Swiss Exchange or the Dusseldorf Stock Exchange where the shares of Newron are listed. This document does not contain or constitute an offer or invitation to purchase or subscribe for any securities of Newron and no part of it shall form the basis of or be relied upon in connection with any contract or commitment whatsoever. 1 Ravi Anand, Alessio Turolla https://orcid.org/0009-0005-2167-61432, Giovanni Chinellato https://orcid.org/0009-0001-7091-86723, Francesca Sansi https://orcid.org/0009-0002-4495-58214, Arjun Roy5, and Richard Hartman https://orcid.org/0000-0002-5980-02006

MILAN & MORRISTOWN, N.J.--(BUSINESS WIRE)-- $NWRN #schizophrenia --Newron Pharmaceuticals S.p.A. (“Newron”) (SIX: NWRN, XETRA: NP5), a biopharmaceutical company focused on the development of novel therapies for patients with diseases of the central and peripheral nervous system, is pleased to note that its partner EA Pharma Co., Ltd. (EAP), has announced today the initiation of its Phase III clinical trial with evenamide, a novel excessive glutamate release modulator, in Japan. Stefan Weber, CEO of Newron Pharmaceuticals , commented: “The initiation of EA Pharma’s Phase III study of evenamide in Japan represents an important step in the global development of the program. This milestone, together with Newron’s ongoing global (excluding EAP territories) ENIGMA-TRS Phase III studies reflects continued progress and momentum for evenamide and further supports its potential as a differentiated add-on therapy in schizophrenia.” The full text of the announcement from EAP is as follows: EA Pharma Announces Initiation of Phase III Clinical Trial of EA8001, a Novel Treatment for Schizophrenia, in Japan EA Pharma Co., Ltd. (Head Office, Chuo-ku, Tokyo, Japan; President, Hidenori Yabune; “EA Pharma”) announced today that Phase III clinical trial of EA8001 (non -proprietary name: evenamide), a novel excessive glutamate release modulator, is now ready to begin in Japan (hereinafter the “Trial”). EA Pharma initiates the Trial after review by the institutional review board of the clinical site and other related procedures. This Trial is a multicenter randomized double-blind placebo-controlled clinical trial in patients with treatment-resistant schizophrenia who show poor or inadequate response to at least two different types of antipsychotics, evaluating the efficacy, safety and tolerability of EA8001 as an add-on treatment. EA Pharma is striving to quickly contribute to addressing the needs of, and increasing the benefits provided to, patients with schizophrenia, their families and healthcare providers. Inquiries EA Pharma Co., Ltd. Corporate Communication Dept. Mail: contact_ea@eapharma.co.jp 《More Information》 1. About schizophrenia Schizophrenia, which approximately 1% of the Japanese population is affected by, consists of positive symptoms (such as hallucinations and delusions), negative symptoms (such as reduced emotions and avolition), and cognitive impairment (such as memory and decision-making difficulties), and those symptoms may cause difficulty in everyday life and social activities [1]. Current antipsychotics mainly function through the dopamine and/or serotonin pathways, and those antipsychotics are known to show side effects (such as extrapyramidal symptoms, weight gain, and prolactin elevation). Among those patients treated with current antipsychotics, a considerable number of patients become treatment-resistant or poor responsive. Therefore, there is a demand for a drug which can address all those points. 2. About evenamide Evenamide is the first new chemical entity that has demonstrated significant benefits in this difficult-to-treat patient population, as seen in the potentially pivotal Phase III study 008A trial [2], as an add-on treatment to second generation anti-psychotics, in 291 poorly responding patients with chronic schizophrenia. The primary endpoint, the Positive and Negative Syndrome Scale (PANSS) [3], and the key secondary endpoint, the Clinical Global Impressions Scale - Severity (CGI-S), were met and showed statistical significance compared to placebo. Importantly, evenamide treatment was associated with statistically significant increase in proportion of patients who experienced “clinically meaningful benefit*” on the outcome variables [4]. *Against placebo in the two categories: at least 20% improvement in PANSS, and Score 2 or below in Clinical Global Impression Scale – Corrections (CGI-C) 3. About Alliance between EA Pharma and Newron Pharmaceuticals S.p.A. EA Pharma obtained the right to develop, manufacture and commercialize evenamide in Japan and other key Asian territories [5] under the license agreement with Newron Pharmaceuticals S.p.A. as of December 2024. For more details, please see . 4. About EA Pharma Co., Ltd. EA Pharma Co., Ltd. is a subsidiary of Eisai Co., Ltd. It was established in April 2016 by integration of the gastrointestinal business unit with more than 60 year’s history of the Eisai Group and the gastrointestinal business unit of the Ajinomoto Group having amino acid as its business core. EA Pharma Co., Ltd., is a specialty pharmaceutical company with a full value chain covering R&D, production & logistics and sales & marketing. For further information on EA Pharma Co., Ltd., please visit [1] National Center of Neurology and Psychiatry ( ) [2] A “pivotal phase III trial” is a key clinical trial to collect definitive evidence of efficacy and safety in primary endpoints that can support a regulatory approval. Usually, data collected from multiple confirmatory trials (pivotal trials) are required for a regulatory approval in many countries. [3] Positive and Negative Syndrome Scale (PANSS) is widely used in clinical trials of schizophrenia and is considered the “gold standard” for assessment of antipsychotic treatment efficacy (Innvo Clin Neurosci, 2017: ) [4] Efficacy and safety of evenamide, a glutamate modulator, added to a second-generation antipsychotic in inadequately/poorly responding patients with chronic schizophrenia: Results from a randomized, double-blind, placebo-controlled, phase 3, international clinical trial. (Neuropharmacology. 2025: ) [5] Brunei, Cambodia, Indonesia, Laos, Malaysia, Myanmar, the Philippines, Singapore, Thailand, Vietnam About Newron Pharmaceuticals Newron (SIX: NWRN, XETRA: NP5) is a biopharmaceutical company focused on the development of innovative therapies for patients with diseases of the central and peripheral nervous system. Headquartered in Bresso near Milan, Italy, the Company has a strong track record of advancing neuroscience-based treatments from discovery to market. Newron’s lead compound, evenamide, is a first-in-class glutamate modulator and has the potential to be the first add-on therapy for treatment-resistant schizophrenia (TRS) and for poorly responding patients with schizophrenia. Evenamide is currently developed in the global pivotal ENIGMA-TRS Phase III development program. Clinical trial results to date demonstrate the benefits of this drug candidate in the TRS as well as poorly responding patient population, with significant improvements across key efficacy measures increasing over time, as well as a favorable safety profile, which is uncommon for available antipsychotic medications. Newron has signed development and commercialization agreements for evenamide with EA Pharma (a subsidiary of Eisai) for Japan and other Asian territories, as well as Myung In Pharm for South Korea. Newron’s first marketed product, Xadago®/safinamide has received marketing authorization for the treatment of Parkinson’s disease in the European Union, Switzerland, the UK, the USA, Australia, Canada, Latin America, Israel, the United Arab Emirates, Japan and South Korea. The product is commercialized by Newron’s partner Zambon, with Supernus Pharmaceuticals holding marketing rights in the U.S., and Meiji Seika responsible for development and commercialization in Japan and other key Asian territories. For more information, please visit: Important Notices This document contains forward-looking statements, including (without limitation) about (1) Newron’s ability to develop and expand its business, successfully complete development of its current product candidates, the timing of commencement of various clinical trials and receipt of data and current and future collaborations for the development and commercialization of its product candidates, (2) the market for drugs to treat CNS diseases and pain conditions, (3) Newron’s financial resources, and (4) assumptions underlying any such statements. In some cases, these statements and assumptions can be identified by the fact that they use words such as “will”, “anticipate”, “estimate”, “expect”, “project”, “intend”, “plan”, “believe”, “target”, and other words and terms of similar meaning. All statements, other than historical facts, contained herein regarding Newron's strategy, goals, plans, future financial position, projected revenues and costs and prospects are forward-looking statements. By their very nature, such statements and assumptions involve inherent risks and uncertainties, both general and specific, and risks exist that predictions, forecasts, projections and other outcomes described, assumed or implied therein will not be achieved. Future events and actual results could differ materially from those set out in, contemplated by or underlying the forward-looking statements due to a number of important factors. These factors include (without limitation) (1) uncertainties in the discovery, development or marketing of products, including without limitation difficulties in enrolling clinical trials, negative results of clinical trials or research projects or unexpected side effects, (2) delay or inability in obtaining regulatory approvals or bringing products to market, (3) future market acceptance of products, (4) loss of or inability to obtain adequate protection for intellectual property rights, (5) inability to raise additional funds, (6) success of existing and entry into future collaborations and licensing agreements, (7) litigation, (8) loss of key executive or other employees, (9) adverse publicity and news coverage, and (10) competition, regulatory, legislative and judicial developments or changes in market and/or overall economic conditions. Newron may not actually achieve the plans, intentions or expectations disclosed in forward-looking statements and assumptions underlying any such statements may prove wrong. Investors should therefore not place undue reliance on them. There can be no assurance that actual results of Newron's research programs, development activities, commercialization plans, collaborations and operations will not differ materially from the expectations set out in such forward-looking statements or underlying assumptions. Newron does not undertake any obligation to publicly update or revise forward-looking statements except as may be required by applicable regulations of the SIX Swiss Exchange or the Dusseldorf Stock Exchange where the shares of Newron are listed. This document does not contain or constitute an offer or invitation to purchase or subscribe for any securities of Newron and no part of it shall form the basis of or be relied upon in connection with any contract or commitment whatsoever. Contacts For more information, please contact: Newron Stefan Weber – CEO; +39 02 6103 46 26, pr@newron.com UK/Europe Simon Conway / Ciara Martin / Natalie Garland-Collins, FTI Consulting; +44 20 3727 1000, SCnewron@fticonsulting.com Switzerland Valentin Handschin, IRF; +41 43 244 81 54, handschin@irf-reputation.ch Germany/Europe Anne Hennecke / Maximilian Schur, MC Services; +49 211 52925227, newron@mc-services.eu USA Paul Sagan, LaVoieHealthScience; +1 617 865 0041, psagan@lavoiehealthscience.com