Neuren Pharmaceuticals Limited ANNUAL REPORT 2025 Improving the lives of people with neurodevelopmental disabilities
Neuren Pharmaceuticals is developing new drug therapies to treat multiple serious neurological conditions, caused by genetic abnormalities or brain injury, that have no or limited approved treatment options. Incorporated in New Zealand and based in Melbourne, Australia, Neuren is listed on the ASX under the code NEU. 2 Chair and CEO message 4 Operating Review 21 Board 22 Executive Team 24 Environmental, Social and Governance (ESG) 31 Directors’ Responsibilities Statement CONTENTS 32 C onsolidated Statement of Profit or Loss and Other Comprehensive Income 33 Consolidated Statement of Financial Position 34 Consolidated Statement of Changes in Equity 35 Consolidated Statement of Cash Flows 36 Notes to the Consolidated Financial Statements 56 Independent Auditor’s Report 59 Additional Information
Royalty income up 15% YoY A$65m Interest income A$12m NPAT without any one-time revenue A$30m Corporate & admin costs only A$6m R&D investment in NNZ-2591 A$36m DAYBUE revenue since launch in 2023 A$510m THE 2025 NUMBERS – GROWING SUSTAINABLE INCOME STRONG DAYBUE® CASH FLOWS ENABLE PURSUIT OF STEP-CHANGE IN VALUE FROM NNZ-2591 Large potential upside for shareholders is enabled by financial strength 5 Phelan-McDermid syndrome Pitt Hopkins syndrome Hypoxic Ischemic Encephalopathy (HIE) NNZ-2591 (ercanetide) indications prioritised for maximum commercial impact Long-term income growth from DAYBUE® (trofinetide) A$510m income from DAYBUE since launch in 2023 A$296 million cash as at 31 Dec 2025 * Rett and Fragile X syndromes are licensed to Acadia, with same economics to Neuren as trofinetide; Neuren retains worldwide rights to all other indications Angelman syndrome, Prader-Willi Syndrome, SYNGAP1, Rett syndrome (Acadia)*, Fragile X syndrome (Acadia)* The 2025 numbers – growing sustainable income • A$65m royalty income up • Interest income A$12m • A$30m NPAT without any • Corporate & admin costs only A$ • R&D investment in NNZ-2591 A$ • A$510m DAYBUE reven - 27 56 65 15 205 157 16 238 221 82 2022 2023 2024 2025 Total Income (including net derivative and FX gain/loss) Royalty One-offs Net Financial income* *Finance Income + net gain / (loss) on financial derivatives + net FX gain / (loss), excluding FX translation * Finance Income + net gain / (loss) on financial derivatives + net FX gain / (loss), excluding FX translation Ex-NA upfront & 1st commercial sale milestone 1st sales milestone & PRV sale Neuren Pharmaceuticals Limited Annual Report 2025 1
CHAIR AND CEO MESSAGE PATRICK DAVIES & JON PILCHER In 2025 Neuren generated profit after tax of A$30 million, driven by DAYBUE® royalties growing by 15% to A$65 million. Cash reserves at the end of the year remained very strong at A$296 million. Neuren’s revenue from Acadia for DAYBUE since launch in 2023 has now exceeded A$500 million, which represents an outstanding success by any measure. This and our continuing disciplined investment in NNZ-2591 place Neuren in an enviable position to create further long-term value for shareholders. The most important part of that value creation is the Phase 3 development program for NNZ-2591 in Phelan-McDermid syndrome (PMS). The commencement of the Koala Phase 3 clinical trial was a pivotal milestone for Neuren. This was the culmination of many months of diligent preparation, including interactions with the US Food and Drug Administration (FDA). We are very encouraged by the support from the PMS community and look forward to building momentum this year as the remaining trial sites begin enrolment. We are proud to be the presenting sponsor of the PMS Foundation Family Conference in Colorado in July 2026, which will be a timely opportunity to engage further with the community. The alignment achieved at two meetings with the FDA means that we are confident a positive result in the Koala trial should enable us to prepare a New Drug Application. In parallel with executing the trial we are completing all the other studies and supply chain activities that are needed to support an application. We are prioritising pursuing indications for NNZ-2591 in which we have the potential to be first to market and maximise the impact for both patients and shareholders. In 2025 the treatment of the consequences of brain injury at birth (HIE) was added to PMS and Pitt Hopkins syndrome as the three highest value priorities. 2025 was a record year for DAYBUE, with sales of US$391 million and more than 1,000 patients treated during Q4. Even more exciting is Acadia’s guidance for 2026 sales of US$460-490 million, which would represent year-on-year growth of between 17% and 25%, assisted by the US launch of DAYBUE STIX, the powder formulation of trofinetide. STIX provides a potentially attractive new option for families who may have declined to try or discontinued the liquid formulation. Acadia has estimated that such families may number as many as 400. Patrick Davies Chair Jon Pilcher CEO As well as the continued growth in the US, we are very pleased that Rett syndrome patients in other parts of the world have been able to receive treatment under Acadia’s named patient programs, which are also providing a growing contribution to sales. Meanwhile, a small clinical study is underway in Japan, with results expected in Q4 2026 or Q1 2027 to support a potential marketing authorisation in that important market. Acadia has demonstrated its ongoing commitment to the Rett syndrome community in Europe through its request for a re-examination of the recent European Medicines Agency decision to deny marketing authorisation. Neuren believes that the community deserves a positive outcome. In the meantime, the fall in our share price following the decision far exceeded the valuation impact on Neuren, which means that if it were to be reversed this would now represent pure upside. Last month we initiated another share buyback program given what we believe is a material undervaluation of our assets in the current market, by reference to our own models and to those of the eight broker research analysts who formally cover Neuren. Our cash position, supported by growing cash flows from the DAYBUE franchise mean that Neuren’s NNZ-2591 development programs remain well funded alongside the buy-back. There is so much to look forward to in 2026 as our strategy advances, encompassing acceleration of enrolment in the Koala trial, initiation of the next stage for Pitt Hopkins and HIE, the anticipated impact of DAYBUE STIX in the US, completion of the small trial to support a marketing application in Japan and the result of the re-examination in Europe. We are grateful to our shareholders and the whole Neuren team for their ongoing dedication to what we all believe is such a meaningful mission. Delivering the impact on patients and their families that we are striving for should ultimately result in highly positive outcomes for all stakeholders. Neuren Pharmaceuticals Limited Annual Report 2025 2
CHAIR AND CEO MESSAGE CONTINUED NEUREN’S VALUES WE ARE PASSIONATE ABOUT MAKING A DIFFERENCE TO THE LIVES OF PATIENTS AND THEIR FAMILIES WE AIM TO EARN THE RESPECT OF EVERYONE WE DEAL WITH WE ARE DETERMINED AND CREATIVE TO BREAK THROUGH BARRIERS WE RECOGNISE THE IMPORTANCE OF ALL STAKEHOLDERS AND ENDEAVOUR TO USE FINANCIAL RESOURCES EFFICIENTLY WE HARNESS THE POWER OF COLLABORATION AND DIFFERENT PERSPECTIVES WE APPLY A QUALITY MINDSET TO EVERYTHING WE DO Jon Pilcher CEO Patrick Davies CHAIR 3 Neuren Pharmaceuticals Limited Annual Report 2025
OPERATING REVIEW by both major types of brain cells – neurons and glia. IGF-1 in the brain is critical both for normal development and to maintain or restore the biological balance required for normal functioning. During development, the brain and the cells that comprise it change rapidly and in complex ways. IGF-1 and its metabolites play a significant role in regulating these changes. In the mature brain, these molecules play an important role in responding to disease, stress and injury. Trofinetide and NNZ-2591 mimic the function of the natural molecules in the brain, however each drug is designed to have a longer half-life in circulation, be suitable for use as an oral medication, more readily cross the blood brain barrier and have better stability for longer and easier storage and shipping. Whereas many drugs typically exert a specific effect on a specific target related to one symptom, trofinetide and NNZ-2591 exert diverse effects which can help to control or normalise abnormal biological processes in the brain. This means that the target is to have a broad impact on the condition rather than aiming to treat one symptom. NEUREN’S GROUND-BREAKING THERAPIES Neuren develops drug therapies for serious neurological conditions, caused by genetic abnormalities or brain injury, that have no or limited approved treatment options. These conditions involve disruptions to brain development or function which lead to a wide range of serious issues affecting nearly every aspect of life. The impact on the patients and their families is severe and life-long. Neuren strives to develop therapies in close collaboration with the leading specialist physicians and the well-organised patient advocacy organisations. Each condition is caused by a different genetic mutation, or in the case of hypoxic-ischemic encephalopathy (HIE) by brain injury resulting from lack of oxygen or blood flow to the brain at birth, but they share similar symptoms and the common characteristic of impaired connections and signalling between brain cells. Neuren’s two novel patented drugs, trofinetide and NNZ-2591 (ercanetide), potentially have broad utility in the treatment of neurological conditions. Both drugs are synthetic analogues of important molecules that occur naturally in the brain and are involved in the biology of IGF-1, a growth factor stimulated by growth hormone. In the central nervous system, IGF-1 is produced 3 Impaired communication between neurons, abnormal formation/pruning of dendrites & chronic inflammation Rett (MECP2) Fragile X (FMR1) Phelan-McDermid (SHANK3) Pitt Hopkins (TCF4) Angelman (UBE3A) | Prader-Willi (15q11-q13) | SYNGAP1-related disorder (SYNGAP1) Neurodevelopmental disorders Hypoxic-Ischemic Encephalopathy (lack of oxygen or blood flow to the brain before, during or shortly after birth) Brain injury Walking and balance issues Anxiety and hyperactivity Seizures Impaired communication Intellectual disability Impaired social interaction Developmental delays Cognitive impairment Seizures Cerebral palsy Impaired hand use Sleep disturbance Gastrointestinal problems Severe impact on nearly every aspect of life Long-term impact on survivors Excitotoxicity, mitochondrial dysfunction, and acute & chronic inflammatory processes Neuren’s drugs target the critical role of IGF-1 in this upstream process, using analogs of naturally occurring peptides that can be taken orally as liquids INTRODUCTION GROUND-BREAKING IMPACT ON PEDIATRIC NEUROLOGICAL ORPHAN INDICATIONS Impaired communication between neurons, abnormal formation/pruning of dendrites & chronic inflammation Excitotoxicity, mitochondrial dysfunction, and acute & chronic inflammatory processes Severe impact on nearly every aspect of life Walking and balance issues Anxiety and hyperactivity Seizures Impaired communication Intellectual disability Impaired social interaction Impaired hand use Sleep disturbance Gastrointestinal problems Neurodevelopmental disorders Long-term impact on survivors Development delays Seizures Cognitive impairment Cerebral palsy Brain injury Neuren’s drugs target the critical role of IGF-1 in this upstream process, using analogs of naturally occurring peptides that can be taken orally as liquids Neuren Pharmaceuticals Limited Annual Report 2025 4
OPERATING REVIEW CONTINUED THE IMPORTANCE OF ORPHAN DRUG DESIGNATION The US Food and Drug Administration (FDA) and European Medicines Agency (EMA) have both granted Orphan Drug designation for trofinetide in Rett syndrome and Fragile X syndrome and for NNZ-2591 in each of Phelan-McDermid, Pitt Hopkins and Angelman syndromes. The FDA has also granted Orphan Drug designation for NNZ-2591 in PraderWilli syndrome. Orphan Drug designation is a special status that the regulators may grant to a drug to treat a rare disease or condition. Amongst other incentives, Orphan Drug designation qualifies the sponsor of the drug for exclusivity periods during which the regulators will not approve a generic competitor product. These marketing exclusivity periods are extremely valuable for the commercialisation of Orphan Drugs. They provide additional protection, along with patents, against generic competitors and potentially can continue to provide protection after patent expiry. The exclusivity periods after marketing authorisation of products approved for pediatric use are 7.5 years in the United States and 12 years in the EMA region. Japan, South Korea and Taiwan also have Orphan Drug programs. As well as the exclusivity periods, Orphan Drugs have many other commercial advantages compared with existing markets that have apparently attractive large sales in which established products and companies have to be displaced. The serious and urgent unmet need results in a more supportive regulatory and pricing environment and strong engagement from the patient community and leading physicians. Historical data indicates a higher probability of achieving regulatory approval and the potential for immediate access to known patients means that a large sales organisation is less important. In short, the Orphan Drug business model targets a leadership position in markets with urgent need, at an attractive price and with a higher probability of getting to market. The conditions that Neuren is aiming to treat are “rare diseases”, however they are not “ultra-rare”, and in each condition there are tens of thousands of potential patients around the world. COMMERCIAL EXCLUSIVITY In addition to the primary protection of the important exclusivity periods from Orphan Drug designation explained above, Neuren has additional commercial protection from issued patents extending as far as 2040 and pending patent applications extending as far as 2046. Since trofinetide and NNZ-2591 are new chemical entities, following the first marketing authorisation for each drug, the term of one patent may potentially be extended by up to 5 years in many countries, including the United States, Europe and Japan. OTHER REGULATORY INCENTIVES The FDA has granted Fast Track and Rare Pediatric Disease designations for NNZ-2591 in each of Phelan-McDermid, Pitt Hopkins and Angelman syndromes. Trofinetide also received Fast Track and Rare Pediatric Disease designations before its approval in the US. Fast Track is a process designed to facilitate the development and expedite the review of drugs to treat serious conditions and fill an unmet medical need. The purpose is to get important new drugs to the patient earlier. Fast Track addresses a broad range of serious conditions. A drug that receives Fast Track designation is eligible for some or all of the following: – More frequent meetings with FDA to discuss the drug’s development plan and ensure collection of appropriate data needed to support drug approval – More frequent written communication from FDA about such things as the design of the proposed clinical trials and use of biomarkers – Eligibility for Accelerated Approval and Priority Review, if relevant criteria are met – Rolling Review, which means that a drug company can submit completed sections of its Biologic License Application (BLA) or New Drug Application (NDA) for review by FDA, rather than waiting until every section of the NDA is completed before the entire application can be reviewed. BLA or NDA review usually does not begin until the drug company has submitted the entire application to the FDA The Rare Pediatric Disease Priority Review Voucher (PRV) program provides for the award of a PRV to drug developers that receive FDA approval for a drug for a designated rare pediatric disease. The voucher entitles the holder to priority review of a different drug or may be transferred or sold to another drug developer. The Rare Pediatric Disease PRV program has been reauthorized by the United States Congress to 30 September 2029. Recently in January and February 2026, two drug developers announced the sale of vouchers for US$200 million and US$205 million respectively. Neuren Pharmaceuticals Limited Annual Report 2025 5
OPERATING REVIEW CONTINUED In December 2025 Acadia received US Food and Drug Administration (FDA) approval of DAYBUE STIX (trofinetide) for oral solution, a dye- and preservative-free powder formulation of trofinetide for the treatment of Rett syndrome in adult and pediatric patients two years of age and older. The new powder formulation offers children and adults living with Rett syndrome new flexibility and choice regarding the dose volume and taste of their DAYBUE treatment, potentially facilitating treatment of a significant number of new patients from families who had declined to try or discontinued the liquid formulation. DAYBUE STIX is being launched on a limited basis in Q1 2026 and more broadly early in Q2 2026. The existing oral solution formulation will remain available. DAYBUE® (TROFINETIDE) FOR RETT SYNDROME 460 177 348 391 490 CY2023 (Apr -Dec) CY2024 CY2025 CY2026 Acadia Guidance DAYBUE Net Sales (US$m) 70 27 56 65 77 CY2023 CY2024 CY2025 CY2026E* Royalty to Neuren (A$m) +18–25% + 8–19% +12% +15% 0 0 026 dia ance m) 70 27 56 65 77 CY2023 CY2024 CY2025 CY2026E* Royalty to Neuren (A$m) + 8–19% +15% * Based on Acadia full year 2026 DAYBUE Net Sales Guidance of US$460490m, conservatively assuming North America royalty rates only (10% of DAYBUE net sales up to US$250m and 12% of DAYBUE net sales between US$250m and US$500m), and AUDUSD of 0.70 to 0.72 In March 2023, Neuren’s exclusive worldwide licensee for trofinetide, Acadia Pharmaceuticals (NASDAQ: ACAD), received FDA approval of DAYBUE® (trofinetide) for the treatment of Rett syndrome in adult and pediatric patients two years of age and older. On 17 April 2023, Acadia launched DAYBUE in the United States as the first ever approved treatment for Rett syndrome. Access to DAYBUE has been well supported by Medicaid and private health insurance payors. During 2025, Acadia activated named patient supply programs across multiple regions including Europe, the Middle East and Latin America. Growing, sustainable income to Neuren from DAYBUE® (trofinetide) in the United States plus international named patient programs Neuren Pharmaceuticals Limited Annual Report 2025 6
76 85 91 97 85 96 101 110 Q1 2024 Q2 2024 Q3 2024 Q4 2024 Q1 2025 Q2 2025 Q3 2025 Q4 2025 920 954 987 Unique patients received DAYBUE in the Quarter 923 917 1,006 1,070 OPERATING REVIEW CONTINUED The number of unique patients receiving a DAYBUE shipment grew to 1,070 in Q4 2025, exceeding 1,000 for the first time. The persistency on therapy rate after 12 months of treatment increased to approximately 55%. There is substantial potential for further growth in the US. The number of diagnosed Rett patients in the US has grown from approximately 4,500 at the launch of DAYBUE to 6,000, with two-thirds of the diagnosed patients yet to try DAYBUE. Prevalence studies suggest the total number of patients may be 6,000 to 9,000. During 2025, Acadia completed an Net sales of DAYBUE in 2025 were US$391 million, with sequential growth in each quarter and record net sales of US$110 million in Q4 2025. Quarterly sales expansion of its DAYBUE field force in the US by ~30% to accelerate future growth in the community outside the Rett syndrome centers of excellence. In Q4 2025 momentum continued to build with 76% of new prescriptions originating from community physicians outside centers of excellence. Acadia has provided guidance for growth in net sales in 2026 to between US$460 million and US$490 million. The guidance comprises sales only from the US and international named patient programs. ABOUT RETT SYNDROME Rett syndrome is a seriously debilitating and life-threatening neurological disorder. It is first recognized in infancy and seen predominantly in girls, but can occur very rarely in boys. At diagnosis, Rett syndrome has often been misdiagnosed as autism, cerebral palsy, or non-specific developmental delay. Most cases of Rett syndrome are caused by mutations on the X chromosome on a gene called MECP2. Rett syndrome strikes all racial and ethnic groups and has been estimated to occur worldwide in 1 of every 10,000 to 15,000 female births, causing problems in brain function that are responsible for cognitive, sensory, emotional, motor and autonomic function. These problems can include learning, speech, sensory sensations, mood, movement, breathing, cardiac function, and even chewing, swallowing, and digestion. Rett syndrome symptoms appear after an early period of apparently normal or near normal development until six to eighteen months of life, when there is a slowing down or stagnation of skills. A period of regression then follows, with loss of communication skills and purposeful hand use, loss or impairment of walking, and the onset of stereotypic hand movements. Other problems frequently include seizures and erratic breathing patterns, an abnormal side-to-side curvature of the spine (scoliosis), and sleep disturbances. i Neuren Pharmaceuticals Limited Annual Report 2025 7
OPERATING REVIEW CONTINUED 1 Acadia estimates 2 Reimbursement currently not recommended by CDA-AMC Approved Mar 2023 Oct 2024 Jan 2026 Approved Active NPP Approved2 Japan 1,000 - 2,000 Rett patients1 Orphan Drug Designation status granted Phase 3 results expected Q4 2026/Q1 2027, to facilitate marketing application in 2027 Europe 9,000 - 12,000 Rett patients1 Active named patient supply programs Plan to request CHMP reexamination, with potential outcome late Q2 2026 RoW Named patient supply programs in select countries Israel Canada 600 - 900 Rett patients1 US 6,000 - 9,000 Rett patients1 receipt of these grounds to re-examine its opinion, with new rapporteurs appointed for the re-examination. This means the CHMP opinion on the re-examination is likely to be at the end of Q2 2026. In the meantime, named patient supply programs are continuing. If granted marketing authorisation, trofinetide would be the first and only approved therapy for Rett syndrome in the European Union. In Japan trofinetide received Orphan Drug Designation and Acadia commenced a small clinical trial to support a marketing application, with results anticipated in Q4 2026 or Q1 2027, facilitating the application in 2027. DAYBUE oral solution was approved in Canada in October 2024 and in Israel in January 2026, although reimbursement of DAYBUE is currently not recommended by Canada’s Drug Agency (CDA-AMC). Further information about DAYBUE, including prescribing information can be accessed at www.DAYBUE.com LONG TERM GROWTH OPPORTUNITY FOR TROFINETIDE THROUGH GLOBAL EXPANSION There is urgent unmet need for a treatment for Rett syndrome around the world, evidenced by communications received from families, patient support groups and physicians. In January 2025, Acadia submitted a Marketing Authorisation Application (MAA) to the European Medicines Agency (EMA) for trofinetide for the treatment of Rett syndrome in adults and pediatric patients two years of age and older. In March 2026, Acadia was informed by the Committee for Medicinal Products for Human Use (CHMP) of the EMA of a negative opinion vote regarding the MAA. Acadia is requesting a re-examination of the opinion by the CHMP. Pursuant to EU legislation, an applicant has the right to request a re-examination of a CHMP opinion within 15 calendar days of receipt of the opinion, followed by submission of the grounds for the request for re-examination within 60 calendar days of receipt of the opinion. The CHMP has up to 60 days after Neuren Pharmaceuticals Limited Annual Report 2025 8
OPERATING REVIEW CONTINUED NEUREN’S ATTRACTIVE ECONOMICS FROM DAYBUE (TROFINETIDE) In the period since launch, Neuren has earned cumulative income from DAYBUE of A$510 million. In 2025, Neuren earned royalty income from DAYBUE of A$65 million. Assuming Acadia’s 2026 net sales guidance for DAYBUE is met and an exchange rate range of 0.70-0.72, Neuren anticipates earning full-year royalties of A$70-77 million. Neuren is eligible to receive ongoing royalties on global net sales of trofinetide, plus one-time milestone payments on achievement of certain events such as first commercial sale in a specific region, and one-time milestone payments on achievement of a series of thresholds of total annual net sales in a specific region. No royalties or similar costs are payable by Neuren to third parties, which means Neuren’s revenue from Acadia flows through to pre-tax profit. The royalty rates and sales milestone payments for a specific region are related to the total amount of annual net sales of trofinetide in all products and indications in that region. Neuren’s economics from DAYBUE in North America and outside North America are set out in the following tables: US$10m upfront in 2018 US$10m in2022 followingacceptanceof NDAfor review US$40m in2023following1st commercialsalein the US US$50m In 2024 one third share of Priority Review Voucher awardedtoAcadia (soldfor US$150m) US$55m Milestone payments related to Fragile X U Tiered Royalty Rates (% of net sales)1 Annual Net Sales Rates ≤US$250m 10% >US$250m, ≤US$500m 12% >US$500m, ≤US$750m 14% >US$750m 15% Sales Milestones1 Net Salesin one calendar year US$m ≥US$250m 50 ≥US$500m 50 ≥US$750m 100 ≥US$1bn 150 U U North America US$100m upfront in 2023 US$35m following 1st commercial sale in Europe US$15m following 1st commercial sale in Japan US$10m following 1st commercial sale of a 2nd indication Europe US$4m following 1st commercial sale of a 2nd indication Japan Sales milestones1 On achievement of escalating annual net sales thresholds: Europe: up to US$170m Japan: up to US$110m RoW :upto US$83m Tiered royalties1 Mid- teens to low- 20s%of net sales Outside North America U U US$10m upfront in 2018 US$10m in2022 followingacceptanceof NDAfor review US$40m in2023following1st commercialsalein the US US$50m In 2024 one third share of Priority Review Voucher awardedtoAcadia (soldfor US$150m) US$55m Milestone payments related to Fragile X U Tiered Royalty Rates (% of net sales)1 Annual Net Sales Rates ≤US$250m 10% >US$250m, ≤US$500m 12% >US$500m, ≤US$750m 14% >US$750m 15% Sales Milestones1 Net Salesin one calendar year US$m ≥US$250m 50 ≥US$500m 50 ≥US$750m 100 ≥US$1bn 150 U U North America US$100m upfront in 2023 US$35m following 1st commercial sale in Europe US$15m following 1st commercial sale in Japan US$10m following 1st commercial sale of a 2nd indication Europe US$4m following 1st commercial sale of a 2nd indication Japan Sales milestones1 On achievement of escalating annual net sales thresholds: Europe: up to US$170m Japan: up to US$110m RoW :upto US$83m Tiered royalties1 Mid- teens to low- 20s%of net sales Outside North America U U 1 Royalty rates payable on the portion of annual net sales that fall within the applicable range. Each sales milestone payment is payable once only A redacted version of the licence agreement between Neuren and Acadia was filed with the US Securities and Exchange Commission as a material contract exhibit to Acadia’s 2023 10-K Annual Report, which is available to view via the SEC Filings section of Acadia’s website. Neuren Pharmaceuticals Limited Annual Report 2025 9
OPERATING REVIEW CONTINUED NNZ-2591 (ERCANETIDE) FOR MULTIPLE NEUROLOGICAL CONDITIONS * Rett and Fragile X syndromes are licensed to Acadia, with same economics to Neuren as trofinetide; Neuren retains worldwide rights to all other indications TO FIND OUT MORE: www.pmsf.org www.pitthopkins.org www.cureshank.org www.hopeforhie.org Neuren is developing NNZ-2591 for multiple serious neurological conditions. The estimated number of potential patients being targeted across these conditions is multiple times larger than Rett syndrome. In designing and executing the NNZ-2591 development program, Neuren has been able to leverage the extensive and highly relevant experience the Neuren team has gained from the trofinetide Rett syndrome program across manufacturing, non-clinical, clinical and regulatory. Neuren is prioritising three indications in which NNZ-2591 can potentially have the maximum commercial value and the largest impact for patients. hareholders is enabled by financial strength 5 Phelan-McDermid syndrome Pitt Hopkins syndrome Hypoxic Ischemic Encephalopathy (HIE) NNZ-2591 (ercanetide) indications prioritised for maximum commercial impact rowth E® AYBUE 3 Angelman syndrome, Prader-Willi Syndrome, SYNGAP1, Rett syndrome (Acadia)*, Fragile X syndrome (Acadia)* NNZ-2591 (ercanetide) indications prioritised for maximum commercial impact Neuren Pharmaceuticals Limited Annual Report 2025 10
OPERATING REVIEW CONTINUED NNZ-2591 Placebo 160 80 80 Double-blind, 13 weeks NNZ-2591 Open label, 12 months Randomised 1:1 giving estimated 95% primary endpoint Screening Up to 4 weeks power for each coPHELAN-MCDERMID SYNDROME (PMS) Commencement of “Koala” - the first ever PMS Phase 3 program During 2025, Neuren agreed the primary endpoints for a single Phase 3 pivotal clinical trial of NNZ-2591 in PMS with the FDA. Alignment with FDA was previously reached on the other key features of the Phase 3 program at an End of Phase 2 Meeting. In the second half of 2025, Neuren initiated the first two sites in the US for the Koala Phase 3 trial and the first participants commenced dosing in February 2026. Koala is a Phase 3, randomized, double-blind, placebo-controlled clinical trial evaluating the safety and efficacy of NNZ-2591 in approximately 160 children aged 3 to 12 years with PMS. A screening period of up to 4 weeks is followed by treatment with NNZ-2591 or placebo for 13 weeks. All participants may be eligible to continue treatment with NNZ-2591 for 12 months in an open-label extension trial. Same age range (3-12) and same length of treatment (13 weeks) as Phase 2 ~20 trial sites, mostly in US Target dosing equivalent to dose tested in Phase 21 Program fully funded from existing cash 1 12.5 mg/kg per day in Phase 3 vs 12 mg/kg in Phase 2, and titration period two weeks in Phase 3 vs six weeks in Phase 2 Neuren Pharmaceuticals Limited Annual Report 2025 11
OPERATING REVIEW CONTINUED 1 NEU-2591-PMS-001: An Open-Label Study of the Safety, Tolerability, and Pharmacokinetics of Oral NNZ-2591 in Phelan-McDermid Syndrome – 13 weeks treatment of patients age 3-12 years at 4 US sites 2 Wilcoxon signed rank test – p-values are nominal without type 1 error control 3 Based on post hoc analysis of overall VABS-3 secondary endpoint The Koala trial co-primary endpoints will be the change from baseline in the Receptive Communication sub-domain of the Vineland Adaptive Behavior Scales, Third Edition (VABS-3 Receptive-Raw Score) and the overall score in the Phelan-McDermid Syndrome Assessment of Change (PMSA-C, previously referred to as CGI-I in Neuren’s Phase 2 trial). Both measures were robustly positive with clinically meaningful improvement in Neuren’s Phase 2 open-label clinical trial. 16 out of 18 children showed improvement measured by the VABS-3 Receptive-Raw Score, with mean improvement of 7.5 from a mean baseline of 29.0 (Wilcoxon signed rank test p=0.0001) and 16 out of 18 children showed improvement from baseline measured by the PMSA-C with a mean score of 2.4 (Wilcoxon signed NNZ-2591 was safe and well tolerated in Phase 2, with no clinically meaningful changes in safety parameters during treatment. Co-primary Endpoints in Phase 2 Results1 Phelan-McDermid Syndrome Assessment of Change (PMSA-C), previously referred to as CGI-I in Phase 2 16/18 subjects showed improvement Mean score: 2.4 (P < 0.00012) Receptive Communication sub-domain of the Vineland Adaptive Behavior Scales, 3rd Edition (VABS-3 Receptive-Raw Score) 16/18 subjects showed improvement Mean improvement: 7.5 (from baseline of 29.0)3 (P = 0.00012)3 Key Secondary Endpoint in Phase 2 Results1 Caregiver Impression of Change (CIC) score 15/18 subjects showed improvement Mean score: 2.7 (P < 0.00032) rank test p<0.0001). The endpoints pair the caregiver’s assessment of change in one important symptom area with the clinician’s assessment of change across multiple aspects of PMS. Communication is one of the most impactful health concerns in PMS reported by caregivers. Receptive communication, as measured by VABS-3 Receptive-Raw Score, is the ability to receive and understand non-verbal and verbal interactions which is a foundational skill for the development of learning, social interaction, and speech. The results of Neuren’s Phase 2 clinical trial have been published in the journal Neurology Genetics (NNZ-2591 in Children and Adolescents With Phelan-McDermid Syndrome | Neurology Genetics). Neuren Pharmaceuticals Limited Annual Report 2025 12
OPERATING REVIEW CONTINUED RESEARCH ARTICLE OPEN ACCESS NNZ-2591 in Children and Adolescents With Phelan-McDermid Syndrome Single-Group, Open-Label, Phase 2 Trial Results Ann M. Neumeyer, 1 Siddharth Srivastava, 2 J. Lloyd Holder, Jr., 3 Mark A. Milad, 4 Liza Squires, 5 Nancy Elizabeth Jones, 5 Larry Glass, 5 and Elizabeth Berry-Kravis 6 Neurol Genet 2026;12:e200338. doi:10.1212/NXG.0000000000200338 Correspondence Dr. Neumeyer ANEUMEYER@mgh.harvard.edu Abstract Background and Objectives Phelan-McDermid syndrome (PMS) is a rare genetic neurodevelopmental disorder with no currently approved treatments. NNZ-2591, a synthetic analog of the insulin-like growth factor 1 metabolite cyclic glycine-proline, was evaluated in children and adolescents with PMS in a phase 2, multisite, open-label clinical trial. Methods Participants aged 3–12 years at screening received twice-daily oral NNZ-2591 for 13 weeks; doses were uptitrated from 4 mg/kg to 12 mg/kg over 6 weeks (NCT05025241). Safety and pharmacokinetic profiles were primary end points; 14 efficacy assessments were secondary end points, which included global and symptom-specific PMS assessments, quality of life, communication, behavior, adaptive behavior/self-care, gastrointestinal health, and sleep assessments. Wilcoxon signed-rank tests evaluated change from or observed change relative to baseline vs the null median, with p < 0.05 indicating significance. Results Eighteen participants received NNZ-2591 (mean [SD] age 8.6 years, mean [SD] weight: 30.4 [10.8] kg). NNZ-2591 was well tolerated; most treatment-emergent adverse events were mild to moderate. Significant improvements from baseline were observed in 10 of 14 efficacy assessments at week 13, including global and symptom-specific PMS assessments, quality of life, behavior, gastrointestinal symptoms, and sleep. At week 13, the PMS-specific Clinical Global Impression (CGI) of Improvement mean (SD) score was 2.4 (0.9) and the median (range) score was 2.0 (1.0, 4.0) (p < 0.0001), with 16 of 18 participants showing improvement; the PMS-specific Caregiver Impression of Change mean (SD) score was 2.7 (1.0) and the median (range) score was 3.0 (1.0, 5.0) (p = 0.0003), with 15 of 18 participants showing improvement. PMS-specific assessment subdomains of communication, cognition/learning, and socialization showed consistent improvements. A 24-hour steadystate area under the curve (AUC 24,ss ) was estimated for each participant using a one-compartment, linear, population pharmacokinetic model where clearance and volume of distribution parameters were scaled by body weight. Participants with an NNZ-2591 AUC 24,ss > 300 μg × h/mL experienced improvements in the PMS-specific CGI of Improvement scores. Discussion For children and adolescents with PMS, NNZ-2591 appeared generally safe, with clinicians and caregivers reporting meaningful improvements in important symptoms of PMS. The benefitrisk and pharmacokinetic profiles support continued evaluation of NNZ-2591 for PMS. Trial Registration Information ClinicalTrials.gov; NCT05025241. Submitted August 24, 2021. First participant enrolled on August 8, 2022. 1 Lurie Center for Autism, Massachusetts General Hospital, Lexington, MA; 2 Department of Neurology, Rosamund Stone Zander Translational Neuroscience Center, Boston Children’s Hospital, Boston, MA; 3 Department of Pediatrics, Baylor College of Medicine, Houston, TX; 4 Milad Pharmaceutical Consulting, Plymouth, MI; 5 Neuren Pharmaceuticals, Camberwell, Australia; 6 Department of Pediatrics, Rush University Medical Center, Chicago, IL. This is an open access article distributed under the terms of the Creative Commons Attribution-Non Commercial-No Derivatives License 4.0 (CCBY-NC-ND), where it is permissible to download and share the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal. Copyright © 2025 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology. e200338(1) MORE ONLINE Supplementary Material Downloaded from https://www.neurology.org by 175.32.225.128 on 19 March 2026 Neuren Pharmaceuticals Limited Annual Report 2025 13
Congress reauthorised the Rare Pediatric Disease PRV program to 30 September 2029. This means that marketing approval by FDA of NNZ-2591 in PMS would qualify Neuren for a PRV, of which Neuren would retain 100% ownership and proceeds of any sale. Strong foundations built for NNZ-2591 Neuren has meticulously built strong foundations to enable late-stage clinical development of NNZ-2591: Clear and consistent efficacy in mouse models Studies in a shank3 mouse model compared normal mice (“wild type”) and mice with a disrupted gene (“knockout”). The knockout mice exhibit behavioural and biochemical deficits that mimic PMS in humans. The wild type mice and the knockout mice were each treated with placebo and NNZ2591. Treatment with NNZ-2591 for 6 weeks eliminated all the deficits so that the knockout mice were indistinguishable from the wild type mice. Treatment had no impact on the wild type mice which is important from a safety point of view. Blood-brain barrier penetration confirmed As well as very high oral bioavailability, good penetration of the blood-brain barrier by NNZ-2591 has been demonstrated in a rodent study. A single dose was administered at 2 dose levels, with the high dose twice the low dose. The concentration of NNZ-2591 in the blood and cerebrospinal fluid was determined after 1.5 hours and again after 4 hours. The amount in the brain tissue was also measured after 4 hours. In each case the concentration was approximately proportional to the dose and after 4 hours the concentration in blood and brain tissue was approximately equivalent. Large scale manufacturing process developed Neuren has successfully developed a proprietary process for manufacturing drug substance at large scale with exceptional purity and high yield. Positive Phase 1 and Phase 2 clinical trial results Neuren completed a Phase 1 clinical trial, in which twice daily oral dosing of NNZ-2591 for seven days was safe and well tolerated in healthy volunteers at doses expected to be within the effective therapeutic range. In an open label Phase 2 trial in PMS patients aged 3 to 12 years at four hospitals in the US, which examined safety, tolerability, pharmacokinetics and efficacy over 13 weeks of treatment with NNZ-2591, significant improvement was assessed by both clinicians and caregivers across multiple efficacy measures. Improvements were consistently seen across clinically important aspects of PMS, including communication, behaviour, cognition/learning and socialisation. OPERATING REVIEW CONTINUED Phelan-McDermid syndrome has an overwhelming unmet medical need PMS is caused by a deletion or other change in the 22q13 region of chromosome 22, which includes the SHANK3 gene, or a mutation of the gene. PMS is also known as 22q13 deletion syndrome. The SHANK3 gene codes for the shank3 protein, which supports the structure of synapses between nerve cells in the brain. PMS has severe quality of life impacts for those living with the syndrome, as well as parents and siblings. There are no approved treatments for PMS despite its severely debilitating impact. The estimated prevalence of PMS is 1% of people diagnosed with autism, or between 1 in 8,000 and 1 in 15,000 males and females.1 It has historically been underdiagnosed, but this is changing with rising awareness and enhancement of genetic testing technologies. In November 2022, an important Externally-Led Patient Focused Drug Development (ELPFDD) Meeting was held, in order for the FDA and other key stakeholders to hear directly from patients, their families, caregivers, and patient advocates about the impact PMS has on patients’ daily lives. The meeting content was collated in a “Voice of the Patient” report. In 2023 for the first time an International Classification of Disease (ICD) code was assigned to PMS. In October 2025 Neuren was granted Fast Track designation by the FDA for the PMS program. Neuren currently holds Rare Pediatric Disease designation for NNZ-2591 in PMS. In February 2026 the United States 1 Phelan McDermid Syndrome Foundation (PMSF) (www.pmsf.org) FROM THE PHELAN-MCDERMID SYNDROME VOICE OF THE PATIENT REPORT: “ PMS has an overwhelming unmet medical need. There are no FDA approved treatments for PMS despite its severely debilitating manifestations. Parents and caregivers are open to trying almost anything to try to relieve their child’s suffering; most have tried an incredibly high number of treatments and approaches for symptom management, with very little success. Some received medications that caused more harm than good.” “ PMS has severe quality of life impacts on those living with the disease, as well as on parents and siblings. Most activities of daily life, including communicating needs or wants, self-care (bathing, dressing, toileting) and socializing with peers/ siblings are affected. Most individuals living with PMS rely on their parents and caregivers for all their daily needs, and many require 24-hour care.” Neuren Pharmaceuticals Limited Annual Report 2025 14
Optimum dose identified In the PMS model, the effect of four escalating dose levels was investigated. The results of this dose ranging study were consistent across all 8 behavioral tests and the incidence of seizures, demonstrating that the second highest dose was the optimum dose level in the mouse model. Comparison with human pharmacokinetic data from the Phase 1 clinical trial has informed the equivalent human dose for the clinical trials in patients. A further observation was that the optimum dose in this 6-week study showed better efficacy than the same dose in an earlier study for 3 weeks, indicating that efficacy increases with treatment duration. OPTIMUM DOSE IN MOUSE MODEL OF PHELANMCDERMID 9 Memory Learning Sociability WT + vehicle KO + vehicle KO + x mg/kg KO + 2x mg/kg KO + 4x mg/kg KO + 8x mg/kg 0% 60% 50% 30% 10% 10% Incidence of seizures OPTIMUM DOSE IN MOUSE MODEL OF PHELANMCDERMID 10 Motor function Anxiety Repetitive behavior Daily living Daily living OPTIMUM DOSE IN MOUSE MODEL OF PHELANMCDERMID 10 Motor function Anxiety Repetitive behavior Daily living Daily living DOSE IN MOUSE MODEL OF PHELAN9 Learning Sociability e KO + vehicle KO + x mg/kg KO + 2x mg/kg KO + 4x mg/kg KO + 8x mg/kg 60% 50% 30% 10% 10% Incidence of seizures OPTIMUM DOSE IN MOUSE MODEL OF PHELANMCDERMID 10 Motor function Anxiety Repetitive behavior Daily living Daily living OPTIMUM DOSE IN MOUSE MODEL OF PHELANMCDERMID 10 Motor function Anxiety Repetitive behavior Daily living Daily living OPERATING REVIEW CONTINUED Neuren Pharmaceuticals Limited Annual Report 2025 15
Effects on biochemistry and brain cell structure confirmed Biochemical testing in the PMS model showed that the abnormal length of dendritic spines between brain cells, the excess activated ERK protein (pERK) and the depressed level of IGF-1 in the knockout mice were all normalised after treatment with NNZ-2591. PITT HOPKINS SYNDROME (PTHS) During 2025 Neuren was granted Fast Track designation by the FDA for the PTHS program and a new patent covering NNZ-2591 to treat PTHS was also granted by the US Patent and Trademark Office, with expected expiry in 2040. In early 2026 Neuren received feedback from the FDA regarding its clinical development plans for PTHS, which indicated that in a controlled trial to demonstrate efficacy of NNZ-2591 , a PTHS-specific clinical global impression (CGI) scale may be used as a co-primary endpoint if it is accompanied by an observer-reported functional outcome measure. This is similar to the approach that was agreed and is being implemented in Neuren’s ongoing Phase 3 trial in Phelan McDermid syndrome (PMS). Neuren is currently assessing alternative trial designs and endpoint analysis methodologies to accommodate that PTHS is significantly rarer and generally more profoundly disabling than PMS. Further interaction with the FDA will likely be required to finalise this assessment. Previously in 2024, Neuren announced positive top-line results from the Phase 2 clinical trial of NNZ-2591 in children with PTHS. After treatment for 13 weeks, 9 out of 11 children showed improvement assessed by clinicians and significant improvement was observed by both clinicians and caregivers in clinically important aspects of PTHS, including communication, social interaction, cognition and motor abilities. The estimated prevalence of PTHS is between 1 in 34,000 and 1 in 41,000 males and females.2 CORRECTING IMPAIRED SIGNALING IN NEURONS Correction of abnormal dendritic spines in mouse models: Left - Phelan-McDermid syndrome (shank3) Right - Fragile X syndrome (fmr1) Abnormal dendrites in shank3 knockout mice Correction in fmr1 knockout mice after treatment with trofinetide (NNZ-2566) Normalisation after treatment with NNZ-2591 OPERATING REVIEW CONTINUED 2 Pitt Hopkins Research Foundation (PHRF) (pitthopkins.org) Neuren Pharmaceuticals Limited Annual Report 2025 16
HYPOXIC ISCHEMIC ENCEPHALOPATHY (HIE) During 2025 Neuren initiated the development of NNZ-2591 for hypoxic-ischemic encephalopathy (HIE), a devastating type of brain injury caused when a baby’s brain does not receive enough oxygen or blood flow before or shortly after birth. Many thousands of babies and children experience HIE every year with estimated incidence rate of 2-3 in every 1,000 full-term births in high income countries and 10-30 per 1,000 live births in low and middle income countries.3 It is one of the leading causes of neonatal death and neurodevelopmental disability worldwide. Neuren believes NNZ-2591 can potentially provide a highly differentiated form of treatment continuing beyond acute treatment in the neonatal intensive care unit to target both the acute effects and chronic impairments resulting from HIE. In September 2025 Neuren commenced a formal partnership with Hope for HIE supporting development of NNZ-2591 to treat HIE. Hope for HIE is the global organisation connecting families, researchers, clinicians, biotech and more to improve the quality of life for children and families impacted by HIE. In February 2026 Neuren received feedback on its plan to submit an IND application for the treatment of HIE and the proposed initial clinical study of the pharmacokinetics, tolerability and safety of NNZ-2591 for one month in neonates and infants with HIE to open the IND. FDA generally accepted this IND-opening clinical study and the doses of NNZ-2591 to be evaluated, providing some guidance on the inclusion/exclusion criteria and safety monitoring. FDA requested that Neuren provides additional juvenile animal study data to support NNZ-2591 dosing in neonatal participants prior to initiating the clinical study. Neuren plans to generate this data before submitting the IND application and commencing the clinical study. In parallel Neuren is continuing to advance the logistical requirements for study execution. FDA also encouraged Neuren to submit a future meeting request to discuss appropriate endpoints, study population and safety monitoring for a subsequent study, which Neuren intends will support registration. OTHER POTENTIAL INDICATIONS The mechanism of action of NNZ-2591 is relevant for many other neurological conditions. Neuren previously announced positive top-line results from the Phase 2 clinical trial of NNZ-2591 in children with Angelman syndrome (AS). After treatment for 13 weeks, 11 out of 13 children showed improvement assessed by clinicians, with improvements seen in clinically important aspects of AS. In the 3-12 years age group all 8 children showed improvement. In 2025 Neuren added SYNGAP1-related disorder (SRD) into its neurodevelopmental disorders pipeline for NNZ-2591. SRD is caused by a variant on the SYNGAP1 gene located on Chromosome 6, which is responsible for producing the SYNGAP1 protein. The protein acts as a regulator in the synapses and insufficient production leads to impaired communication between neurons. This results in the many neurological issues seen in SRD patients including intellectual disability, low muscle tone, global development delay, epilepsy, sensory processing disorder, gross and fine motor skill delays, coordination disorder, speech delay, sleep and behavior disorder and autism spectrum disorder. In an in-vitro model of SRD in human iPSC-derived neurons, treatment with NNZ-2591 reversed the neuronal dysfunction caused by SYNGAP1 haploinsufficiency. As part of the expanded global partnership with Acadia signed in July 2023, Neuren granted Acadia exclusive worldwide licence for NNZ-2591 solely in Rett syndrome and Fragile X syndrome, which enabled coordinated global development and removed restrictions on Neuren for NNZ2591 in those two indications. Neuren retains worldwide rights to NNZ-2591 in all other indications. Potential future payments to Neuren related to NNZ-2591 in Rett syndrome and Fragile X syndrome are identical to the payments for trofinetide in each of North America and outside North America. Acadia is responsible for all costs of development and commercialization in those two indications. OPERATING REVIEW CONTINUED 3 Hope for HIE (Hope for HIE - Hypoxic Ischemic Encephalopathy) Neuren Pharmaceuticals Limited Annual Report 2025 17
OPERATING REVIEW CONTINUED The consolidated financial statements are presented on pages 32 to 55. All amounts in the consolidated Financial Statements are shown in Australian dollars unless otherwise stated. As shown in the table above, in 2025 royalty revenue of A$64.6 million was earned under the license agreement with Acadia, up 15% from A$56.2 million in 2024. Interest income was A$12.2 million (2024: A$11.0 million). In 2024 revenue from Acadia also included one-time sales milestone revenue of A$80.5 million, as DAYBUE net sales for the year in North America exceeded US$250 million, and one-time revenue from Neuren’s share of Priority Review Voucher sale proceeds of A$76.5 million. Other income includes a foreign currency gain of A$8.0 million mainly due to the translation of cash and short-term investments held in Australian dollars to the US dollars functional currency (2024: A$7.2 million loss). In 2024, there was a A$3.6 million gain on the fair value of outstanding forward contracts to sell Australian dollars and buy US dollars. Research and development costs increased by A$3.4 million to A$36.4 million for 2025, with higher expenditure due to the start-up of the Phase 3 trial of NNZ-2591 in PMS. Corporate and administrative costs of A$6.2 million in 2025 increased by A$1.5 million from the prior period, mainly due to increased share-based payments expense relating to new share options issued during 2025. A loss of A$3.3 million on the fair value of outstanding forward contracts to sell Australian dollars and buy US dollars was recognised in 2025 (2024: A$3.6 million gain). Income tax expense for 2025 was A$8.5 million (2024: A$40.9 million). The Group’s net profit after income tax for the year ended 31 December 2025 was A$30.4 million (2024: A$142.0 million). FINANCE Summary Financials 2025 $’m 2024 $’m Royalty income 64.6 56.2 Interest income 12.2 11.0 76.8 67.2 One-time revenue from first sales milestone – 80.5 One-time revenue from sale of Priority Review Voucher – 76.5 – 157.0 Foreign currency gains 8.0 3.6 Total income 84.8 227.8 Research & Development costs (36.4) (33.0) Corporate & Administration (6.2) (4.7) Foreign currency losses (3.3) (7.2) Profit before income tax expense 38.9 182.9 Income tax expense (8.5) (40.9) Profit after tax expense 30.4 142.0 Cash and short-term investments at 31 December 296.1 222.2 Cash flow (used in)/received from operations 125.4 (11.3) Cash flow (used in)/ from financing (33.2) (8.8) Neuren Pharmaceuticals Limited Annual Report 2025 18
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