Announcement PDF Investor Presentation 8 November 2023 IMPROVING THE LIVES OF PEOPLE WITH NEURODEVELOPMENTAL DISABILITIES Pa g e□ 1 Forward looking statements This presentation contains forward looking statements that involve risks and uncertainties. Although we believe that the expectations reflected in the forward looking statements are reasonable at this time, Neuren can give no assurance that these expectations will prove to be correct. Actual results could differ materially from those anticipated. Reasons may include risks associated with drug development and manufacture, risks inherent in the regulatory processes, delays in clinical trials, risks associated with patent protection, future capital needs or other general risks or factors. 2 Leadership in neurodevelopmental disorder therapy development Developing new therapies for debilitating neurodevelopmental disorders that emerge in early childhood and are characterised by impaired connections and signalling between brain cells World’s Clinical development in 1st and only approved therapy for Rett Syndrome 1 5 more neurodevelopmental disorders, all with Orphan Drug designation, with no existing approved therapies2 no royalties payable to 3rd parties Incorporated in New Zealand, based in Melbourne, Australia, listed on ASX (Code: NEU) 1 Currently approved in US only 2 Except growth hormone to treat some aspects of Prader-Willi syndrome 3 Seeking a ground-breaking impact on neurodevelopmental disorders Rett Fragile X Phelan-McDermid Angelman Pitt Hopkins Prader-Willi MECP2 FMR1 SHANK3 UBE3A TCF4 15q11-q13 Impaired communication between neurons, abnormal formation/pruning of dendrites & chronic inflammation Neuren’s drugs target the critical role of IGF-1 in this upstream process, using analogs of peptides that can be taken orally as liquids Severe impact on nearly every aspect of life walking and balance issues anxiety and hyperactivity seizures speech impairment intellectual disability breathing irregularities impaired hand use sleep disturbance gastrointestinal problems 4 Attractiveness of Orphan Drug model Neuren is targeting multiple “rare diseases”, but they are not “ultra-rare” • 1 2 Incentivise rare disease drug development Priority review by regulators (e.g. 6 months in US instead of 10 months) and higher probability of approval • 3 4 Marketing exclusivity periods protect against generics independent of patents (7.5 years in US, 12 years in EU, 10 years in Japan, South Korea and Taiwan, China has proposed to introduce 7 years) • • Urgent unmet need results in strong engagement from patient community and leading physicians, and immediate access to known patients Attractive pricing environment 5 Commercial and late-stage pipeline Indication Rett Compound Trofinetide Geography Phase 1 Phase 2 Phase 3 Registration Commercial rights US RoW NNZ-2591 World Trofinetide World NNZ-2591 World PhelanMcDermid NNZ-2591 World Pitt Hopkins NNZ-2591 World Angelman NNZ-2591 World PraderWilli NNZ-2591 World Fragile X Preclinical Phase 2 topline results in Dec 2023 6 Financial strength to maximise growth opportunities DAYBUE Net Sales (US$m) Royalty to Neuren (A$m) 13.7 88 48.1 3.5 23 Q2 2023* 135.3 12.5 10.4 80 67 Neuren cash flows from operating activities (A$m) Q3 2023 Q4 2023 Acadia Guidance Q2 2023* Q3 2023 (based on actual net sales)^ Q4 2023 (based on Acadia Guidance)^ -3.2 Q1 2023 Q2 2023 Q3 2023 Cash balance 30 Sep 2023E net sales of US$170m – US$178m 2023E royalty of A$26m – A$28m A$230m * Since launch to 30 Jun 2023 ^ Based on 10% of DAYBUE net sales and AUDUSD of 0.6433 for Q3 and 0.6400 for Q4 7 Ongoing value creation with significant upside NEU 1H 2023 DAYBUE launched in US DAYBUE's successful launch A$ evidenced by consecutive 25.00 quarterly sales since launch all beating 23.00 expectations 21.00 NEU and Acadia expands global partnership for trofinetide 19.00 Average Broker Valuation 6 Nov: A$21.03 (A$17.50 – A$24.56) 17.00 15.00 13.00 11.00 FDA approval of DAYBUE Share price 6 Nov: A$12.78 9.00 7.00 5.00 Jan-23 Feb-23 Mar-23 Apr-23 May-23 Jun-23 Jul-23 Aug-23 Sep-23 Oct-23 Nov-23 Historical average broker valuation include Bell Potter, E&P, Jefferies, MST (until 14 Jul 2023), Petra and Wilsons (since 2 Mar 2023) 8 Three key drivers transforming near term value 1 3 Realise Neuren’s share of trofinetide value in the US through Acadia’s successful commercialization of Confirm efficacy of NNZ-2591 in Phase 2 trials for four valuable indications, with global rights retained by Neuren 2 Realise Neuren’s share of trofinetide ex-US value through expanded global partnership with Acadia First top-line results in Dec 2023 for Phelan-McDermid syndrome 9 Trofinetide 10 Trofinetide North America – DAYBUE™ US launch in April 2023 Potential Rett patients US Economics to Neuren: 6,000 - 9,0001  US$10m upfront in 2018 4,5001 Currently identified Rett patients DAYBUE Net Sales (US$m) 67  US$40m in Q2 2023 following 1st commercial sale in the US 88 US$33m one third share of Priority Review Voucher awarded to Acadia (assuming market value US$100m) 80 US$55m Milestone payments related to Fragile X 23 Q2 2023*  US$10m in 2022 following acceptance of NDA for review Tiered Royalty Rates (% of net sales)2 Q3 2023 Q4 2023 Acadia Guidance 2023E net sales of US$170m – US$178m * Since launch to 30 Jun 2023 1 Acadia estimates 2 Royalty rates payable on the portion of annual net sales that fall within the applicable range Sales Milestones Annual Net Sales Rates Net Sales in one calendar year ≤US$250m 10% ≥US$250m 50 >US$250m, ≤US$500m 12% ≥US$500m 50 >US$500m, ≤US$750m 14% ≥US$750m 100 >US$750m 15% ≥US$1bn 150 US$m 11 Exceptional DAYBUE US launch – as of Acadia Q3 results announcement Strong and broad-based demand • 800 patients on DAYBUE as at 30 Sep 20231 • Surge in initial demand has exceeded pre-launch expectations • 81% of patients remain on therapy 4 months after starting treatment2 • Clinical efficacy, medical education and GI management measures have produced significant benefits • 75-80% compliance to labeled dose at 3 months • 80% of covered lives covered by formal plans, up from • 70%+ in September • ~33% in August • 20% in July 1 Net of any discontinuations 2 Measured by confirmed discontinuations only Positive caregiver testimonials “Her feet are much closer together with a more normal gait… When she's standing her feet are at less than a 45 degree angle now, so even in one day, there was a great improvement in the way she walks.” “She is using her right hand more. She’s able to raise her right arm and help caregivers put on her shirt, and touch her nose and head using her right hand when previously she did not use this hand at all.” “Her speech has improved and she’s able to communicate with people more, as well as make better eye contact.” “[She] is able to communicate more with her eyes. She will look at her cup and then back at caregiver, and when given water will gulp it down. She also looked at her empty tray as if to ask for food.” “She is more alert, communicates better and her motor skills have improved.” 12 Trofinetide outside North America – expansion of Acadia partnership Transaction in July 2023 leverages Acadia’s unique knowledge and expertise from successful DAYBUE development and commercialization in the US and the established supply chain; Acadia responsible for all costs Economics to Neuren:  US$100m upfront 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 Europe Japan Other Potential Rett patients 9,000 14,0001 2,000 3,0001 ~30,0002 Currently identified Rett patients ~4,0002 ~1,0002 ~2,0002 Sales milestones On achievement of escalating annual net sales thresholds: Europe: up to US$170m Japan: up to US$110m RoW: up to US$83m Tiered royalties Mid-teens to low-20s % of net sales 1 Acadia estimates 2 Neuren estimates based on prevalence studies and patient organisations 13 NNZ-2591 14 5x larger opportunity for NNZ-2591 Potential patients Disorder Gene mutation Published prevalence estimates US1 Europe1 RoW1, 2 PhelanMcDermid SHANK3 1/8,000 to 1/15,000 males and females 24,000 31,000 103,500 Pitt Hopkins TCF4 1/34,000 to 1/41,000 males and females 6,000 8,000 28,000 Angelman UBE3A 1/12,000 to 1/24,000 males and females 16,000 20,000 66,000 Prader-Willi 15q11-q13 1/10,000 to 1/30,000 males and females 17,000 21,000 72,000 63,000 80,000 270,000 • Current opportunity for NNZ-2591 is more than 5 times the Rett Syndrome opportunity3 • There are many other neurodevelopmental disorders potentially relevant for NNZ-2591 mechanism of action • Rett and Fragile X syndromes are licensed to Acadia, with same economics to Neuren as trofinetide; Neuren retains worldwide rights to all other indications 1 Estimates derived by applying the mid-point of the prevalence estimate range to the populations under 60 years 2 RoW comprises Japan, China (urban population), Brazil, Israel, South Korea, Australia and New Zealand 3 Based on number of potential patients globally 15 NNZ-2591 has ideal attributes leading into Phase 2  Novel mechanism of action  Clear and consistent efficacy in mouse models of each syndrome  Biochemical effects in the brain confirmed  Optimum dose identified  Demonstrated high oral bioavailability and blood-brain barrier penetration  IND-enabling program of non-clinical toxicology and CMC studies completed  Proprietary drug substance manufacturing process with exceptional purity and high yield, administered as patient-friendly liquid dose  Safe and well tolerated in Phase 1 trial  Orphan designations from FDA and EMA  INDs approved by FDA for Phelan-McDermid, Angelman, Pitt Hopkins and Prader-Willi syndromes 16 Key features of first Phase 2 trials Overall aim – expedite data that informs the design of subsequent registration trials and prepare for Phase 3 in parallel • Prioritising speed to data • Maximising opportunity to demonstrate effects • • • Confirm safety and PK in pediatric patients PhelanMcDermid Pitt Hopkins Angelman Prader-Willi n subjects Up to 20 Up to 20 Up to 20 Up to 20 Age range 3 to 12 3 to 17 3 to 17 4 to 12 Location US US Australia US Assess treatment impact across multiple efficacy measures to select primary endpoint for registration trial First top-line results in Dec 2023 for PhelanMcDermid syndrome NNZ-2591 treatment Baseline observation Week 0 Follow-up Up-titration Week 4 Week 10 Week 17 Week 19 Phase 3 preparation Non-clinical toxicity studies and optimisation of drug product and drug substance manufacturing 17 Phelan-McDermid syndrome has an overwhelming unmet medical need Cause of the syndrome Deletion or variation in the SHANK3 gene on chromosome 22 Broad and severe impact on life Intellectual impairment Behavioural issues Sleep disorders Seizures (~40% of patients) Absent or delayed speech Feeding difficulties Motor delays Low muscle tone SHANK3 protein plays a role in the formation, maintenance and function of dendrites and synapses Sweat less, risk of overheating High pain tolerance Difficulties toilet training (~3/4 of patients) GI dysfunction (most commonly constipation) Walking abnormalities Frequent hospitalization and heightened risk of accidents From Voice of the Patient Report Externally-Led Patient-Focused Drug Development Meeting 8 Nov 2022 “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.” 18 Historically under-diagnosed, but this is changing Estimated prevalence is 1% of people with autism - 1/8,000 to 1/15,000 males and females1 Potential PMS patients US Europe Japan China Other2 17,000 – 32,0003 21,000 – 41,0003 5,000 - 9,0003 51,000 – 95,0003 16,000 - 31,0003 Phelan-McDermid Syndrome Foundation members 2,937 Currently 3,216 1,739 US members 3,106 2,688 2,394 2,108 1,735 1,437 1,239 75% of PMS patients have been diagnosed with an ASD ~1% of autism patients have SHANK3 mutations 1,002 2014 Opportunity to accelerate diagnosis 2017 2020 2023 • Rising awareness • EL-PFDD meeting with FDA in 2022 • ICD code assigned in 2023 • Enhanced genetic testing technologies • Expanding ADDM network sites Autism US ADDM tracks 440k children with autism spectrum disorder 1 Phelan McDermid Syndrome Foundation (PMSF) (www.pmsf.org) 2 Brazil, Israel, South Korea, Australia and New Zealand 3 Estimates based on United Nations population data 2022, derived by applying the estimated prevalence range to the populations under 60 years (urban population only for China) 19 Phelan McDermid syndrome affects all genders and ages % currently diagnosed patients by gender1 % currently diagnosed patients by age group1 34% 36% 29% 48% 17% 52% 15% 16% 13% 12% 9% 5% 5% 5% 4% 1% Male Female < 12 m 1-2 yrs 3-4 yrs 5-10 yrs 11-20 yrs21-30 yrs31-40 yrs41-60 yrs Patients current age 60+ When first diagnosed 1 Estimates based on survey of participants in the Externally-Led Patient Focused Drug Development (EL-PFDD) meeting on Phelan-McDermid Syndrome 8 Nov 2022 20 Neuren has opportunity to achieve first approved treatment in PMS Phase 2 data imminent • Results expected in December 2023 • Orphan Drug designation in US and EU • Phase 2 clinical development in the US under an IND • Eligible for Rare Pediatric Disease Designation Priority Review Voucher program Limited products in development Company Neuren collaborating with all stakeholders Product Development Stage Phase 2 results in Dec 2023 #2 Phase 2 terminated early #3 Phase 1 #4 Pre-clinical #5 Pre-clinical Leading clinicians 21 Neuren’s Phase 2 trial in children with Phelan-McDermid syndrome First study in pediatric patients, collecting the data needed to design a registration study 4 US sites: Rush University, Massachusetts General Hospital, Boston Children’s Hospital and Texas Children’s Hospital n subjects: Up to 20 Age range: 3 to 12 NNZ-2591 treatment Baseline observation Week 0 Up-titration Week 4 Week 10 Secondary endpoints Primary endpoints Safety, tolerability and PK + Follow-up Range of efficacy measures collecting information from clinicians and caregivers on overall change in PMS (e.g. CGI-I), change in specific aspects of PMS (e.g. communication and behaviour) and quality of life Week 17 Week 19 Enables selection of the best primary efficacy endpoint or endpoints for a registration study 22 Consistent efficacy & clear dose response for NNZ-2591 in shank3 model Memory Learning Sociability Repetitive behavior Daily living Daily living Incidence of seizures 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% Abnormal dendrites in shank3 knockout mice cells in culture (pg/ml) Anxiety pERK Motor function length (µm) In biochemical testing, NNZ-2591 was shown to normalise the abnormal length of dendrite spines between brain cells, the excess activated ERK protein (pERK) and the depressed level of IGF-1 in shank3 knockout mice Normalisation after treatment with NNZ-2591 23 Consistent efficacy in models of Pitt Hopkins, Angelman and Prader-Willi Hypoactivity & anxiety Daily living Sociability Daily living Motor Cognition Angelman Hypoactivity Daily living Learning & Memory Sociability Repetitive behavior Motor performance Pitt Hopkins Obesity Circulating IGF-1 levels Cognition Hypoactivity Hypoactivity Daily living Social preference Social interaction Anxiety PraderWilli 24 Highlights 25 Highlights 1 2 DAYBUETM (trofinetide) approved by US FDA as the first and only treatment for Rett syndrome, launched by partner Acadia in Apr 2023 4 Accelerating Phase 2 development of NNZ-2591 in 4 indications, with potential markets 5x Rett syndrome. First top-line results in Dec 2023 3 Total economics to Neuren from global trofinetide partnership with Acadia up to US$1bn1 plus 10 to low 20s % royalties 5 Successful DAYBUE US launch, with expected net sales of US$170m–178m2 in 2023 6 NNZ-2591 novel mechanism of action has many more potential applications, with Rett and Fragile X licensed to Acadia A$230m cash at 30 Sep 2023 – well positioned to maximize the benefits of all value creating opportunities 1 Including payments already received and future payments 2 Q2 actual net sales of US$23m, Q3 actual net sales of US$67m and Q4 net sales guidance of US$80m – US$88m 26 CONTACT Jon Pilcher, CEO jpilcher@neurenpharma.com +61 438 422 271 27 Novel mechanisms of action - trofinetide Trofinetide • Trofinetide is an investigational drug and a novel synthetic analog of GPE, the aminoterminal tripeptide of IGF-1 Proposed Mechanism of Action1 Rett syndrome features: • Insufficient formation of new synapses by neurons • Excessive pruning of existing synapses by overactive microglia Trofinetide is thought to: • Improve synaptic function and restore synaptic structure • Inhibit overactivation of inflammatory microglia and astrocytes • Increase the amount of IGF-1 in the brain GPE=glycine-proline-glutamate; IGF-1= Insulin-like growth factor 1 1 Chahrour, Science, 2008; Itoh, J Neuropath Exp Neurol, 2007; Bourguignon, Brain Res, 1999; Tropea, PNAS, 2009 Source: Acadia Lavender Study Results Presentation https://ir.acadia-pharm.com/static-files/84457c64-60ab-4b2f-a166-edc1d465f4a8 28 Sustained and continued improvement observed in trials RSBQ Baseline LAVENDER (12 weeks) Placebocontrolled LILAC (40 weeks) Open-label extension Dose Group RSBQ mean change (12 wks) Dose Group Trofinetide -5.1 Trofinetide Placebo -1.7 RSBQ mean change from Lavender baseline to end of Lilac (52 wks) n/a CGI-I Score (at 12 wks) Trofinetide 3.5 Placebo 3.8 New Lilac Baseline CGI-I Lavender Baseline Trofinetide Dose Group -7.3 Dose Group Trofinetide -7.0 CGI-I Score (at 40 wks) 3.1 n/a Trofinetide RSBQ scores improved ≥7 points from Lavender baseline 3.2 CGI-I improvements:  Trofinetide group: 0.5 improvement in Lavender, then 0.9 improvement in Lilac  Trofinetide crossovers: 0.8 improvement in Lilac Source: Acadia presentation (Acadia Corporate Presentation (4Q22 Earnings), Lavender Study Results (acadia.com)) RSBQ: n=161 for Lavender at 12 weeks; n=88 for Lilac at 40 weeks. CGI-I: n=163 for Lavender at 12 weeks; n=91 for Lilac at 40 weeks. CGI-I uses a 7-point Likert scale; a score of 4 = no improvement; >4 = worsening and <4 = improvement. 29 Novel mechanisms of action – NNZ-2591 Reversible binding regulates bioavailability IGF-1 Produce essential growth factor Activates PI3K-AktmTOR and Ras-MAPKERK signaling pathways in neurons, regulating formation of new synapses IGF-1 receptor on cell surface • NNZ-2591 is a synthetic analog of cyclic glycine proline, a peptide that occurs naturally in the brain, designed to be more stable, orally bioavailable and readily cross the blood-brain barrier • NNZ-2591 can regulate the amount of IGF-1 that is available to activate IGF-1 receptors • The effects of NNZ-2591 are “state-dependent” – correcting impairment, but not impacting normal cells IGF Binding Protein‐3 Competitively binds to binding protein, regulating IGF-1 binding1 NNZ-2591 1 doi: 10.1038/srep04388: Guan et al, 2017: Cyclic glycine-proline (cGP) regulates IGF-1 homeostasis by altering the binding of IGFBP-3 to IGF-1 30