Announcement PDF Corporate Presentation 29 May 2024 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 MECP2 Fragile X FMR1 Phelan-McDermid Angelman SHANK3 UBE3A Pitt Hopkins TCF4 Prader-Willi 15q11-q13 Neuren’s drugs Impaired communication between neurons, abnormal formation/pruning of dendrites & chronic inflammation 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 Impaired communication intellectual disability Impaired social interaction impaired hand use sleep disturbance gastrointestinal problems 4 Commercial and late-stage pipeline Indication Compound Trofinetide Rett Geography Preclinical Phase 2 Phase 3 Registration Commercial rights US RoW NNZ-2591 World Trofinetide World NNZ-2591 World Phelan-McDermid NNZ-2591 World Positive Phase 2 results Pitt Hopkins NNZ-2591 World Positive Phase 2 results Angelman NNZ-2591 World Phase 2 top-line results in Q3 2024 Prader-Willi NNZ-2591 World Undisclosed Indications NNZ-2591 World Fragile X 5 Financial strength to maximise growth opportunities A$m 2023 Profit After Tax A$157.1m 6 Growing sustainable income from commercialised product DAYBUE Net Sales (US$m) Royalty and Sales Milestone Payments to Neuren (A$m) 420 147 138 370 87 70 177 80-87.5 61 67 21-23 23 Q2 2023 # 76-82 45-55 76 13 27 10 12 4 Q3 2023 Q4 2023 CY2023 Q1 2024 CY2024 Acadia Guidance Q2 2023 Q3 2023 Q4 2023 CY2023 Q1 2024E~ Royalty only* Royalty + Sales Milestone^ Historical Acadia guidance CY2024 2023 net sales of US$177m 2024E net sales of US$370 – 420m 2023E royalty of A$27m 2024E royalty of A$61 – 70m, plus A$77m sales milestone ~ Based on 10% of DAYBUE net sales and AUDUSD of 0.652294 * Based on 10% of DAYBUE net sales up to US$250m and 12% of DAYBUE net sales between US$250m and US$500m, and AUDUSD of 0.65 ^ Neuren will be entitled to US$50m sales milestones (receivable in Q1 2025) if CY2024 DAYBUE net sales reaches US$250m; assumes AUDUSD of 0.65 7 Three key drivers transforming near term value Realise Neuren’s share of 1 trofinetide 3 value in the US through Acadia’s successful commercialization of Confirm efficacy of NNZ-2591 in Phase 2 trials for multiple indications, with global rights retained by Neuren  Positive top-line results for Phelan-McDermid syndrome 2 Realise Neuren’s share of trofinetide ex-US value through expanded global partnership with Acadia  Positive top-line results for Pitt Hopkins syndrome • Top-line results for Angelman syndrome in Q3 2024 8 DAYBUE / Trofinetide 9 North America – DAYBUE US launch in April 2023 Potential Rett patients Currently identified Rett patients US Canada Economics to Neuren: 6,000 9,0001 600 - 9001  US$10m upfront in 2018 5,0001 NDS accepted for priority review, potential approval around year-end 20243 As of 3 May 2024: >1,300 patients initiated therapy, 862 active on therapy  US$40m in Q2 2023 following 1st commercial sale in the US US$33m one third share of Priority Review Voucher awarded to Acadia (assuming market value US$100m) US$55m Milestone payments related to Fragile X 420 Tiered Royalty Rates (% of net sales)2 370 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$1bn 150 DAYBUE Net Sales (US$m) 177 CY2023  US$10m in 2022 following acceptance of NDA for review CY2024 Acadia Guidance 1 Acadia estimates 2 Royalty rates payable on the portion of annual net sales that fall within the applicable range Sales Milestones US$m 3 Acadia First Quarter 2024 Earnings Call presentation in May 2024 10 Meaningful real world benefits reported LILAC-2 Caregiver Exit Interviews1 Area/type of improvement with trofinetide reported by ≥15% of caregivers, n (%) Real World Experience1 Caregivers N=25 (%) Engagement with others 11 (42.3) Hand use 10 (38.5) Eye gaze 8 (30.8) Attention/focus/concentration 7 (26.9) Tobii eye trackers use 7 (26.9) Ability to make sounds 6 (23.1) Happier mood or disposition 6 (23.1) Ability to walk 5 (19.2) Alertness 5 (19.2) New words 5 (19.2) Seizures 4 (15.4) Aware of environment 4 (15.4) Repetitive hand movements 4 (15.4) “It was her engagement level with the world outside of her – to me and to friends in school; it just blossomed, and it was like a light was turned on.” “Her verbalization definitely improved, and she started saying more things.” “Picking up things a lot more (mostly her cup), happens daily and she is now trying to drink by herself.” “Improved cognitive ability, and [the parents] are hearing new words or words they have not heard in a while.” 1 Acadia Fourth Quarter and Full Year 2023 Earnings Call presentation in Feb 2024 11 Persistency rates improving in new patient cohorts Persistency Rates (Based on confirmed discontinuations and patients who were 60 days past their scheduled refill) 80% 75% 66% 76% 64% 68%70% Acadia estimates 63% 58% 58% 51% 50% 50% 47% 40% n.a. Month 4 Month 5 Month 6 Lilac clinical trial experience n.a. n.a. n.a. n.a. Month 7 Month 9 Long term Previously presented real world 1 Feb-24 May-24 2 1 Acadia Fourth Quarter and Full Year 2023 Earnings Call presentation in Feb 2024 2 Acadia First Quarter 2024 Earnings Call presentation in May 2024 12 Outside North America Economics to Neuren: Europe Japan Other Potential Rett patients 9,000 14,0001 1,000 2,0001 ~30,0002 Currently identified Rett patients ~4,0002 ~800 1,0002 ~2,0002  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: Pediatric investigation plan (PIP) filed with and accepted by EMA, with a potential Marketing Authorisation Application filing in Q1 20253 • Japan: Formal meeting with Japanese regulatory agency (PMDA) scheduled in 2Q24 to discuss clinical plan3 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 3 Acadia First Quarter 2024 Earnings Call presentation in May 2024 13 NNZ-2591 14 Regulating IGF-1 in the brain 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 15 Multiple indications opportunity for NNZ-2591 Pitt Hopkins syndrome NNZ-2591 PhelanMcDermid syndrome Angelman syndrome (Q3 2024) • Prader-Willi syndrome Positive results from Phelan McDermid syndrome and Pitt Hopkins syndrome Phase 2 trials • Other undisclosed indications Top-line results from Angelman syndrome Phase 2 trial expected in Q3 2024 • Rett syndrome (Acadia) End of Phase 2 meeting with FDA for Phelan McDermid syndrome planned Q3 2024 • The mechanism of action of NNZ-2591 is relevant for many other neurodevelopmental synaptopathies • Rett and Fragile X syndromes are licensed to Acadia, with same economics to Neuren as trofinetide; Neuren retains worldwide rights to all other indications Fragile X syndrome (Acadia) 16 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, Pitt Hopkins, Angelman and Prader-Willi syndromes 17 Clear efficacy and dose response in Phelan-McDermid syndrome model Memory Learning Sociability Daily living Daily living Repetitive behavior (pg/ml) Anxiety pERK Motor function length (m) In biochemical testing, NNZ-2591 was shown to normalize the abnormal length of dendritic spines that form the synapse, the excess activated ERK protein (pERK) and the depressed level of IGF-1 in shank3 knockout mice Incidence of audiogenic 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 Normalization after treatment with NNZ-2591 18 Consistent efficacy in Pitt Hopkins, Angelman and Prader-Willi models Hypoactivity Daily living Learning & Memory Hypoactivity & anxiety Daily living Daily living Sociability Repetitive behavior Motor performance Pitt Hopkins Sociability Motor Cognition Angelman Obesity Circulating IGF-1 levels Cognition Hypoactivity Hypoactivity Daily living Social preference Social interaction Anxiety PraderWilli 19 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 NNZ-2591 treatment Screening /Baseline Week 0 Follow-up Up-titration to 12 mg/kg BID Week 4 Week 10 Week 17 Week 19 Phase 3 preparation Non-clinical toxicity studies and optimisation of drug product and drug substance manufacturing • Prioritising speed to data and maximising opportunity to demonstrate effects • Confirm safety and PK in pediatric patients • Assess treatment impact across multiple efficacy measures to select primary endpoint for registration trial • Positive results for Phelan-McDermid syndrome and Pitt Hopkins syndrome • Top-line result for Angelman syndrome in Q3 2024 • Manufacturing for Phase 3 commenced 20 Phase 2 trial results validating multi-indication platform Phelan-McDermid syndrome N=18, 13 weeks Pitt Hopkins syndrome N=11, 13 weeks General safety & tolerability Safe and well tolerated, with no meaningful trends in laboratory values or other safety parameters during treatment Safe and well tolerated, with no meaningful trends in laboratory values or other safety parameters during treatment Serious TEAEs 1 unrelated to drug 0 Mean CGI-I 2.4 (89% shown improvement) 2.6 (82% shown improvement) Mean CIC 2.7 (83% shown improvement) 3.0 (73% shown improvement) # patients had CGI-S improvement of 1 7 (39%) 6 (55%) # syndrome-specific efficacy measures statistically significant1 5/5 4/4 1 Wilcoxon signed rank test 21 PhelanMcDermid syndrome (PMS) 22 PMS has 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) Language deficits 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.” 23 PMS is 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 Currently 3,106 members Opportunity to accelerate diagnosis 3,584 1,739 US 2,688 2,937 2,394 2,108 1,735 1,002 1,239 1,437 2014 2015 2016 2017 2018 2019 2020 2021 2022 2023 75% of PMS patients have been diagnosed with an ASD ~1% of autism patients have SHANK3 mutations • 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) 24 PMS 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 25 Neuren is leading development of a first approved treatment for PMS Phase 2 Program Status • • • • Phase 2 clinical development in the US under an IND Limited products in development Company End of Phase 2 Meeting with FDA planned Q3 2024 Orphan Drug designation in US and EU Eligible for Rare Pediatric Disease Designation Priority Review Voucher program Neuren engaging with all stakeholders Product Development Stage Positive Phase 2 trial #2 Phase 2 trial closed Jan 2021 #3 Phase 1 #4 Phase 1 #5 Pre-clinical Leading clinicians 26 Neuren’s Phase 2 trial in children with PMS 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: 18 Age range: 3 to 12 (mean 8.6) Endpoints • • Primary endpoints are safety, tolerability and PK A key objective is selection of the best primary efficacy endpoint or endpoints for a registration study Week 17 Week 10 PMS specific efficacy measurements Symptom Specific Communication Global • CGI-I • Caregiver Impression of Change (CIC) Secondary endpoints include 14 efficacy measurements • • CGI-S • GI Health • GIHQ Follow-up Up-titration to 12 mg/kg BID Week 4 Week 0 • NNZ-2591 treatment Screening /Baseline PMS Clinician Domain Specific Rating Scale Caregiver Top 3 Concerns • MB-CDI • ORCA Quality of Life • QI-Disability • ICND Sleep • CSHQ Week 19 Behaviour • Aberrant Behavior Checklist-2 • Behavior Problems Inventory • Vineland Adaptive Behavior Scales 27 Phase 2 clinical trial results highlights • NNZ-2591 was safe and well tolerated, with no clinically significant changes in laboratory values or other safety parameters during treatment • Significant improvement was assessed by both clinicians and caregivers across multiple efficacy measures • Improvements were consistently seen across clinically important aspects of Phelan-McDermid syndrome, including communication, behaviour, cognition/learning and socialisation • Clinician and caregiver global efficacy measures showed a level of improvement typically considered clinically meaningful: • • PMS Clinical Global Impression of Improvement (CGI-I) – mean score of 2.4 with 16 out of 18 children showing improvement assessed by clinicians • PMS Caregiver Overall Impression of Change (CIC) – mean score of 2.7 with 15 out of 18 children showing improvement assessed by caregivers For 10 out of 14 efficacy endpoints, improvement from baseline on overall/total scores was statistically significant (p<0.05)1 1 Wilcoxon signed rank test 28 Safety and tolerability summary NNZ-2591 was safe and well tolerated TEAEs in 2 or more subjects ✓ Well tolerated Event N=18 n (%) Event N=18 n (%) 1 Serious TEAE (gastroenteritis) not related to study drug, occurred during safety follow-up period after end of treatment Constipation 2 (11.1) Somnolence 3 (16.7) Diarrhea 2 (11.1) Pyrexia 3 (16.7) Nausea 2 (11.1) Fatigue 2 (11.1) 3 discontinuations due to TEAEs not related to study drug: 2 due to testing positive for COVID-19 and 1 due to seizures Vomiting 2 (11.1) Aggression 2 (11.1) COVID-19 3 (16.7) Insomnia 2 (11.1) Nasopharyngitis 2 (11.1) Decreased Appetite 3 (16.7) Otitis Media 2 (11.1) Rhinorrhea 2 (11.1) Psychomotor Hyperactivity 4 (22.2) ✓ Most Treatment Emergent Adverse Events (TEAE) were mild to moderate • • ✓ No clinically significant changes in laboratory values, electrocardiogram (ECG) or other safety parameters were observed during treatment 29 Efficacy endpoints summary Efficacy measures and p-values1 (Total/Overall scores) Behaviour Global • Statistically significant improvement vs baseline in 10/14 efficacy endpoints • • CGI-I 2.4 Mean of and Median of 2.0 with p-value <0.0001 CIC 2.7 Mean of and Median of 3.0 with p-value =0.0003 CGI-I <0.0001 CIC 0.0003 CGI-S 0.0156 GI Health GIHQ total frequency 0.0013 Aberrant Behavior Checklist-2 total 0.0013 Behavior Problems Inventory total frequency 0.0326 Vineland Adaptive Behavior Scales Composite 0.1710 Symptom Specific Quality of Life QL InventoryDisability total 0.0066 PMS Clinician Domain Specific Rating Scale total Impact of Childhood Neurologic Disability 0.1094 Caregiver Top 3 Concerns total 0.0156 0.0005 Communication Sleep CSHQ total 1 Wilcoxon signed rank test 0.0191 MB-CDI Total Vocabulary 0.0647 ORCA T-Score 0.0714 30 Best practice implemented for PMS-specific CGI-I and CIC measures • Both CGI-I and CIC scores reflect overall improvement from baseline 1 – Very Much Improved Clinical Global Impression of Improvement (CGI-I) Caregiver Impression of Change (CIC) Scoring Clinician gives an overall score and domain scores Caregiver gives an overall score and domain scores Also identifies the one symptom area that has most influenced his or her rating of the child’s overall function Domain Anchors • Expressive Communication • Communication • Receptive Communication • Social interaction • Gross Motor Function • Behavior • Fine Motor Function • Motor abilities • Social Interaction • Seizures • Cognition and Learning • • Self-Care Cognitive abilities/ability to learn • Self-care skills • GI problems • Sensory sensitivities 2 – Much Improved 3 – Minimally Improved 4 – No Change 5 – Minimally Worse 6 – Much Worse 7 – Very Much Worse • All clinician raters complete training to calibrate scoring and interpretation of the scoring anchors amongst raters. Training was done at study start up and a follow-up calibration training was done during the study 31 PMS CGI-I (clinician) results by subject and by domain Mean CGI-I score of 2.4 with 16 out of 18 children showing improvement Improvement 32 PMS CIC (caregiver) results by subject and by domain Mean CIC score of 2.7 with 15 out of 18 children showing improvement Improvement 33 PMS Clinical Global Impression of Severity (CGI-S) and Caregiver Top 3 Concerns results by domain 7 subjects improved by one point on the overall CGI-S score after 13 weeks of treatment and improvement was observed in the most common concerns of caregivers (communication, behaviour, social interaction, self-care) CGI-S domains Caregiver Top 3 Concerns (Domains based on frequency of nomination) Improvement Improvement 34 Quality of Life Inventory-Disability results by subject and by subscale Improvement Improvement 35 Aberrant Behavior Checklist-2 results by subject and by subscale Improvement Improvement Subjects with a score of zero not shown 36 Child Sleep Habits Questionnaire results by subject and by subscale Improvement Improvement Subjects with a score of zero not shown 37 Gastrointestinal Health Questionnaire results by subject and by subscale Improvement Improvement Acknowledgment: GIHQ developed by Kathleen J. Motil, MD, PhD, Baylor College of Medicine 38 ORCA T-Score and MB-CDI Total Vocabulary results by subject Improvements in communication observed in ORCA T-Score and MB-CDI Total Vocabulary, as well as domains/subscales in CGI-I, CGI-S, CIC and Caregiver Top 3 Concerns ORCA T-Score Improvement MB-CDI Total Vocabulary Improvement 39 Clinician and caregiver testimonials Clinicians Caregivers “Marked improvement in expressive language and moderate improvement in socialization.” “Using more words while retaining eye contact… Improved pretend play… Initiating eye contact” “Teachers noted improvement in learning new skills.” “Less scripting, less stimming… More flexible with changes… In general, they are more safe-even at bus stop” “Able to focus work at school, both to the things they always enjoy and new tasks.” “Expressive communication- significant improvement in using more complex phrases, better back and forth communication. Better expressing needs. Some commentary on how mom is feeling, "I want you to be happy".” “Expressive communication- babbling much more than baseline.” “More focused , engaged, aware of their environment, people.” “So much happier, not throwing self to ground when can’t get his way” “More attentive and it makes for an easy learner, Now can focus better on what we are trying to teach.” “A few 1-2 word phrases that were not at baseline “oh boy”, “Hi Mama”, “I love you”, “oh my”.” “Attention span is great right now… He can focus long enough to complete tasks and try new things.” “Gross motor- Stronger climbing ladders, comes downstairs which never did before, Walks upstairs without help (needed help at baseline).” “Can now run instead of walking fast… Good balance, not needing assistance on stairs.” 40 Pitt Hopkins syndrome (PTHS) 41 PTHS overview Cause of the syndrome Deletion or variation in the TCF4 gene on chromosome 18 TCF4 protein plays a role in the formation, maintenance and function of dendrites and synapses Broad and severe impact on life Patients stories Intellectual impairment Behavioural issues Sensory processing disorder Sleep disorders Seizures Vision impairment (severe myopia) Language deficits Breathing problems (hyperventilation, apnea, breath-holding) Feeding difficulties Pitt Hopkins Research Foundation Motor impairments including hypotonia (low muscle tone) and gross and fine motor delays GI dysfunction (gastroesophageal reflux and constipation) Walking abnormalities “She was tested earlier for Angelman and Rett Syndrome, but they were of course negative. I had a strange feeling that something was wrong with her already when she was a newborn…I started to see different doctors with her, but they just told me nothing was wrong, until we met a Neurologist who told us that she had Cerebral Palsy and that she would not able to walk, ever…She doesn’t talk but when she was about one year old she was saying a few words that never ever came back...” “Caleb is currently 10 months old and he does not sit or roll yet and is not really interested in toys. He is currently in an early intervention program and is going through physical therapy, and sees a vision teacher and special education teacher…It has not been an easy journey thus far. I still do not how and where I get all my strength from. I know things will only get harder as he gets older but I am ready to accept the challenge and take each day as it comes.” 42 PTHS is historically under-diagnosed, but this is changing Estimated prevalence is 1/34,000 to 1/41,000 males and females1 Potential PTHS patients US Europe Japan China Other2 6,000 – 7,0003 8,000 – 9,0003 1,000 - 2,0003 18,000 – 22,0003 6,000 - 7,0003 Pitt Hopkins Syndrome Census – initiated Q1 20231 1,391 1,318 1,237 1,188 1,083 Q1 2023 Q2 2023 Q3 2023 Q4 2023 Currently 497 in US & Canada, 329 in EMA & UK, 248 in China, 60 in ANZ Q1 2024 Opportunity to accelerate diagnosis Clinical similarities between PTHS, Rett and Angelman syndromes calling for TCF4 screening in suspected Rett or Angelman patients4 • Rising awareness • ICD code assigned in 2020 • Enhanced genetic testing technologies • Expanding ADDM network sites Autism US ADDM tracks 440k children with autism spectrum disorder 1 Pitt Hopkins Research Foundation (PHRF) (pitthopkins.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) 4 Takano et al, “Two percent of patients suspected of having Angelman syndrome have TCF4 mutations” Clin Genet. 2010 Sep;78(3):282-8; Armani et al, “Transcription factor 4 and myocyte enhancer factor 2C mutations are not common causes of Rett syndrome” Am J Med Genet A. 2012;158A(4):713–9 43 Neuren is leading development of a first approved treatment for PTHS Neuren Program Status • Positive Phase 2 trial • Clinical development in the US under an IND Limited products in development Company Neuren engaging with all stakeholders Product Development Stage • Orphan Drug designation in US and EU Successful Phase 2 • Eligible for Rare Pediatric Disease Designation Priority Review Voucher program #2 Phase 2 (research institute sponsored, focusing on GI symptoms) #3 Phase 1/2a trial (not yet recruiting) #4 Preclinical Leading clinicians 44 Neuren’s Phase 2 trial in children with PTHS First study in pediatric patients, collecting the data needed to design a registration study 5 US sites: Rush University, UTSW, UCSF, UAB, Colorado Children’s Hospital • • • n subjects: 16 Age range: 3 to 17 (mean 9.1) NNZ-2591 treatment Screening /Baseline Up-titration to 12 mg/kg BID Week 4 Week 0 PTHS specific efficacy measurements Primary endpoints were safety, tolerability and PK Global A key objective is selection of the best primary efficacy endpoint or endpoints for a registration study Week 17 Week 10 Endpoints Secondary endpoints included 14 efficacy measurements, including 4 specifically designed for PTHS Follow-up • CGI-I • Caregiver Impression of Change (CIC) • CGI-S + Week 19 10 other non PTHS specific measures that had been used in other conditions Symptom Specific • Caregiver Top 3 Concerns 45 Phase 2 clinical trial results highlights • NNZ-2591 was safe and well tolerated, with no meaningful trends in laboratory values or other safety parameters during treatment • Statistically significant improvement from baseline assessed by both clinicians and caregivers in all 4 efficacy measures specifically designed for Pitt Hopkins syndrome (p<0.05)1 • Clinician and caregiver global efficacy measures showed a level of improvement considered clinically meaningf