Announcement PDF Improving the lives of people with neurodevelopmental disabilities Neuren Pharmaceuticals Limited ANNUAL REPORT 2023 Neuren Pharmaceuticals is developing new therapies for debilitating neurodevelopmental disorders that emerge in early childhood and are characterised by impaired connections and signalling between brain cells. Incorporated in New Zealand and based in Melbourne, Australia, Neuren is listed on the ASX under the code NEU. Contents 1 Neuren’s value proposition 2 Chair and CEO message 4 Operating Review 22 Board 23 Executive Team 24 Corporate Governance 30 Consolidated Statement of Comprehensive Income 31 Consolidated Statement of Financial Position 32 Consolidated Statement of Changes in Equity 33 Consolidated Statement of Cash Flows 34 Notes to the Consolidated Financial Statements 51 Independent Auditor’s Report 53 Additional Information Neuren Pharmaceuticals Limited Annual Repor t 2023 N E U R E N ’ S V A LU E P R O P O S I T I O N Key achievements in 2023 A$157 million profit after tax for 2023 Approval and successful launch of DAYBUE™ (trofinetide) in the US as the first approved treatment for Rett syndrome, with net sales for 2023 since launch in April of US$177 million Expansion of DAYBUE™ (trofinetide) partnership with Acadia to include ex-North America, delivering A$146 million up-front plus attractive future royalties and milestone payments Highly encouraging positive results in Phase 2 trial of NNZ-2591 for Phelan-McDermid syndrome Completion of enrolment in Phase 2 trials of NNZ-2591 for Pitt Hopkins and Angelman syndromes Leading pipeline in neurodevelopmental disorders Indication Rett Compound Geography Phase 1 Phase 2 Phase 3 Registration Commercial rights US Trofinetide 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 pharmaceuticals 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 Positive top-line results for Phelan-McDermid syndrome • Top-line results for Pitt Hopkins and Angelman syndromes in Q2 and Q3 2024 Realise Neuren’s share of trofinetide ex-US value through expanded global partnership with Acadia 1 Neuren Pharmaceuticals Limited Annual Repor t 2023 CHAIR AND CEO MESSAGE P AT R I C K D A V I E S & J O N P I L C H E R Jon Pilcher CEO Patrick Davies Chair 2023 was a transformational year for Neuren. In all three areas of the business, we achieved the key planned milestones that generated very significant value for all stakeholders. In December 2023 we announced highly encouraging results from our Phase 2 clinical trial of NNZ-2591 in Phelan-McDermid syndrome. These results exceeded our expectations, both in the consistency of the findings and the magnitude of improvements seen across clinically important aspects of Phelan-McDermid syndrome, including communication, behaviour, cognition/learning and socialisation. Neuren is currently leading the way in striving to achieve the first approved treatment for PhelanMcDermid syndrome and the team is very excited by that prospect. The approval of DAYBUE™ by the US Food and Drug Administration (FDA) in March 2023 as the first ever treatment for Rett syndrome was a proud moment for the Neuren team. Our partner Acadia launched DAYBUE a month later. In our message to you last year, we stated that we were confident Acadia was very well placed for successful commercialisation. The launch was indeed highly successful and 2023 net sales of US$177 million in less than 9 months, with Acadia’s guidance for net sales to more than double in 2024, is an outstanding outcome. We are very encouraged by testimonials from families about the impact of treatment. We have noted before that Neuren has no cost attached to the royalty and milestone revenue we receive from Acadia, which therefore flows straight into pre-tax profit. The impact of this was evident in our financial results for 2023, the highlight of which was profit after tax of $157 million. This reflected revenue from Acadia of A$232 million, comprising royalty of A$27 million, a milestone payment of A$59 million and A$146 million from the expanded worldwide agreement. In July 2023 we expanded our partnership with Acadia for DAYBUE from North America to worldwide, following a competitive partnering process. Acadia is in a unique position of being able to leverage knowledge of all aspects of the development, marketing and distribution of DAYBUE. The expanded agreement delivered to Neuren US$100 million up-front and very attractive future economics linked to launches and sales in key territories. Neuren was promoted into the S&P/ASX 200 index in September 2023 and was the best performing ASX 200 stock in 2023, with a share price increase of 214%. We now have many more institutional shareholders and a high level of interest and engagement from the financial markets community. We continue to seek higher interest and investment, both in Australia and overseas, assisted by a wide range of intermediaries. In October 2023, Neuren was presented with the 2023 Australian Growth Company of the Year Award for Health and Life Sciences. 2 Neuren Pharmaceuticals Limited Annual Repor t 2023 CHAIR AND CEO MESSAGE CONTINUED 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 NEUREN’S VALUES We are determined and creative to break through barriers We harness the power of collaboration and different perspectives We recognise the importance of all stakeholders and endeavour to use financial resources efficiently The Neuren team is far from complacent following the success of the last two years. We are acutely aware that it follows, and has been built on, a ten-year journey since our first clinical trial in Rett syndrome and that many loyal and committed shareholders have accompanied us on that journey. The experience we have gained on the ten-year journey is extremely valuable. Everything we have learnt from the development of trofinetide in Rett syndrome is directly relevant to our development of NNZ-2591 in other neurodevelopmental disorders, led by Phelan-McDermid syndrome. We believe that this and the connection of both drugs to IGF-1 enhances the risk profile of the NNZ-2591 programs. Neuren is in a very strong financial position, with cash and short-term investments of more than A$200 million and the ongoing revenues from DAYBUE. This supports our commitment to achieving the best outcome for shareholders by pursuing value-adding opportunities to their fullest potential. For NNZ-2591, we will continue to evaluate all options to achieve this as the events of this year unfold. We are grateful to our shareholders, both longstanding and new, and all the patient communities for the support that is so critical for our success. We commend and thank the Neuren team for their achievements and dedication, assisted by a range of development partners. There is so much more to achieve and 2024 is another very important year for the business. We look forward to the continued progress of DAYBUE, both in the US and in other territories. We await the results of the Phase 2 trials of NNZ2591 for Pitt Hopkins syndrome in Q2 2024 and for Angelman syndrome in Q3 2024. In the meantime, the team is highly focused on advancing the Phelan-McDermid syndrome program. We are diligently preparing for an End of Phase 2 Meeting with the FDA and are commencing manufacture of the drug supplies that will be required for a Phase 3 program. We are also actively exploring further potential indications for NNZ-2591 and will say more about this as our assessment progresses. Patrick Davies Chair 3 Jon Pilcher CEO Neuren Pharmaceuticals Limited Annual Repor t 2023 O P E R AT I N G R E V I E W Treating neurodevelopmental disorders Rett Fragile X PhelanMcDermid 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 impaired communication intellectual disability impaired social interaction impaired hand use sleep disturbance gastrointestinal problems NEUREN’S GROUND -BREAKING THER APIES THE IMPORTANCE OF ORPHAN DRUG DESIGNATION Neuren focuses on developing treatments for debilitating neurodevelopmental disorders that emerge in early childhood and stem from problems in brain development which lead to a wide range of serious issues affecting nearly every aspect of life. These neurodevelopmental disorders have severe life-long impact on the patients and their families. Each neurodevelopmental disorder is caused by a different genetic mutation, but in many cases, they share similar symptoms and the common characteristic of impaired connections and signalling between brain cells. 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, Angelman and Pitt Hopkins 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. Neuren currently has two novel patented drugs, trofinetide and NNZ-2591, which potentially have broad utility in the treatment of neurological disorders. Both drugs are synthetic analogues of important molecules that occur naturally in the brain, aiming to improve the impaired connections and signalling, meaning that the drug’s target is to have a broad impact on the disorder rather than aiming to treat one symptom. Both drugs can be administered orally in a patient-friendly liquid dose. A critical feature of Neuren’s work to develop therapies for each of these disorders is close collaboration with the leading specialist physicians and with the well-organised patient advocacy organisations. 4 Neuren Pharmaceuticals Limited Annual Repor t 2023 O P E R AT I N G R E V I E W CONTINUED 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. 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. TROFINETIDE FOR RETT SYNDROME Successful launch of DAYBUE™ (trofinetide) in the United States In March 2023, Neuren’s partner for trofinetide, Acadia Pharmaceuticals (NASDAQ: ACAD), received US Food and Drug Administration (FDA) approval of DAYBUETM (trofinetide) for the treatment of Rett syndrome in adult and pediatric patients two years of age and older. On 17 April 2023, Acadia Pharmaceuticals launched DAYBUE™ (trofinetide) in the United States as the first approved treatment for Rett syndrome. 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 neurodevelopmental disorders that Neuren is aiming to treat are “rare diseases”, however they are not “ultrarare”, and in each disorder there are tens of thousands of potential patients. Adoption of DAYBUE in the diagnosed Rett syndrome population has been faster than expected, with approximately 860 patients on DAYBUE at the end of February 2024. Caregivers and physicians have continued to report meaningful improvements in patients and the high demand has been well supported by access from Medicaid and private health insurance payors. In the United States there are approximately 5,000 diagnosed Rett syndrome patients and prevalence studies suggest the total number of patients may be 6,000 to 9,000. COMMERCIAL EXCLUSIVIT Y 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 and pending patent applications, which extend as far as 2041. Since trofinetide and NNZ-2591 are new chemical entities, following the first marketing Acadia reported net sales of US$177 million for 2023 and has provided guidance for net sales in 2024 of between US$370 million and US$420 million. DAYBUE Net Sales (US$m) 420 370 80-87.5 87 177 Q4 2023 CY2023 67 21-23 23 Q2 2023 # 45-55 Q3 2023 CY2024 Acadia Guidance Historical Acadia guidance 2023 net sales of US$177m 2024E net sales of US$370 – 420m Further information about DAYBUE, including prescribing information can be accessed at www.DAYBUE.com 5 * Ba US$ ^ Ne reac Neuren Pharmaceuticals Limited Annual Repor t 2023 O P E R AT I N G R E V I E W CONTINUED A characteristic of all long-term medicines is that not all patients who commence treatment will persist with treatment. Furthermore, for patients and caregivers, adjusting to a novel treatment regimen can take time, especially when it is the first treatment ever to become available. The number of patients commencing treatment and the proportion that persist with treatment long-term are key factors in the sales outcome. Acadia has provided detailed metrics for real world persistency since launch, which continues to outperform the clinical trial experience and has improved as new patient cohorts are added. The Acadia’s earnings callp presentation ino February Pchart ersbelow isteshows ncythe radata tereported s impinro vingQ4in new atient c hort2024. s The real world persistency has consistently tracked at more than 10 percentage points above clinical experience and monthly cohort persistency rates are trending up. Persistency Rates1 (Based on confirmed discontinuations and patients who were 60 days past their scheduled refill) 75% 80% 66% 76% 70% 68% 64% 63% 58% 51% n.a. Month 4 Month 5 Lilac-1 experience 1 n.a. Month 6 Previously presented real world Month 7 Current real world Acadia Fourth Quarter and Full Year 2023and Earnings presentation in Feb 2024 Call presentation in Feb 2024 1 Acadia Fourth Quarter FullCallYear 2023 Earnings 14 Growing sustainable income to Neuren In June 2023, Neuren received from Acadia a milestone payment of US$40 million earned following the first commercial sale of DAYBUE (trofinetide). Neuren is eligible to receive ongoing royalties on net sales of trofinetide in North America, plus milestone payments of up to US$350m on achievement of a series of four thresholds of total annual net sales, plus one third of the market value of the Rare Pediatric Disease Priority Review Voucher that was awarded to Acadia by the FDA upon approval of the New Drug Application (NDA)”, to be paid when Acadia sells or uses the voucher. Neuren estimates the value of its one third share as US$33 million. No royalties or similar costs are payable by Neuren to third parties, which means Neuren’s revenue from Acadia will flow through to pre-tax profit. The royalty rates and sales milestone payments are related to the total amount of annual net sales of trofinetide in all indications in North America, as set out in the following tables: Tiered royalty rates (% of net sales)1 Sales milestone payments1 Annual Net Sales Rates Net Sales in one calendar year US$m ≤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$1bn 150 1 Royalty rates payable on the portion of annual net sales that fall within the applicable range. Each sales milestone payment is payable once only. 6 Neuren Pharmaceuticals Limited Annual Repor t 2023 O P E R AT I N G R E V I E W CONTINUED Royalty and Sales Milestone to Neuren (A$m) of US$177 DAYBUENet Netsales Sales (US$m)million in 2023 delivered royalties of A$27 million to 420 Neuren. Assuming Acadia’s guidance for 2024 is met and an exchange rate of 0.65, Neuren anticipates370 royalties of A$61-70 million (US$3945 million), plus A$77 million (US$50 million) 87 from the first 177 sales milestone 80-87.5 payment due for the first calendar year in which net sales exceed 67 US$250 million. The milestone 45-55 3 payment would be earned as revenue in 2024 and received in Q1CY2024 2025. Acadia 2023 Q3 2023 Q4 2023 CY2023 Guidance Acadia anticipates potential approval of a New Drug Submission (NDS) filing Historical Acadia guidance for trofinetide in Canada around year-end 2024. There are currently 2023 net600 sales of US$177m to 900 Rett patients in Canada. 2024E net sales of US$370 – 420m Any net sales in Canada will be included in the North America net sales for the purpose of calculating royalties and sales milestone payments to Neuren. 147 138 70 10 4 Q2 2023 Q3 2023 13 27 Q4 2023 CY2023 61 Royalty only* Royalty + Sales Milestone^ CY2024 2023E royalty of A$27m 2024E royalty of A$61 – 70m, plus A$77m sales milestone * Based on 10% of DAYBUE net sales up to US$250m and 12% of DAYBUE net sales * Basedbetween on 10% ofUS$250m DAYBUE net sales up to US$250m and 12% of and US$500m, and AUDUSD ofDAYBUE 0.65 net sales between US$250m and US$500m, and AUDUSD of 0.65 ^ Neuren will betoentitled US$50m sales milestones in Q1 2025) ifnetCY2024 ^ Neuren will be entitled US$50mto sales milestones (receivable in Q1(receivable 2025) if CY2024 DAYBUE sales net sales reaches assumes AUDUSD of 0.65 reachesDAYBUE US$250m; assumes AUDUSDUS$250m; of 0.65 1 7 Neuren Pharmaceuticals Limited Annual Repor t 2023 O P E R AT I N G R E V I E W CONTINUED Development and commercialisation outside North America In July 2023 Neuren and Acadia expanded their partnership for trofinetide from North America to worldwide. Neuren received US$100 million up-front and is eligible to receive milestone payments and royalties related to development and commercialization of trofinetide outside North America as set out in the table below. Trofinetide Payment Upon 1st commercial sale for Rett in Europe US$35m Upon 1 commercial sale for Rett in Japan US$15m Upon 1st commercial sale for second indication in Europe US$10m Upon 1st commercial sale for second indication in Japan US$4m Total development milestones US$64m st Europe Up to US$170m Japan Up to $110m Rest of World Up to US$83m Total sales milestones on achievement of escalating annual net sales thresholds Up to US$363m Mid-teen to low twenties per cent Tiered royalties on net sales A redacted version of the expanded 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. Following the expansion of the partnership with Acadia for trofinetide to worldwide, Acadia is now advancing in key markets outside North America. For Europe, Acadia is engaging with the European Medicines Agency (EMA) in Q1 2024, with a potential Marketing Authorisation Application filing in H1 2025. For Japan, Acadia is engaging with the regulator, Pharmaceuticals and Medical Devices Agency (PMDA) in 2024. 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. The estimated number of potential patients and currently identified patients is shown in the table below. Neuren expects rates of diagnosis to increase with greater awareness and accelerate with the availability of a treatment. Potential Rett patients Europe Japan Other 9,000 – 14,0001 1,000 – 2,0001 ~30,0002 ~4,0002 ~800 – 1,0002 ~2,0002 Currently identified Rett patients 1 2 Acadia estimates Neuren estimates based on prevalence studies and patient organisations i 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. 8 Neuren Pharmaceuticals Limited Annual Repor t 2023 O P E R AT I N G R E V I E W CONTINUED NNZ-2591 FOR MULTIPLE NEURODEVELOPMENTAL DISORDERS Neuren is developing NNZ-2591 for four other serious neurodevelopmental disorders that emerge in early childhood and have no or limited approved treatment options. The estimated number of potential patients being targeted across these four disorders is more than five times larger than Rett syndrome. Potential patients US1 Europe1 RoW1, 2 1/8,000 to 1/15,000 males and females 24,000 31,000 104,000 TCF4 1/34,000 to 1/41,000 males and females 6,000 8,000 28,000 Angelman UBE3A 1/10,000 to 1/20,000 males and females 19,000 24,000 81,000 Prader-Willi 15q11-q13 1/10,000 to 1/30,000 males and females 17,000 21,000 72,000 66,000 84,000 285,000 Disorder Gene mutation Published prevalence estimates Phelan-McDermid SHANK3 Pitt Hopkins 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 All four programs have been granted Orphan Drug designation by the US Food and Drug Administration (FDA) and are being developed under Investigational New Drug (IND) applications. In designing and executing the NNZ-2591 development program, Neuren has been able to leverage the extensive and highly relevant experience the management team has gained from the trofinetide Rett syndrome program across manufacturing, non-clinical, clinical and regulatory. Phase 2 clinical trials Phase 2 clinical trials are being conducted in all four indications. The open label trials are each enrolling up to 20 children to examine safety, tolerability, pharmacokinetics and efficacy over 13 weeks of treatment with NNZ-2591. All subjects receive NNZ-2591 as an oral liquid dose daily, with escalation in two stages up to the target dose during the first 6 weeks of treatment, subject to independent review of safety and tolerability data. The study begins with 4 weeks of observation to thoroughly examine baseline characteristics prior to treatment, against which safety and efficacy are assessed for each child. This is followed by the treatment period of 13 weeks. A follow-up assessment is made 2 weeks after the end of treatment. The overall aim of these first trials is to expedite the generation of data that will enable the subsequent trials to be designed as registration trials. In 2023 positive results were achieved in the Phelan-McDermid syndrome trial and enrolment was completed in both the Pitt Hopkins and Angelman syndrome trials. Top-line results are anticipated for Pitt Hopkins in Q2 2024 and for Angelman in Q3 2024. Phelan-McDermid 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 NNZ-2591 treatment Screening/Baseline Follow-up Up-titration to 12mg/kg BID Week 0 Week 4 Week 10 Week 17 Phase 3 preparation Non-clinical toxicity studies and optimisation of drug product and drug substance manufacturing 9 Week 19 Neuren Pharmaceuticals Limited Annual Repor t 2023 O P E R AT I N G R E V I E W CONTINUED Positive results in Phelan-McDermid syndrome Phase 2 trial In December 2023, Neuren announced positive top-line results from the Phase 2 clinical trial of NNZ-2591 in children with Phelan-McDermid syndrome. NNZ-2591 was well tolerated and demonstrated a good safety profile. There was only one serious treatment emergent adverse event (TEAE) of gastroenteritis, which was not related to study drug and occurred during the safety follow-up period after end of treatment. Three subjects discontinued due to TEAEs, two testing positive for COVID-19 and one due to seizures that were not related to study drug. No clinically significant changes in laboratory values, electrocardiogram (ECG) or other safety parameters were observed during treatment. TEAEs occurring in two or more subjects are listed in the following table: N=18 n (%) Event N=18 n (%) Event Constipation 2 (11.1) Somnolence 3 (16.7) Diarrhea 2 (11.1) Pyrexia 3 (16.7) Nausea 2 (11.1) Fatigue 2 (11.1) 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) Significant improvement was observed by both clinicians and caregivers from treatment, across multiple efficacy measures. Improvements were consistently seen across many of the core PMS characteristics. The results for the global efficacy measures rated by both clinicians and caregivers showed a level of improvement typically considered clinically meaningful. 16 out of 18 children showed improvement measured by the Clinical Global Impression of Improvement (CGI-I), an assessment by the clinician of the child’s overall status compared with baseline. The mean CGI-I score was 2.4. 10 children received a score of either 1 (“very much improved”) or 2 (“much improved”). 15 out of 18 children showed improvement measured by the Caregiver Overall Impression of Change (CIC), an assessment by the caregiver of the child’s overall status compared with baseline. The mean CIC score was 2.7. Seven children received a score of either 1 (“very much improved”) Eorf2fi(“much cacyimproved”). endpoCGI-I intand s sCIC um aryscales in which scores of 1, 2 or 3 indicate improvement. arem 7 point 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 Mean CIC of 2.7 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 Behavior Problems Inventory total frequency 0.0326 Vineland Adaptive Behavior Scales Composite 0.1710 QL InventoryDisability total 0.0066 PMS Clinician Domain Specific Rating Scale total 0.0156 Impact of Childhood Neurologic Disability 0.1094 Caregiver Top 3 Concerns total 0.0005 Communication CSHQ total 1 0.0013 Symptom Specific Quality of Life Sleep 1 Aberrant Behavior Checklist-2 total 0.0191 Wilcoxon signed rank test MB-CDI Total Vocabulary 0.0647 ORCA T-Score 0.0714 Wilcoxon signed rank test 30 10 Neuren Pharmaceuticals Limited Annual Repor t 2023 Significant improvement assessed by both clinicians a O P E R AT I N G R E V I E W CONTINUED Clinician and caregiver global efficacy measures showed a level of imp considered clinically meaningful Meanscore CGI-I score of 2.4 with16 16out out of children Mean CGI-I of 2.4 with of1818 children showing improvement showing improvement Mean CIC score of 2.7 with showing impro Waterfall Plot of CGI-I Overall Score ITT Population Score at Week 13 EOT (Visit 16) 1 - Very Much Improved 2- Much Improved 3 - Minimally Improved 4 - No Change ssed by both clinicians and caregivers 5 - Minimally Worse 6 - Much Worse 7 - Very Much Worse measures showed a level of improvement ty