Investor presentation 25 Feb 2022
2022-02-24 · Neuren Pharmaceuticals Limited · original neurenpharma.com ↗
IMPROVING THE LIVES OF PEOPLE WITH NEURODEVELOPMENTAL DISABILITIES 25 February 2022 1 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. FORWARD LOOKING STATEMENTS 2 POSITIVE PHASE 3 RESULTS BEGIN NEUREN TRANSFORMATION Robustly positive top-line results for trofinetide Phase 3 trial in Rett syndrome: Statistically significant improvement over placebo for both co-primary efficacy endpoints: RSBQ (p=0.0175) and CGI-I (p=0.0030), as well as key secondary endpoint: caregiver scale of ability to communicate (p=0.0064) Rett syndrome NDA submission expected mid-2022, with potential for approval Q1 2023 Neuren potential revenue from Acadia over 2022 and 2023 for Rett syndrome in the US alone of A$115 million1 plus double-digit percentage royalties on net sales Partnering interest from multiple companies for ex-North America Large potential upside from NNZ-2591: Multiple indications and global rights retained Funded for Phase 2 trials and Phase 3 preparation in 4 disorders Potential markets more than 5 times Rett syndrome 3 1 Assuming a New Drug Application (NDA) is approved by the FDA, the product is launched in the US, US$33m is received as one thir d share of the value of a Rare Pediatric Disease Priority Review Voucher if awarded upon approval of a NDA, and a USD/AUD exchange rate of 0.72 TREATING NEURODEVELOPMENTAL DISORDERS 4 Rett Fragile X Phelan- McDermid Angelman Pitt Hopkins Prader-Willi MECP2 FMR1 SHANK3 UBE3A TCF4 15q11-q13 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 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 Compound Indication Preclinical Phase 1 Phase 2 Phase 3 Commercial Partner Trofinetide Rett syndrome1 (North America) Fragile X syndrome1 (North America) NNZ-2591 Phelan- McDermid syndrome2 Commence H1 2022 Results H1 2023 Angelman syndrome2 Pitt Hopkins syndrome2 Prader-Willi syndrome3 Commencement expected mid-2022 LEADING PIPELINE IN NEURODEVELOPMENTAL DISORDERS 1 Orphan Drug designation in US and EU, Fast Track designation in US 2 Orphan Drug designation in US and EU 3 Orphan Drug designation in US 5 THREE KEY DRIVERS TRANSFORMING NEAR TERM VALUE Realise Neuren’s share of trofinetide value in the US through Acadia’s New Drug Application for Rett syndrome Implement commercial strategy for trofinetide ex-North America, using US data for registration Confirm efficacy of NNZ-2591 in Phase 2 trials for 4 valuable indications 6 STOCK INFORMATION (ASX: NEU) Current share register composition (126 million quoted shares – top 20 hold 50%) Current analyst risk-adjusted valuations per share: A$5.10 – A$7.70 52 week price range: A$1.20 - A$4.49 Retail, 63% Institutions, 30% Management, 7% A$37 million cash at 31 December 2021 – well funded to execute NNZ-2591 Phase 2 trials and preparation for Phase 3 7 KEY MILESTONES IN NEXT 18 MONTHS Acadia pre-NDA meeting with FDA for Rett syndrome (Q1 2022) 8 Acadia New Drug Application (NDA) for Rett syndrome (mid-2022) Phase 2 trial results in 4 indications (H1 2023) Approval of NDA for Rett syndrome (Q1 2023) Commercial partnerships ex- North America for Rett syndrome Commence Phase 2 trials in Angelman, Phelan-McDermid and Pitt Hopkins syndromes Commence Prader-Willi syndrome Phase 2 trial TROFINETIDE FOR RETT SYNDROME 9 TROFINETIDE FOR RETT SYNDROME 10 Trofinetide is an investigational drug and a novel synthetic analog of GPE, the amino-terminal tripeptide of IGF-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 Trofinetide GPE=glycine-proline-glutamate; IGF-1= Insulin-like growth factor 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 RETT SYNDROME PHASE 3 AND NDA LAVENDER randomised, double-blind, placebo-controlled trial: 187 females aged 5 to 20 years RSBQ (caregiver) and CGI-I (physician) at 12 weeks co-primary efficacy endpoints LAVENDER Baseline Week 12 PLACEBO TROFINETIDE LILAC Week 52 TROFINETIDE LILAC-2 TROFINETIDE Double-blind Open-label Continued Access 11 Acadia plans to submit NDA mid-2022; Orphan Drug qualifies for 6 months Priority Review, which means potential for approval in Q1 2023 NDA based on pivotal efficacy from positive Phase 3 trial, supportive efficacy from Neuren’s positive Phase 2 trial, safety data from completed and ongoing studies LAVENDER TOP-LINE EFFICACY RESULTS 12 Source: Acadia Lavender Study Top-Line Results Presentation https://ir.acadia-pharm.com/static-files/84457c64-60ab-4b2f-a166-edc1d465f4a8 RETT SYNDROME OPPORTUNITY Estimates US Europe Japan China urban Other Asia Potential patients1 10,000 13,000 3,000 28,000 6,000 Patients currently identified 5,000 4,000 1,000 2,000 ‘00s 1 Potential patient estimates derived by applying the mid-point of the published prevalence estimate range to the populations under 60 years 13 North America Neuren potential revenue from Acadia: US$10 million in 2022 following acceptance of NDA for review US$40 million in 2023 following first commercial sale in the US US$33 million in 2023 one third share of Priority Review Voucher estimated value1 Up to US$350 million on achievement of thresholds of annual net sales Tiered, escalating double digit percentage royalties on net sales Peak annual sales potential in US at least US$500m2 Orphan exclusivity plus patent to 2035 1 Assuming Rare Pediatric Disease Priority Review Voucher is awarded upon approval of a NDA and has a market value of US$100m 2 Acadia 2Q18 Earnings Call presentation and Jefferies Healthcare Conference 2 June 2021 Ex-North America Partnering interest from multiple companies for individual countries and broader regions Neuren has full access to US data for registration ex-North America Strong interest from families, advocacy groups and physicians Lower diagnosis rates expected to increase with awareness and accelerate with availability of a treatment NNZ-2591 FOR MULTIPLE NEURODEVELOPMENTAL DISORDERS 14 NNZ-2591 MECHANISM OF ACTION 15 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-1 receptor on cell surface IGF-1 Reversible binding regulates bioavailability IGF Binding Protein-3 NNZ-2591 Competitively binds to binding protein, regulating IGF-1 binding1 Produce essential growth factor IGF-1 Activates PI3K–Akt–mTOR and Ras–MAPK- ERK signalling pathways in neurons, regulating formation of new synapses IGF-1 1 doi: 10.1038/srep04388: Guan et al, 2017: Cyclic glycine-proline regulates IGF-1 homeostasis by altering the binding of IGFBP-3 to IGF-1 FIVE TIMES LARGER OPPORTUNITY FOR NNZ-2591 Disorder Gene mutation Published prevalence estimates Potential patients US1 Europe1 Asia1, 2 Phelan- McDermid SHANK3 1/8,000 to 1/15,000 males and females 22,000 28,000 81,000 Angelman UBE3A 1/12,000 to 1/24,000 males and females 14,000 18,000 52,000 Pitt Hopkins TCF4 1/34,000 to 1/41,000 males and females 7,000 9,000 25,000 Prader-Willi 15q11-q13 1/10,000 to 1/30,000 males and females 13,000 16,000 47,000 56,000 71,000 205,000 1 Estimates derived by applying the mid-point of the prevalence estimate range to the populations under 60 years 2 Asia comprises Japan, Korea, Taiwan, Israel and urban populations of China and Russia 3 Based on number of addressable patients globally 16 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 Neuren retains global rights 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 and optimum dose confirmed 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 17 KEY FEATURES OF FIRST PHASE 2 TRIALS Overall aim – expedite data that enables subsequent trials to be designed as registration trials and prepare for Phase 3 in parallel Prioritising speed to data: AS trial in Australia, PMS and PTHS trials in US Up to 20 patients in each trial, all patients receive drug Maximising opportunity to demonstrate effects: Pediatric patients 13 weeks’ treatment following well-characterised baseline period Confirm safety and PK in pediatric patients Assess treatment impact across multiple efficacy measures to select primary endpoint for registration trial Commencing H1 2022, results expected in H1 2023 Executing foundational preparations for Phase 3 across all indications 18 CONTACT 19 Jon Pilcher, CEO [email protected] +61 438 422 271 APPENDIX 1 – NNZ-2591 DATA 20 PHASE 1 CLINICAL TRIAL HIGHLIGHTS Twice daily dosing for 7 days in healthy volunteers was safe and well tolerated at the dose level to be tested in Phase 2 trials No SAEs, no clinically significant findings in lab or cardiac tests All AEs mild or moderate and resolved during the trial At highest dose all AEs were mild apart from one moderate Most common AE was drowsiness = Good safety and tolerability profile for dosing patients in Phase 2 21 CONSISTENT EFFICACY AND DOSE RESPONSE IN PHELAN- MCDERMID MODEL 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. In the shank3 knockout mouse model, wild type mice and knockout mice were treated with placebo or 4 escalating dose levels of NNZ-2591 for 6 weeks. Results clearly indicate 2nd highest dose as optimum dose, informing dose selection for clinical trials in patients. 22 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 CONSISTENT EFFICACY AND DOSE RESPONSE IN PHELAN- MCDERMID MODEL 23 Motor function Anxiety Repetitive behavior Daily living Daily living BIOCHEMICAL EFFECTS CONFIRMED IN SHANK3 MODEL 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. WT + VehicleKO + Vehicle KO + NNZ2591 8000 10000 12000 14000 16000mIGF-1 (pg/ml) WT + VehicleKO + Vehicle KO + NNZ2591 0 1 2 3 4Basal pERK WT + VehicleKO + Vehicle KO + NNZ2591 10nM KO + NNZ2591 50nM 0 500 1000 1500 2000Dendritic length (µm) 24 Abnormal dendrites in shank3 knockout mice Normalisation after treatment with NNZ-2591 CONSISTENT EFFICACY IN ANGELMAN MODEL AS is caused by a deletion or mutation in the ubiquitin protein ligase E3A (UBE3A) gene on chromosome 15. In the ube3a knockout mouse model, which resembles features of AS in humans, wild type and knockout mice were each treated with placebo or NNZ- 2591 for 6 weeks. Treatment with NNZ-2591 normalized all the deficits in the knockout mice, including eliminating seizures, and had no effect on the wild type mice. WT-vehicle Ube3a m−/p+ + vehicle WT+ NNZ2591 Ube3a m−/p+ + NNZ2591 0 20 40 60 80 Distance travelled (cm) WT-vehicle Ube3a m−/p+ + vehicle WT+ NNZ2591 Ube3a m−/p+ + NNZ2591 0 2 4 6 Nest Building quality (grade 1 to 5) WT-vehicle Ube3a m−/p+ + vehicle WT+ NNZ2591 Ube3a m−/p+ + NNZ2591 0 5 10 15 20Marble burying (n) WT-vehicle Ube3a m−/p+ + vehicle WT+ NNZ2591 Ube3a m−/p+ + NNZ2591 0 50 100 150 200Time spent with the novel mouse (s) WT-vehicle Ube3a m−/p+ + vehicle WT+ NNZ2591 Ube3a m−/p+ + NNZ2591 0 20 40 60 80Floating time (%) WT-vehicle Ube3a m−/p+ + vehicle WT+ NNZ2591 Ube3a m−/p+ + NNZ2591 0 2 4 6 8 Number of Platform crosses 25 Daily living Daily living Sociability Hypoactivity & anxiety Motor Cognition CONSISTENT EFFICACY IN PITT HOPKINS MODEL PTHS is caused by the loss of one copy or a mutation of the TCF4 gene on chromosome 18. In the tcf4 mutation mouse model, which exhibits features of PTHS in humans, wild type mice and knockout mice were treated with placebo or NNZ-2591 for 6 weeks. Treatment with NNZ-2591 normalized all the deficits in the knockout mice and had no effect on the wild type mice. 26 WT + Vehicle Tcf4 +/_ + Vehicle WT+ NNZ2591 Tcf4 +/_ + NNZ2591 0.0 0.2 0.4 0.6 0.8 1.0Force (N) WT + Vehicle Tcf4 +/_ + Vehicle WT+ NNZ2591 Tcf4 +/_ + NNZ2591 0 50 100 150Time spent grooming (s) N_WT + Vehicle N_Tcf4 +/_ + Vehicle N_WT+ NNZ2591 N_Tcf4 +/_ + NNZ2591 0 20 40 60Time spent with the novel mouse (s) WT + Vehicle Tcf4 +/_ + Vehicle WT+ NNZ2591 Tcf4 +/_ + NNZ2591 0 20 40 60 Freezing in % of 5min WT + Vehicle Tcf4 +/_ + Vehicle WT+ NNZ2591 Tcf4 +/_ + NNZ2591 0 2 4 6 Nest Building quality (grade 1 to 5) WT + Vehicle Tcf4 +/_ + Vehicle WT+ NNZ2591 Tcf4 +/_ + NNZ2591 0 50 100 150Distance travelled Hypoactivity Daily living Motor performanceSociability Repetitive behavior Learning & Memory CONSISTENT EFFICACY IN PRADER-WILLI MODEL PWS is caused by mutations in the 15q11-q13 region of chromosome 15. In the Magel2-null mouse model, which exhibits features of PWS in humans, wild type mice and knockout mice were treated with placebo or NNZ-2591 for 6 weeks. Treatment with NNZ-2591 normalized fat mass, insulin levels, IGF-1 levels and all the behavioral deficits in the knockout mice and had no effect on the wild type mice. 27 CONSISTENT EFFICACY IN PRADER-WILLI MODEL 28 APPENDIX 2 – TROFINETIDE LICENCE 29 TROFINETIDE LICENCE AGREEMENT WITH ACADIA Partnership commenced in August 2018, providing the necessary funding and capabilities to execute Phase 3 and commercialise trofinetide in the US Redacted agreement is available in ACADIA’s 2018 10K filing Territory North America (Neuren retains all rights ex-North America) Indications All, including Rett syndrome and Fragile X syndrome Future development costs Funded by ACADIA Use of data Each party has access to all data for use in its territory Development Milestones US$105m on achievement of 5 milestones across Rett and Fragile X Commercial Milestones US$350m on achievement of 4 thresholds for total annual net sales Royalties Double-digit % royalties with % escalating in 4 tiers of total annual net sales Rare Pediatric Disease Priority Review Voucher Neuren receives 1/3 of voucher market value (recent sale average US$100m) Non-compete Neuren may not develop a competing product in indications for which ACADIA develops and commercialises trofinetide 30
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