Neurizon Therapeutics Limited · ASX:NUZ
Neurizon Therapeutics — PharmAust — ANZCVS Annual Scientific Conference (Science Week) 2021
33 slides from Neurizon Therapeutics's conference presentation, Jul 9, 2021
Slide 1: Science Week Conference Presentation
Science Week Conference Presentation For personal use only 9 July 2021 – Perth, Australia: PharmAust Limited (ASX: PAA), a clinical-stage biotechnology company is pleased to provide the enclosed presentation which will be presented today by Chief Scientific Officer, Dr Richard Mollard, at the Austra
Slide 2: Monepantel: from registered livestock anthelmintic to phase II pet dog anticancer drug
rsonal use only Monepantel: from registered livestock anthelmintic to phase II pet dog anticancer drug
Slide 3: Disclosure Statement
Disclosure Statement rsonal use only Presenter: Dr Richard Mollard BSc (Hons) PhD MBA Disclosure: I have the following relationships to disclose: 1. PharmAust: Chief Scientific Officer 2. Pitney Pharmaceuticals Pty Ltd: Chief Executive Officer Off-label Drug Use Disclosure: I will discuss investigat
Slide 4: About PharmAust Ltd
ABOUT PHARMAUST LTD (ASX: PAA) rsonal use only • Australian clinical stage oncology, neurodegenerative and antiviral company • Lead drug monepantel (MPL) being developed (“repurposed”) for dog and human oncology and human neurodegenerative diseases and viral infections • Wholly owned and subsidiary,
Slide 5: Monepantel: Registered Veterinary Product
MONEPANTEL: ANTHELMINTIC MONEPANTEL: REGISTERED VETERINARY PRODUCT REGISTRATION > 38 JURISDICTIONS rsonal use only • European Union: 28 countries Switzerland • South Africa Iceland • New Zealand Lichtenstein • Australia Norway • Argentina Chile • Uruguay ANTHELMINTIC ACETYLCHOLINE RECEPTORS • Not pr
Slide 6: Molecule and Chemical/Physical Properties
MONEPANTEL: MOLECULE CHEMICAL/ PHYSICAL PROPERTIES rsonal use only Monepantel (Mpl) MW 473 Da S- and R- enantiomers Monepantel sulfone (MplS) MW 504 Da S-Mpl White powder Solubility water = 0.08 mg/L MP = ~ 148ºC (B), = ~125 ºC (A) Stability = > 1 year (4 - 30 ºC) Small hydrophobic insoluble molecul
Slide 7: Deg-3 Nicotinic Acetylcholine Receptor Agonist
MONEPANTEL: ANTHELMINTIC Deg-3 NICOTINIC ACETYLYCHOLINE RECEPTOR (AchR) AGONIST rsonal use only Deg-3 nicotinic acetylcholine receptor (AchR) subfamily (i) Acr-23 (Caenorhabditis elegans: Cel-arc-23) (ii) Des-2 (Haemonchus contortus: Hco-des-2) (iii) Mptl-1 (Haemonchus contortus: Hco-mptl-1 Rufener
Slide 8: Anthelmintics and Anticancer Drugs
MONEPANTEL: ANTHELMINTIC ANTHELMINTICS AND ANTICANCER DRUGS rsonal use only 1 Chu et al., Anticancer research 29, 3791-3796 (2009) 2 Pourgholami et al., Canc chemo pharma 55, 425-432 (2005) 3 Castro et al. Red biol 10, 90-99 (2016) 4 Pourgholami et al., Clin canc res 12, 1928-1935 (2006) 5 Pourghola
Slide 9: In Vitro Cancer and Non-Cancer Cell Line EC50s
MONEPANTEL: ANTICANCER DRUG IN VITRO CANCER AND NON-CANCER CELL LINE EC50S rsonal use only Bahrami et al., 2014, Am J Cancer Res PMCID: PMC4163619 PharmAust unpublished data Monepantel demonstrates a 10 fold therapeutic index relevant to numerous cancer cell lines (compare malignant cell line IC50s
Slide 10: Monepantel In Vivo Xenograft Mouse Studies
MONEPANTEL: ANTICANCER DRUG MONEPANTEL IN VIVO XENOGRAFT NOD SCID MOUSE CANCER CELL LINE STUDIES rsonal use only Ataie-Kochoie et al., 2018, Am J Cancer Res PMCID: PMC6220142 PharmAust unpublished data • Monepantel demonstrates activity against ovarian, colorectal, pancreatic cancers in vivo • Incre
Slide 11: mTOR Pathway Changes In Vitro and In Vivo
MONEPANTEL: ANTICANCER DRUG MTOR PATHWAY CHANGES IN VITRO AND IN VIVO POST MONEPANTEL rsonal use only Data from Western Blot analyses demonstrates, consistent dampening of p-RPS6KB1 (S6K1/2 in the adjacent figure) levels in numerous cells lines and quickly. These data suggest mTOR pathway inhibition
Slide 12: Comparative Structure
MONEPANTEL: ANTICANCER DRUG COMPARATIVE STRUCTURE mTOR inhibition by rapamycin Monepantel and the rapalogs rsonal use only MTORC1 Banaszynski et al., 2005 J Am Chem Soc DOI: 10.1021/ja043277y European Medicines Agency; Wikipedia Obvious different structure to rapamycin and the rapalogs Perhaps diffe
Slide 13: Monepantel Anticancer Activity Conclusions
MONEPANTEL: ANTICANCER DRUG MONEPANTEL ANTICANCER ACTIVITY CONCLUSIONS rsonal use only • Nicotinic receptors are apparently not involved: contrary to anthelmintic activity • Both S- and R-enantiomer possesses anticancer activity: contrary to anthelmintic activity • Monepantel sulfone possesses antic
Slide 14: Repeat Dose Safety Studies in Dogs
MONEPANTEL: SAFETY REPEAT DOSE SAFETY STUDIES IN DOGS rsonal use only • No significant toxicity • Centrilobular hypertrophy, increased liver enzyme levels and reduced weight gain https://apvma.gov.au/sites/default/files/publication/14141-prs-monepantel.pdf; https://www.ema.europa.eu/documents/scient
Slide 15: Sheep Pharmacokinetics
MONEPANTEL: PHARMACOKINETICS SHEEP PHARMACOKINETICS rsonal use only Karadzovska et al., 2009. J. vet. Pharmacol. Therap. 32, 359 Pharmacokinetics in sheep, dogs, rats and mice well known
Slide 16: Metabolic Pathway and Elimination
MONEPANTEL: METABOLISM METABOLIC PATHWAY AND ELIMINATION METABOLISM ELIMINATION rsonal use only 14C-Mpl secreted mainly (90%) through the feces 2.5 mg/kg bw rats = 3 days 5.0 mg/kg bw sheep = 2 – 3 weeks Boison and Sanders, 2012 http://www.fao.org/fileadmin/user_upload/vetdrug/docs/12-2012-monepante
Slide 17: Monepantel: Human Phase I/II Study
rsonal use only MONEPANTEL: HUMAN PHASE I/II STUDY Principal Investigator: Site 1: Department of Medical Oncology, Royal Adelaide Hospital: Professor Michael Brown Director, Cancer Clinic Trials Unit Royal Adelaide Hospital North Terrace ADELAIDE, SA 5000
Slide 18: Human Phase I/II PK and PD
MONEPANTEL: HUMAN PHASE I/II STUDY HUMAN PHASE I/II PK and PD • Tolerability, PK, PD and PET-CT rsonal use only • Daily administration for 28 days • Level 1: 6 enrolments, 5 mg/kg bw • Level 2: 2 enrolments, 25 mg/kg bw Mislang et al., 20201, Cancer Chemother Pharmacol doi: 10.1007/s00280-020-04146-
Slide 19: Human Phase I/II Tumour Measurements
MONEPANTEL: HUMAN PHASE I/II STUDY HUMAN PHASE I/II TUMOUR MEASUREMENTS PA02 NSCLC Target Lesions D(-1) D29 D (%) rsonal use only Left upper lobe medial 63 60 -5 Right superior hilum 38 29 -24 Left lower lobe 30 36 20 Sum 131 125 -5 PA04 CR-PAC Target Lesions Pre-aortic lymph node 20 22 10 Left para
Slide 20: Human Phase I/II Conclusions
MONEPANTEL: HUMAN PHASE I/II STUDY HUMAN PHASE I/II CONCLUSIONS rsonal use only • Safe • Unpalatable taste • No SAEs related to the study drug • Minor AEs (dysgeusia, dyspepsia, vomiting) • Good PK for 0 - 24 h • Poor compliance after D1 (unpalatability) • Reduction in PD markers • RECIST1.1 = 2 x S
Slide 21: Monepantel: Pet Dog Phase I/II Study
rsonal use only MONEPANTEL: PET DOG PHASE I/II STUDY Principal Investigator: Dr Angela Frimberger Director, Cancer Clinic Trials Unit Animal Referral Hospital Homebush Sydney, NSW, 2140
Slide 22: Dog Phase I/II Tolerance, Safety, PK and PD
MONEPANTEL: PET DOG PHASE I/II STUDY DOG PHASE I/II Tolerance, Safety, PK and PD rsonal use only Seven pet dogs with treatment naïve B cell lymphoma As with studies in mouse xenografts and cancer cell lines, the mTOR marker p-RPS6KB1 is reduced in these dogs blood cells following monepantel treatmen
Slide 23: Dog Phase I/II Conclusions
MONEPANTEL: PET DOG PHASE I/II STUDY DOG PHASE I/II CONCLUSIONS rsonal use only PharmAust Targeting Regression and Stable Disease • Safe – achieved endpoint • Apparent poor taste • No SAEs related to the study drug • AEs = nausea and vomiting • Reduction in mTOR pathway activity marker • 6/7 dogs wi
Slide 24: Tablet Taste: Preclinical and Clinical Testing
MONEPANTEL: TABLET DEVELOPMENT TABLET TASTE: PRECLINICAL AND CLINICAL TESTING rsonal use only Tablet Stability Data • GMP batch 1 = 24 months • GMP batch 2 = 19 months • No reportable impurities Poor palatability resolved Highly stable tablet
Slide 25: Monepantel: Phase II Pet Dog Trial: Tablets
rsonal use only MONEPANTEL: PHASE II PET DOG TRIAL: TABLETS Principal Investigators: Dr Claire Cannon Dr Kim Agnew Participating Sites U-Vet Werribee, Melbourne (Claire Cannon) VSS Underwood, Brisbane (Catherine Chan) ARH Homebush, Sydney (Sonya Yu) WAVES Success, Perth (Sue Bennett) UVTHS Camperdow
Slide 26: Trial Design: Precedent
MONEPANTEL: PHASE II PET DOG TRIAL: TABLETS TRIAL DESIGN: PRECEDENT Pet dogs with treatment naïve B cell lymphoma rsonal use only 1) CHOP TREATMENT 2) NO TREATMENT • PFS in remission upon CHOP completion • PFS from day of achieving CR on CHOP • PFS from date of start of treatment Mn ST = mean surviv
Slide 27: Trial Design: Adaptive Bayesian Approach
MONEPANTEL: PHASE II PET DOG TRIAL: TABLETS TRIAL DESIGN: ADAPTIVE BAYESIAN APPROACH B Cell Lymphoma rsonal use only 1. ORR (α,β;0.05,0.2) ORR = overall response rate (p0,p1;0.05,0.25) OCB = objective clinical benefit CR, PR: (r1,n1; 1,8) y n CR, PR: (r,n; 3,18) y n α = 0.05 (Pr incorrectly rejectin
Slide 28: Trial Design: Screening and Treatment Schedule
MONEPANTEL: PHASE II PET DOG TRIAL: TABLETS TRIAL DESIGN: SCREENING AND TREATMENT SCHEDULE rsonal use only
Slide 29: Enrolled Pet Dog Characteristics
MONEPANTEL: PHASE II PET DOG TRIAL: TABLETS ENROLLED PET DOG CHARACTERISTICS rsonal use only All advanced stage disease pet dogs
Slide 30: Peripheral Nodal Lymphoma Measurements
MONEPANTEL: PHASE II PET DOG TRIAL: TABLETS PERIPHERAL NODAL LYMPHOMA MEASUREMENTS rsonal use only • SD = Stable disease • PR = Partial response • PD = Progressive disease • N/A = no measurements available • N/P = no measurements provided • * six lesions included Monepantel is highly effective in co
Slide 31: VCOG RECIST v1.0 Outcomes for Peripheral Nodal Lymphoma
MONEPANTEL: PHASE II PET DOG TRIAL: TABLETS VCOG RECIST v1.0 OUTCOMES FOR PERIPHERAL NODAL LYMPHOMA rsonal use only • SD = Stable disease • PR = Partial response • PD = Progressive disease • N/A = no measurements available • N/P = not provided (not measured) • (x) only D14 available Vail et al., 201
Slide 32: Anticancer Conclusions: Major Findings
MONEPANTEL: ANTICANCER CONCLUSIONS MAJOR FINDINGS rsonal use only • Monepantel inhibits mTOR pathway activity (p-RPS6KB1) • Stage 1 of Bayesian design demonstrates that monepantel tablets provide objective anticancer activity • Stage 1 of Bayesian design demonstrates that monepantel tablets provide
Slide 33: Acknowledgements
ACKNOWLEDGEMENTS Human Studies Tablet Pet Dog Trial Prof Michael Brown, Royal Adelaide Hospital Dr Claire Cannon, U-Vet, Melbourne Dr Anna Mislang, Royal Adelaide Hospital Dr Kim Agnew, KAP Consulting, Sydney rsonal use only Dr Gonzalo Tapia Rico, Royal Adelaide Hospital Assoc Prof Peter Bennett, UT
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