Pyc Therapeutics Limited · ASX:PYC
Pyc Therapeutics — Phylogica — BIO-Europe 2017
35 slides from Pyc Therapeutics's conference presentation, Nov 6, 2017
Slide 1: Phylogica: Creating better drugs through revolutionary intracellular therapeutics
For personal use only Phylogica Creating better drugs through revolutionary intracellular therapeutics Phylogica datapack November 2017, BIO-Europe
Slide 2: Disclaimer
Disclaimer For personal use only The purpose of the presentation is to provide an update of the business of Phylogica Limited (ASX:PYC) [‘Phylogica’]. These slides have been prepared as a presentation aid only and the information they contain may require further explanation and/or clarification. Acc
Slide 3: About Us
About Us For personal use only What Who are What do makes us we? we do? unique? Biotech platform Expand the reach of Our proprietary library technology that biologic drugs to the of cell-penetrating enhances a highly previously peptides coupled with potent class of undruggable our sophisticated biol
Slide 4: Experienced Management Team
Experienced Management Team For personal use only In mid 2017 Phylogica revitalised its management team with senior Pharma and commercial executives: Core Management Team Deep executive and commercial Highly seasoned pharmaceutical experience executive § Executive at $3B energy utility; Ms Stephanie
Slide 5: Scientific Advisory Board
Scientific Advisory Board For personal use only In October 2017 Phylogica established and made first appointments to its Scientific Advisory Board: Dr Steve Doberstein joined Nektar Therapeutics in 2010 as Senior Vice Professor Judy Lieberman Prof Judy Lieberman is the Chair in Cellular President an
Slide 6: Our library of Phylomers
Our library of Phylomers® § Phylomers are peptides derived from evolutionary For personal use only diverse eubacterial and archaebacterial genomes and more recently from viral genomes (selected genes only) § Enriched for natural secondary structures which have evolved for high affinity and biologica
Slide 7: The Problem: drug cargoes are trapped in the endosomes
The Problem: drug cargoes are trapped in the endosomes For personal use only Contact triggers 99% of drug Drug contacts cell formation of trapped in membrane endosomes endosome Drug CPP Drug target Drug target Budding Cytoplasm endosome Endosome Cell membrane Conventional CPPs are often only active
Slide 8: Our Solution: Phylogica's endosomal escape trap
Our Solution: Phylogica’s endosomal escape trap For personal use only 4. SA -Repeat Avitag Phylomer V biopanning (x2) - sequencing 1. 3. 1. Phage is taken up by endosomes T7 Phage 2. Library 2. FPP mediates phage release BirA 3. Biotinylation of Avitag 4. Capture of biotinylated phage on Streptavidi
Slide 9: Significant constraints in existing drug discovery approaches
Significant constraints in existing drug discovery approaches For personal use only The Our problem? solution? Drug discovery growth We can bring biologics stagnating as biologics into the cell, unlocking currently limited to the potential of these extracellular targets powerful drugs by (unable to
Slide 10: Validation of FPP endosomal escape using the split GFP complementation assay
Validation of FPP endosomal escape using the split GFP complementation assay For personal use only Our split GFP assay identifies FPPs that escape the endosome, to deliver cargoes to the cytoplasm 10
Slide 11: Validation of FPP endosomal escape using split GFP complementation assay
Validation of FPP endosomal escape using the split GFP complementation % complemented assay cells (HCC-827) For personal use only 100 Protein Conc. % Green cells (Split-GFP +ve) 20µM 80 10µM 160 fold 5µM 37 fold 2.5µM 60 1.25µM 0.667µM 40 20 0 1 22 35 9 n P1 4 PP T T T 2 N J0 R D A Pe TA hC A PE VP
Slide 12: Phylogica is creating a versatile 'bank' of FPPs
Phylogica is creating a versatile ‘bank’ of FPPs to serve multiple requirements For personal use only § Identifying new and more potent FPPs from our patented libraries Potency § Maturing existing FPPs to increase their potency, i.e. through rational design § Identifying FPPs with high potency for a
Slide 13: Building a comprehensive matrix of FPPs for different cargoes and cell types
Phylogica is building a comprehensive matrix of FPPs to target different cargoes and cell types For personal use only FPP validation matrix Small Oligo- Bispecific Expand to protein/ Antibody nucleotide compounds new Peptides Scaffolds Enzymes fragments (PMO) cargoes Breast tumour Blood cancer Conce
Slide 14: FPPs deliver a diverse class of cargoes
FPPs deliver a diverse class of cargoes For personal use only Cargo Class Cargo Size/Charge Toxin / large protein Bouganin 28 kDa, pI 7.8 Small protein Omomyc 11 kDa, pI 9.6 scaffold Enzymatic protein 𝛽-lactamase 42 KDa, pI 5.5 50 kDa MW, Large disordered 600 kDa equiv. PAS protein hydrodynamic…
Slide 15: Efficient delivery of Phylomer CPPs into brain endothelial cells
Efficient delivery of Phylomer CPPs into brain endothelial cells For personal use only bEnd.3 CHO-K1 SVEC4-10 -ve control CPP1 CPP2 CPP3 NOTE: These Phylomers have not been validated using Phylogica’s endosomal escape validation assays Phylomer CPPs can efficiently enter mouse brain endothelial cell
Slide 16: FPPs show no evidence of toxicity
FPPs show no evidence of toxicity For personal use only Toxicity in adult male C57BL/6J mice, 40mg/kg dose, daily injections for 7 days FPP (n=6) Untreated (n=4) Mean StDev Mean StDev Significance ALT, U/L 59.73 39.09 107.60 18.54 No, p=0.054 AST, U/L 84.98 69.05 81.61 44.02 No, p=0.94 Urea, mg/dL 5
Slide 17: FPP1 has been significantly improved upon, new variants being validated
FPP1 has been significantly improved upon, and new variants are being validated in vitro For personal use only CHO-K1 cells September 1746 SAR Peptides - β-lactamase Assay (All Product Positive Events) 80 Attune - 28 September 2017 4uM 2uM 60 Frequency (%) 1uM 0.5uM 40 1746c27 20 FPP1 0 FPP2 cell en
Slide 18: FPPs compatible with engineering approaches to enhance pharmacological properties
FPPs are compatible with engineering approaches to enhance pharmacological properties For personal use only Strategies - Increase receptor cycling Desired Effects - Increase protein size and negative charge Serum half-life extension - Fc Fusion Reduced clearance - Albumin - ABDCon - PEGylation - PAS
Slide 19: Efficient delivery of an FPP-conjugated enzyme (b-Lactamase)
Efficient delivery of an FPP-conjugated enzyme (b-Lactamase, BLA) For personal use only Blue Fluorescence; CHO-K1 cells incubated with 1746c27-BLA Blue fluorescence, CHO-K1 cells incubated with FPP1-BLA for 1 h - BLA (4uM) FPP1- BLA (4 uM) FPP-mediated cell entry CCF2AM (510) B-lactamase (V450) FPPs
Slide 20: Optimised FPPs mediate enhanced delivery of b-Lactamase into breast cancer cells
Optimised FPPs mediate enhanced delivery of b-Lactamase into breast cancer cells For personal use only Blue fluorescence, T47D cells incubated with FPP1-BLA or optimised variant, FPP2 for 1 h 1 µM 2 µM 4 µM FPP1-BLA 1 uM 2 uM 4 uM FPP2-BLA Our FPPs are constantly being improved for enhanced delivery
Slide 21: Efficient cytoplasmic delivery of proteins using split b-Lactamase assay
Efficient cytoplasmic delivery of proteins using a split b-Lactamase complementation assay For personal use only Blue Fluorescence; CHO-CBLA cells incubated with FPP1-NBLA (8 µM) Stably'transfected mammalian' cell Only endosomal NBLA escape leads to CBLA NBLA CBLA b-lactamase complementation and sig
Slide 22: Dystrophin levels restored by FPP-mediated delivery of DMD PMO in vivo
Dystrophin levels are restored by FPP-mediated delivery of DMD1 PMO2 in vivo For personal use only Dystrophin levels and muscle architecture, C57BL/10ScSnmdx mice Treated mice Untreated mice DMD oligo FPP1-DMD oligo Normal DMD Leg Diaphragm Heart Collaborator: Sue Fletcher, Centre for Comparative Ge
Slide 23: FPP-delivered pro-apoptotic peptide impacts cell viability across cell lines
FPP-delivered pro-apoptotic peptide (PAP) significantly impact cell viability in a range of cell lines For personal use only Cell viability after 24 h 150 100 ** % Viability ** *** **** CHO-K1 MDA468 50 MCF-7 0 T47D 46 AP P P 46 AP P P 46 AP P P 46 AP P P A TA PA A TA PA A TA PA A TA PA 17 T-P -P 17
Slide 24: Oncology Pipeline harnesses our FPP technology to reach intracellular targets
Phylogica’s Oncology Pipeline harnesses our FPP technology to reach intracellular targets For personal use only § Phylomer screens against validated and clinically relevant oncology targets – cMyc, N-Myc, Stat5 and YB1 § Validated hits already exceed potency of gold standard inhibitors § Stat5 and Y
Slide 25: FPP-Omomyc inhibits breast cancer cell growth in vivo
FPP-Omomyc inhibits breast cancer cell growth in vivo For personal use only Tumour volume, T11 triple negative Animals with tumours, T11 triple negative breast cancer graft in mice breast cancer graft in mice Injection i.t Vehicle Omomyc FPP3 FPP3-Omomyc Vehicle Omomyc FPP3 FPP3-Omomyc Collaborator:
Slide 26: FPP-Omomyc is active across multiple cell types
FPP-Omomyc is active across multiple cell types For personal use only Cell line Disease Cell Line Characteristics T47D Breast cancer p53 mut(hetero), Myc+++ MDA-MB-468 Breast cancer p53 mut(hetero), triple -ve SUM159 Breast cancer Basal, Triple -ve B1.15 (mouse) Breast Cancer Basal, Brca-/- A1.8 (mo
Slide 27: Potent activity of bi-specific compound targeting BCL/MCL and MYC
Potent activity of bi-specific compound targeting BCL/MCL and MYC in EµMyc lymphoma cells For personal use only Cell viability after 24 h, EµMyc murine lymphoma cells FPP Bim - Omomyc FPP Omomyc/Bim bispecific in Eu-myc cells (24h) 100 IC50 = 2.2 µM % Viability FPP1-Omomyc FPP-omomyc FPP1-Bim FPP-Bi
Slide 28: iMyc outperforms Omomyc and small molecule MYC inhibitors in AMO-1 cells
iMyc outperforms Omomyc and small molecule MYC inhibitors in AMO-1 human myeloma cells For personal use only AMO-1 ATP ATP DMSO Activity Activity (%) 24hrs - Combined data DMSO control DMSO FPP1 1746c27 Phylogica’s 140 after 24 h AMO-1 ATP Activity 24hrs - Combined data 1746c27 Omomyc His_Omyc (UQ)
Slide 29: High affinity primary 'iMyc' Phylomers against human c-MYC
High affinity primary ‘iMyc’ Phylomers against human c-MYC For personal use only Human c-MYC Binding Affinity; kD determined using Octet® Systems kD (nM) kD (nM) (Mean) (SD) MAX 47.1 11.2 iMyc1 30.4 4.3 iMyc2 176.2 107.9 Omomyc 191.5 34.5 (n > 3) Phylogica’s first generation iMyc phylomers have targ
Slide 30: FPP targets cross presenting dendritic cells for peptide vaccine
FPP efficiently targets cross presenting dendritic cells for an effective peptide vaccine For personal use only Collaborator: Jason Waithman, Telethon Kids Institute • FPP3 and XCR1 ligand facilitate internalisation into cells • Only endosomal escaping CPPs will result in CD8+ T cell expansion via M
Slide 31: FPP delivered antigen leads to greater expansion of CD8+ T cells than TAT
FPP delivered antigen leads to greater expansion of CD8+ T cells compared to TAT For personal use only CD8+ T cells (%), mice CD8primed with FPP3-Ag or TAT-Ag for 14 days. Analysis of T cells 7 T cell expansion days post-challenge 2 nmol dose 4.0 ** Percent CD8 (%) 3.5 **** ** CD8+ T cells attack tu
Slide 32: Partnering Strategy
Partnering Strategy For personal use only Helping customers add value to their … and partnering with academia to enhance existing drugs … the value of our library 32
Slide 33: Antimicrobials
Antimicrobials For personal use only The Problem: Antimicrobial resistance is one of the 3 most important health problems Our Solution: Phylogica’s diverse platform and proprietory cell penetrating peptide discovery technology is being harnessed to discover novel antibiotics sensitive resistant – Ou
Slide 34: PYC platform solutions: every step of the way
PYC platform solutions: every step of the way For personal use only Phylomer screens - Tailored FPP for intracellular delivery - Phylomer for inhibition In vitro validation Our Client In vivo validation Preclinical product 34
Slide 35: Phylogica adds value to customer drugs
Phylogica adds value to customer drugs For personal use only Typical drug DRUG PRECLINICAL CLINICAL FDA APPROVAL discovery process DISCOVERY (animal testing) (human trials) Typical Timelines 5 years 1.5 years 6 years 1-2 years Determination Drug safety & Drug safety & Regulatory Key of a suitable ef