Avacta Group Plc · LSE:AVCT
Avacta — Investor Day (February 2019)
67 slides from Avacta's investor day presentation, Feb 14, 2019
Slide 1: London Science Day
London Science Day February 14th Royal College of Physicians
Slide 2: Affimers: A Powerful Therapeutic Platform
Affimers: A Powerful Therapeutic Platform Avacta London Science Day Affimer Biotherapeutics: Shaping the Future of Cancer Therapy Amrik Basran PhD Chief Scientific Officer
Slide 3: Affimers: Best-in-class Antibody Mimetics
Affimers: Best-in-class Antibody Mimetics Based on naturally occurring proteins (Stefin A) and engineered Differentiating Features Compared to to stably display two loops forming a binding surface. Antibodies and Other Mimetic Scaffolds • Smaller and simpler structure than antibodies • Well behaved,
Slide 4: The Challenge for Cancer Therapies
The Challenge for Cancer Therapies Increasing safety and efficacy? Bispecific Formats, Novel Drug Conjugates + + Adapted from https://obroncology.com/ Doyle, C., October 2015 Edition Vol.11, Issue 10 © Avacta Life Sciences 2019 (CONFIDENTIAL) Slide | 4
Slide 5: Affimer Formats: Fc and In-line Fusions
Affimer Formats: Fc and In-line Fusions © Avacta Life Sciences 2019 (CONFIDENTIAL) Slide | 5
Slide 6: PD-L1 Programme: AVA04-251 Fc1
PD-L1 Programme: AVA04-251 Fc1 AVA04-251 hFc1 Biacore Kinetics • Lead molecule AVA04-251 formatted as an Fc and shown to be potent • Highly expressed from ExpiHEK and CHO during transient expression (>250 mg/L) • Single dose mouse PK gave half-life of ~120 hrs 6 AVA04-251 Fc SEC-HPLC AVA04-251 Fc AV
Slide 7: AVA04-251 hFc1: Storage at 200 mg/ml at +4 C
AVA04-251 hFc1: Storage at 200 mg/ml at +4 C Sample % Monomer AVA04-251 hFc1 at AVA04-251 hFc1 Day 1 97.9 200 mg/ml (PBS) Day 7 97.2 Day 21 96.0 Day 28 95.7 Day 47 95.8 2 Months 95.2 3 Months 95.7 4 Months 93.3 5 Months 92.9 6 Months 92.0 7 Months 92.2 • AVA04-251 hFc1 concentrated to ~200 mg/ml an
Slide 8: AVA04-251 Fc SEB and MLR Assays
AVA04-251 Fc SEB and MLR Assays T-cell Activation using T-cell Activation Activity by MLR Staphylococcus enterotoxin B (SEB) SQT-Gly Fc AVA04- Avelumab hIgG1 251 Fc All proteins are at 70 nM © Avacta Life Sciences 2019 (CONFIDENTIAL) Slide | 8
Slide 9: AVA04 251-Fc Efficacy: hPD-L1 MC38 Model
AVA04 251-Fc Efficacy: hPD-L1 MC38 Model hPD-L1 MC38 Syngeneic Model hPD-L1 MC38 Syngeneic Model Affimer Fcs (10mg/kg) Antibodies (5mg/kg) 3000 Tumour Volume (mm3) Tumour Volume (mm3) 2000 Vehicle SQT-Gly Fc AVA04-251 Fc 1000 0 D0 D3 D7 D10 D13 Days post randomization Days post randomization • Anti-
Slide 10: mAb-Affimer Bi-specifics: Avastin-AVA04-251
mAb-Affimer Bi-specifics: Avastin-AVA04-251 Single Dose Mouse PK (10 mg/kg) % injected to T=0 Avastin-A(EAAAK)3-251 Time (hours) AVA04-251 Fc
Slide 11: PD-L1/LAG-3 Programme: AVA21 Bispecific Fc Fusions
PD-L1/LAG-3 Programme: AVA21 Bispecific Fc Fusions PD-L1 Binding ELISA AVA21-06 AVA04 IC50 (pM) AVA21-06 20 AVA21-07 15 AVA19-1 AVA04 Fc 30 LAG-3 Binding ELISA kDa L NR R AVA21-07 3 IC50 (pM) 140 115 AVA04 80 70 10 45 0nm - 6 30n m AVA21-06 Ab sorban ce 50 2 40 30 AVA21-07 20 25 AVA19-1 Fc 20 AVA19-
Slide 12: AVA04-251 Dimer: Storage at 80 and 400 mg/ml
AVA04-251 Dimer: Storage at 80 and 400 mg/ml (+4 C) Sample % Dimer AVA04-251 dimer at 80 mg/ml (PBS) Day 1 100 Long/rigid linker 2 Months 99.0 A(EAAAK)6 5 Months 98.4 6 Months 98.0 8 Months 97.0 10 Months 96.3 Sample % Dimer AVA04-251 dimer at Day 1 100 400 mg/ml (PBS) Day 16 97.9 Long/rigid linker
Slide 13: Affimer XT: Half-life Extension Platform
Affimer XT : Half-life Extension Platform Affimer XT Platform IgG/Fc Fusions PEGylation Serum Albumin Utilising IgG FcRn recycling Increased hydrodynamic size Affimer biotherapeutic binds to maintain high serum of the protein to prevent to SA in the circulation levels clearance via the kidneys Direc
Slide 14: AVA21 ILF XT Format
AVA21 ILF XT Format (1) AVA21_08_XT AVA04 XT AVA19-1 (2) AVA21_09_XT AVA04 XT AVA19-2 © Avacta Life Sciences 2019 (CONFIDENTIAL) Slide | 14
Slide 15: Co-stimulatory Activation of the Immune System
Co-stimulatory Activation of the Immune System • Benefits of improved efficacy by combining check-point blockade with agonistic immunotherapy giving a synergistic effect (e.g. PD- (L)1 blockade with CD40 agonism) • Bispecific biologics targeted to the tumour microenvironment (TME), cluster and activ
Slide 16: Affimer Formatting for Agonism
Affimer Formatting for Agonism Fcγ independent/ dependent cross-linking Cancer Cell Target No activation Low level of High level of Low level of High level of High level of activation activation activation activation activation © Avacta Life Sciences 2019 (CONFIDENTIAL) Slide | 16
Slide 17: PoC for an Fc Formatted Affimer Agonist (CD40)
PoC for an Fc Formatted Affimer Agonist (CD40) CD-40/CD40L HEK Blue report gene assay • Phage selections carried out against human CD40 • Lead clone AVA23-18 was formatted on an Fc and shown to agonise CD40 on HEK Blue cells in vitro © Avacta Life Sciences 2019 (CONFIDENTIAL) Slide | 17
Slide 18: Gene Delivery of Affimer Therapeutics
Gene Delivery of Affimer Therapeutics © Avacta Life Sciences 2019 (CONFIDENTIAL) Slide | 18
Slide 19: A Game Changer?
A Game Changer? Tumour Microenvironment (TME) DNA, RNA or viral Demonstrated that delivery of functional Affimers can be expressed and anchored at “Encoded Affimer” the cell surface and modulate pathways Anchoring to the cell membrane Secretion of Affimer Transcription therapeutics to Translation mo
Slide 20: PoC for Gene Delivered Membrane Bound Affimer Agonists (CD40)
PoC for Gene Delivered Membrane Bound Affimer Agonists (CD40) • AVA23-18 was encoded and used to CD40 binding Affimer transform HEK293 cells. Linker • The Affimer is expressed, folds correctly and can agonise CD40 on the cell Transmembrane domain surface (HEK Blue) Slide | 20 © Avacta Life Sciences
Slide 21: PoC for Gene Delivered Secreted Affimer Therapies
PoC for Gene Delivered Secreted Affimer Therapies: In vivo Affimer-Fc Production in Mice Muscle Tissue Protein expressed into the bloodstream Electroporation Serum Level following Single Affimer 1 Affimer 2 mAb Electroporation Time (days) Time (days) Time (days) 21 © Avacta Life Sciences 2019 (CONFI
Slide 22: Affimer: A Powerful Therapeutic Platform
Affimer®: A Powerful Therapeutic Platform Slide | 22
Slide 23: Affimer
Affimer
Slide 24: Extending the Benefits of Immunotherapy Beyond Inflamed Tumours
Extending the Benefits of Immunotherapy Beyond Inflamed Tumours with Affimer Molecules Avacta London Science Day Affimer Biotherapeutics: Shaping the Future of Cancer Therapy Jose Saro MD Chief Medical Officer
Slide 25: Solid Tumors: Tumor Phenotype by T-cell Staining
Solid Tumors: Tumor Phenotype by T-cell Staining Inflamed Non-inflamed TILs PD-L1 expression CD8+ T cells Genomic instability Pre-existing immunity 20-30% patients 70-80% patients © Avacta Life Sciences 2019 (CONFIDENTIAL) Slide | 25 Levitsky, SITC 2014
Slide 26: Response to Checkpoint Inhibition
Response to Checkpoint Inhibition Inflamed Non-inflamed Can responses Can we convert these to be improved? responsive? Tumor phenotype by T cell staining 20-30% patients 70-80% patients Responsive to Checkpoint Non-responsive to Checkpoint inhibition inhibition © Avacta Life Sciences 2019 (CONFIDENT
Slide 27: Solid Tumor Microenvironment Immuno-phenotypes
Solid Tumor Microenvironment Immuno-phenotypes Inflamed Non-Inflamed Pre-existing Immunity Excluded Infiltrate Immunologically Ignorant Mutational Load TILs Angiogenesis Hegde PS et al., CCR, 2018 Proliferating CD8 T cells/IFNg Reactive stroma Tumors/ PD-L1 MDSCs Low Class I Respond favorably to Con
Slide 28: The Cancer-Immunity Cycle
The Cancer-Immunity Cycle 3 Priming and activation 4 Trafficking of T-cells to tumors Active T cell Active T cell 5 Infiltration of T-cells Accessing into tumors the tumor Dendritic Initiating and propagating cell anti-cancer immunity TUMOR MICROENVIRONMENT 6 Recognition of Cancer-cell recognition a
Slide 29: Manipulating the Immune Response in Cancer
Manipulating the Immune Response in Cancer Gene delivery Sensitize tumor cells to immunotherapies T cell production: Enhance effectors Reduce Tregs Vaccines: exogenous vs “endogenous” T cell function: Enhance effectors Block suppression Promote infiltration Inhibit Tregs Mellman et al (2011) Nature
Slide 30: Pre-existing Immunity Phenotype
Pre-existing Immunity Phenotype: The T-Cell army armed and ready The T-cell army by Jerome Groupman The New Yorker, April 23rd, 2012 PD-L1 CD8 Powderly et al. MPDL3280A Anti-PDL1 Phase I ASCO 2013 Slide | 30 © Avacta Life Sciences 2019 (CONFIDENTIAL)
Slide 31: Mutational Load Contributes to Clinical Benefit to Checkpoint Inhibition
Mutational Load Contributes to Clinical Benefit to Checkpoint Inhibition Inflamed • PD-L1 expression • IFN-g producing CD8+ T cells • Genomic instability • Pre-existing immunity © Avacta Life Sciences 2019 (CONFIDENTIAL) Slide | 31
Slide 32: Checkpoint Inhibition Works Best in Tumors with IFNg Producing CD8+ T-cells
Checkpoint Inhibition Works Best in Tumors with Increased expression of IFNg Producing CD8+ T-cells Inflamed Tumor gene expression of IFNg signature in POPLAR • PD-L1 expression • IFN-g producing CD8+ T cells • Genomic instability • Pre-existing immunity Zou W, Ballinger M, Miley N, Kowanetz M © Ava
Slide 33: Excluded Phenotype
Excluded Phenotype: The T cell army can’t cross the “river” The T-cell army by Jerome Groupman The New Yorker, April 23rd, 2012 Powderly et al. MPDL3280A Anti-PDL1 Phase I ASCO 2013 Slide | 33 © Avacta Life Sciences 2019 (CONFIDENTIAL)
Slide 34: Stromal Signatures Associated with Poor Prognosis: TNBC, CRC
Stromal Signatures Associated with Poor Prognosis: TNBC, CRC Molinero L, SABCS 2015 34 Similar observations made in CRC (AVANT) Slide | 34 © Avacta Life Sciences 2019 (CONFIDENTIAL)
Slide 35: Differentiated Affimer Therapeutics
Differentiated Affimer Therapeutics ❖ Ease of formatting, small size and stability Monomeric to Multi-specific Formats Serum Half-Life Conjugates Each Affimer can have tailored affinity Tunable from hours to Conjugates with toxins, mAbs and binding kinetics (Kd, koff, kon) weeks and other therapeuti
Slide 36: Strategy: Building an Innovative Drug Pipeline
Strategy Building an Innovative Drug Pipeline Novel TME active drug conjugates built on PD-L1 anchored multi-specifics Non-inflamed Tumours Strategy: Inflamed Tumours Strategy: Combinations with Pro-inflammatory Multi-specific Therapies Drugs 70% 70%patients patients 30% patients Key Benefits: Forma
Slide 37: Differentiated Affimer Therapeutics
Differentiated Affimer Therapeutics Lead Programme Discovery Pre-clinical Phase 1 Optimisation Checkpoint Antagonists AVA-004 PD-L1 AVA-021 Bispecific AVA-017 LAG-3 Affimer TMACTM Drug Conjugates AVA-040 PD-L1/I-DASH Technology Development AVA-003 Affimer XT (serum albumin) Undisclosed PK/ADME Modif
Slide 38: Immunologically Ignorant Phenotype
Immunologically Ignorant Phenotype: Sometimes No One is at Home Cancer No T-cell Army The T-cell army by Jerome Groupman The New Yorker, April 23rd, 2012 Molinero, et al. ASCO 2103 © Avacta Life Sciences 2019 (CONFIDENTIAL) Slide | 38
Slide 39: Differentiated Affimer Therapeutics
Differentiated Affimer Therapeutics ❖ High cellular expression levels DNA, RNA or viral Inhibition of intracellular targets delivery of the Example: b-catenin Affimer gene Secretion from the cell for intra- Cell membrane tumoral or systemic delivery. anchoring for Example: expression from targeting
Slide 40: Avacta's Mission
Avacta’s Mission • Avacta’s mission is to build a pipeline of innovative and differentiated Affimer drugs to extend the benefits of immunotherapy to cancer patients that currently do not respond to available checkpoint inhibitor treatments. • Avacta’s immediate focus on combinations and novel tumour
Slide 41: Affimer
Affimer
Slide 42: Immuno-oncology Active Affimer Drug Conjugates
Immuno-oncology Active Affimer Drug Conjugates Potent Combination of Adaptive and Innate Immune Inducers Avacta London Science Day Affimer Biotherapeutics: Shaping the Future of Cancer Therapy William Bachovchin, PhD Professor, Tufts University School of Medicine Founder, BACH Biosciences LLP
Slide 43: TME-activated Affimer Drug Conjugates (TMACs)
TME-activated Affimer Drug Conjugates (TMACs) TMAC Program combines non-internalizing Checkpoint Inhibitory Affimers with Potent Drug Moieties capable of disrupting the tumor stroma and inducing strong innate inflammatory and adaptive immune responses. Inert when linked Drug Moiety Linker Affimer In
Slide 44: TME-activated Affimer Drug Conjugates (TMACs)
TME-activated Affimer Drug Conjugates (TMACs) AVA-004/100| FAPa-activated anti-PD-L1/I-DASH Inhibitor TMAC Drug Moiety Checkpoint Inhibitor(s) PD-L1 (monomeric or dimeric) I-DASH Inhibitor • Potent Immune Inducer: Induces macrophage pyroptosis which • Synergism: PD-L1 inhibitors have demonstrated ac
Slide 45: FAP-Cleavable Linker
FAP-Cleavable Linker Slide | 45
Slide 46: Targeting Enzyme FAPa: A TME-upregulated Activator
Targeting Enzyme FAPa: A TME-upregulated Activator Source: Bach Biosciences LLP Adapted from Dolznig et al. Cancer Immun. 2005 Aug 3;5:10 Fapa is selectively overexpressed in the tumour microenvironment of most solid tumours – TMAC exploits the difference in enzyme activity between normal and tumour
Slide 47: FAPa Elevated in Liver Metastasis Sites
Tumour Models Indicate FAPa is also Elevated in Liver Metastasis Sites FAPa expression in sites of liver metastasis indicates potential for targeting by TMACs • Tumour cells derived from genetically engineered (Apcflox/flox KrasG12D p53flox/flox) mice were implanted in spleens • FAP enzymatic activi
Slide 48: TME Activated Substrate: Very Tightly Controlled
TME Activated Substrate: Very Tightly Controlled FAPa-Selective Activation TMAC program includes highly selective linker/substrate for FAPa release of warheads Prototypical FAPa – activated Linker Warhead is Bortezomib (Velcade) analog [warhead released] (ng/mL) In Vitro Activation Rates Warhead Rel
Slide 49: Drug Moieties
Drug Moieties © Avacta Life Sciences 2019 (CONFIDENTIAL) Slide | 49
Slide 50: Modular Design Enabled
Modular Design Enabled Linking Chemistry + Spacer Enzyme Cleavage Site Optional: self immolative linker Drug Moiety I-DASH Inhibitor B(OH)2 FAP substrate 4087 extended linker TRL7/8 Agonist 4087E-2 in vitro activation by FAP and PREP 8×10-9 7×10-9 MMP2 substrate Released warhead(M/sec) 6×10-9 5×10-9
Slide 51: I-DASH Inhibitor: Differentiated from Traditional ADC Warheads
I-DASH Inhibitor: Differentiated from Traditional ADC Warheads Very Potent Drug Moiety with Immuno- oncology Mechanism-of-Action © Avacta Life Sciences 2019 (CONFIDENTIAL) Slide | 51
Slide 52: I-DASH Inhibitor: Exploits Macrophage-Selective Cell Death Pathway
I-DASH Inhibitor: Exploits Macrophage-Selective Cell Death Pathway Pyroptosis leads to “inflammatory death” Pyroptosis Apoptosis I-DASH Inhibitors Induce Both Adaptive and Innate Immune Responses One of the key mechanism-of-action to I-DASH Inhibitor Antitumor Activity is Induction of Macrophage Pyr
Slide 53: I-DASH Inhibitor: Induce Macrophage Pyroptosis
I-DASH Inhibitor: Induce Macrophage Pyroptosis Direct and Indirect Effects * Immunostimulatory Biological and Immunological Mechanisms-of- Action and Effects Determined in Collaboration Cytokines with National Cancer Institute (NIH), Fox Chase Cancer Center and Memorial Sloan Kettering Increase (loc
Slide 54: Syngeneic Model: MB49
Syngeneic Model: MB49 (urothelial carcinoma) AVA-004 182-Fc is an Fc formatted (bivalent) version of an affimer that binds to mouse PD-L1 with high affinity Affimer (PDL1 182) and Avelumab both have demonstrated antitumor activity that is significantly enhanced in combination with an I-DASH Inhibito
Slide 55: Syngeneic Model: MB49
Syngeneic Model: MB49 (urothelial carcinoma) Vehicle 400 mg PDL1 182 200 mg PDL1 182 200 mg PDL1 182 + I-DASH Vehicle + I-DASH 200 mg Avelumab 200 mg Avelumab + I-DASH Multiple animals in the I-DASH Inhibitor combination groups were fully regressed by end of drug dosing portion of study © Avacta Lif
Slide 56: Syngeneic Model: hPD-L1 MC38
Syngeneic Model: “hPD-L1” MC38 (mouse colon adenocarcinoma with human PD-L1 knock-in) AVA-004 251-Fc is an Fc formatted (bivalent) version of an affimer that binds to human PD-L1 with high affinity + I-DASH + I-DASH Affimer (PDL1 251) and Atezolizumab both have demonstrated antitumor activity that i
Slide 57: Syngeneic Model: hPD-L1 MC38
Syngeneic Model: “hPD-L1” MC38 (mouse colon adenocarcinoma with human PD-L1 knock-in) SQT-GLY Fc 10mg/kg + I-DASH AVA04 251 Fc 10mg/kg + I-DASH SQT-GLY Fc 10mg/kg + I-DASH AVA04 251 Fc 10mg/kg AVA04 251 Fc 10mg/kg + I-DASH AVA04 251 Fc 10mg/kg Affimer +/- I-DASH Inhibitor Atezolizumab 5 mg/kg AVA04
Slide 58: I-DASH Inhibitor: MOA is Dependent on Caspase-1
I-DASH Inhibitor: MOA is Dependent Caspase-1 on Pilot KO Efficacy Caspase-1 Study Caspase-1 KO Efficacy Pilot Study G-CSF in Mouse Serum Following PO Dosing with 100 mg I-DASH Inhibitor Macrophage lacking Caspase-1 are no Vehicle longer sensitive to I-DASH Inhibitors 20 mg I-DASH MB49 Mouse Model •
Slide 59: I-DASH Inhibitors Modify Immune Response Towards Inflamed Phenotype
I-DASH Inhibitors Modify Immune Response in Tumours Towards Inflamed Phenotype I-DASH Inhibitor Efficacy is Dependent on T-cells I-DASH Inhibitor I-DASH + anti-CD4/8 T-cell depletion with anti-CD4 and/or anti-CD8 I-DASH + anti-CD4 I-DASH + anti-CD8 monoclonal antibodies as significantly reduces I- A
Slide 60: I-DASH Inhibitors Accelerate T Cell Priming via Dendritic Cell Trafficking
I-DASH Inhibitors Accelerate T Cell Priming via Modulation of Dendritic Cell Trafficking I-DASH Inhibitor exposed CD11c+ cells No I-DASH Inhibitor + I-DASH Inhibitor post injection Antitumor activity with I- DASH Inhibitors is associated with increased trafficking of DCs into Tumor and TDLNs. Purifi
Slide 61: I-DASH Inhibitors: Induce Macrophage Pyroptosis
I-DASH Inhibitors: Induce Macrophage Pyroptosis Direct and Indirect Effects * Immunostimulatory Biological and Immunological Mechanisms-of- Action and Effects Determined in Collaboration Cytokines with National Cancer Institute (NIH), Fox Chase Cancer Center and Memorial Sloan Kettering Increase (lo
Slide 62: Affimer
Affimer
Slide 63: Closing Remarks
Avacta London Science Day Affimer Biotherapeutics: Shaping the Future of Cancer Therapy Closing Remarks Alastair Smith, PhD Chief Executive Officer
Slide 64: Affimer: A Powerful Therapeutic Platform
Affimer®: A Powerful Therapeutic Platform Slide | 64
Slide 65: Strategy: Building an Innovative Drug Pipeline
Strategy Building an Innovative Drug Pipeline Significant clinical, commercial and shareholder value will be created through development of a pipeline of innovative, I-O active Affimer drug conjugates built upon multi-specific Affimer ICP therapies which extend the benefits of cancer immunotherapy t
Slide 66: Closing Remarks
Closing Remarks • Major near-term value inflection points: • Additional validating commercial partnerships • Clinical data for the Affimer platform • Plus: • First TMAC molecule efficacy in vitro and in animal models • Candidate selection and pre-clinical development milestones for PD-L1 programme •
Slide 67: Affimer
Affimer