Avacta Group PLC · LSE:AVCT
Avacta — Investor Day (February 2023)
120 slides from Avacta's investor day presentation, Feb 23, 2023
Slide 1: Avacta Therapeutics Science Day
Avacta Therapeutics Science Day 23 February, 2023
Slide 2: Agenda
13:20 Strategic Overview Alastair Smith, CEO 13:35 Transforming treatment outcomes for cancer patients Fiona McLaughlin, CSO 14:05 Opportunities and challenges for cell and gene therapies for oncology and beyond Dr Krishna Komanduri 14:45 Break 14:55 ALS-6000-101 Phase 1a Clinical Study Update Andre
Slide 3: Strategic Overview
Strategic Overview Dr. Alastair Smith, Chief Executive Officer, Avacta Therapeutics
Slide 4: Avacta Therapeutics Science Day
Avacta Therapeutics Science Day © Avacta Group plc 2023 (CONFIDENTIAL) 4
Slide 5: Our guests
Our guests Krishna Komanduri, MD William D. Tap, MD Physician-in-chief of the Helen Diller Family Chief, Sarcoma Medical Oncology Service Comprehensive Cancer Center (HDFCCC) and Memorial Sloan Kettering Cancer Center Clinical Director of the UCSF Living Therapeutics Initiative © Avacta Group plc 20
Slide 6: Avacta Group plc
Avacta Group plc Our purpose is to improve patients’ lives and grow shareholder value by developing novel cancer therapies and powerful diagnostics using our proprietary Affimer® and pre|CISION™ platforms Therapeutics Diagnostics Harnessing our proprietary technologies to M&A-led strategy to build a
Slide 7: Avacta Therapeutics Vision and Strategy
Avacta Therapeutics Improving cancer patients’ lives through innovation and partnership Vision Strategy Our vision is to deliver • Use our proprietary innovative oncology drugs pre|CISIONTM and that transform treatment Affimer® platforms to outcomes to improve develop best-in-class and cancer patien
Slide 8: Avacta Therapeutics
Avacta Therapeutics Harnessing the pre|CISIONTM and Affimer® drug platforms enables a differentiated approach to delivering innovative cancer therapeutics © Avacta Group plc 2023 (CONFIDENTIAL) 8
Slide 9: www.avacta.com
www.avacta.com www.avacta.com
Slide 10: Transforming treatment outcomes for cancer patients
Transforming treatment outcomes for cancer patients Dr. Fiona McLaughlin, Chief Scientific Officer, Avacta Therapeutics
Slide 11: Avacta Therapeutics Pipeline – 2023
Avacta Therapeutics Pipeline – 2023 11
Slide 12: pre|CISION tumour targeted masking technology
pre|CISIONTM tumour targeted masking technology Cancer-associated fibroblasts (CAFs) are a FAP is a membrane bound protease that pre|CISIONTM substrate is cleaved by FAP to major component of the tumour is expressed on the surface of CAFs release a warhead selectively in the tumour microenvironment
Slide 13: pre|CISION new MOA video animation available
pre|CISIONTM new MOA video animation available View the video at www.avacta.com/therapeutics 13
Slide 14: Delivering warheads direct to the tumour
Delivering warheads direct to the tumour 14
Slide 15: pre|CISION
pre| CISION” ® —@Q * Chemotherapy, cytotoxic payloads and IO drugs are not tumour-selective + Off and on target effects systemically limit Therapeutic Index + Unmet need to differentiate between tumour and normal cells * Mask the activity of highly active agents systemically + Activate selectively i
Slide 16: AVA6000: Targeting chemotherapy to the tumour microenvironment
AVA6000: Targeting chemotherapy to the tumour microenvironment Doxorubicin Inactive AVA6000 (warhead) “leaving group” FAPa Enzyme-Mediated Hydrolysis of AVA6000 + H2 O AVA6000 is inactive until it is cleaved by Fibroblast Activating Protein (FAP) to release the anthracycline Doxorubicin 16
Slide 17: AVA6000 is selectively cleaved by FAP to release its warhead
AVA6000 is selectively cleaved by FAP to release its warhead and kills tumours AVA6000 is exquisitely selective for In this PDX model using tumour cells from a cleavage by the protease FAPa heavily pretreated sarcoma patient, AVA6000 markedly reduces tumour growth Data presented at AACR April 2022 a
Slide 18: AVA3996 – the 2nd pre|CISION Candidate
AVA3996 – the 2nd pre|CISIONTM Candidate FAPa Enzyme-Mediated Hydrolysis of AVA39996 AVA3996 FAP activated proteasome inhibitor New Chemical Entity Proven specificity for FAPa versus other proteases Delivers proteasome inhibitor directly to the tumour microenvironment In IND enabling studies FIH pla
Slide 19: AVA3996 – Improved Therapeutic Index vs Velcade
AVA3996 – Improved Therapeutic Index vs Velcade in patient derived tumours AVA3996 flat lines tumour growth without weight loss MV18341: Efficacy of AV3996 in Mel13281 Body Weight Loss FAP+ve NMRI mice, melanoma PDX model BIW s.c. treatments 33.00 2.0 Vehicle Vehicle 31.00 AVA3996 50mg/kg AV3996 29.
Slide 20: AVA3996 – Efficacy in two further patient derived models
AVA3996 – Efficacy demonstrated in two further patient derived, solid tumour models MV18322_1: Efficacy of AV3996 in Co13120 MV18407: Efficacy of AV3996 in Sarc4183 FAP+ve NMRI colorectal mice, BIW PDX model* s.c. treatments FAP+ve NMRI sarcoma mice, BIW PDX model* s.c. treatments 0.4 1.0 Vehicle Ve
Slide 21: Exquisitely selective for target of interest
Exquisitely selective for target of interest Flexible solutions for difficult-to-drug targets 21
Slide 22: Affimer Next Generation Biotherapeutics
Affimer® Next Generation Biotherapeutics What is an Affimer®? Technical Benefits Differentiated Biotherapies Based on a naturally occurring human Smaller (14 kD), simpler and more robust, Flexible solutions for difficult-to-drug protein (stefin A) and engineered to soluble and stable than antibodies
Slide 23: AVA021: PDL1/LAG3
AVA021: PDL1/LAG3 Immunosuppressive functions of the immune Next Generation Immunotherapies checkpoint inhibitor LAG-3 Tumour cells have the ability to evade adaptive immune-mediated killing The tumour microenvironment becomes immunosuppressive and over time tumour infiltrating T cells (TILs) become
Slide 24: AVA028: Immunocytokine PD-L1/IL-2
AVA028: Immunocytokine PD-L1/IL-2 Flexible solutions for multi-specifics Prototype Affimer Immunocytokine – PD-L1/IL-2 Immune checkpoint inhibitors have revolutionised the treatment of certain tumour In-line-fusion Formats Fc Formats types. However, despite major advances in immunotherapy to treat c
Slide 25: Tumour Microenvironment Activated Conjugates
Tumour Microenvironment Activated Conjugates Tumour Microenvironment Activated Conjugates Proof of concept – FAPa release of warhead in tumour vs serum and Targeting Affimers Cytotoxin linked to Affimer® immunotherapy/targeting by Concentration of warhead (µM) pre|CISIONTM linker Cytotoxin released
Slide 26: Key Partnerships
Key Partnerships Fully funded key partnerships potentially accelerate clinical validation of our platforms 26
Slide 27: AffyXell – Joint Venture in the Cell & Gene Space
AffyXell – Joint Venture in the Cell & Gene Space A joint venture in South Korea with Daewoong Pharmaceutical to develop engineered mesenchymal stem cells that express and secrete immuno-modulatory Affimer molecules to treat autoimmune diseases Next-generation Stem Cell Therapies Renewable “off the
Slide 28: AFX-001 in vivo efficacy in GVHD mouse models
I - Genetically =) | [AFX- 001] /n vivo Efficacy it in GVHD mouse models of the Anti-CD40L Affimer secreted from AFX-001 AFX-001 demonstrated superior efficacy in mouse acute GVHD model. AFX-001 has been confirmed the MoA in vitro and in vivo proof-of-concept (PoC) studies. = Animal Model Test Artic
Slide 29: LG Chem – multi-target partnership
LG Chem – multi-target partnership A multi-target development partnership and licensing deal worth up to $310 million with a focus on oncology and inflammatory diseases PDL1/XT Antagonist PD1/PDL1 axis Affimer inhibitor Half-life extension using Affimer XT® a human serum albumin binder Small size po
Slide 30: Avacta Therapeutics Pipeline
Avacta Therapeutics Pipeline Multiple internal assets from research to clinic Next-Gen preCISION assets designed and developed in-house Affimers targeting tumour/IO compartment validate platform Novel Affimer programmes include multi-specific and difficult-to-drug targets Multiple Partnered Affimer
Slide 31: Q&A
Avacta Q&A
Slide 32: Opportunities and challenges for cell and gene therapies for oncology and beyond
Opportunities and challenges for cell and gene therapies for oncology and beyond Krishna Komanduri, MD, FASTCT Julius R. Krevans Distinguished Professor of Medicine Chief, Division of Hematology/Oncology, UCSF Health Physician-in-Chief, Helen Diller Family Comprehensive Cancer Center Scientific Advi
Slide 33: Disclosures
Disclosures § Ad hoc Consulting: Iovance, Incyte, BMS, Cargo Therapeutics, Instil Bio, CRISPR therapeutics, Genentech/Roche § Scientific Advisory Board: Aegle Therapeutics, Avacta Therapeutics 33 Presentation Title
Slide 34: Alfred Velpeau describes leukemia in 1825
Alfred Velpeau describes leukemia in 1825 La Leçon d'anatomie de Velpeau à la Charité, François-Nicolas-Augustin Feyen-Perrin, 1864
Slide 35: Leukemia publications 1825-2000
1825-1950: ~1000 publications about leukemia 1960s Combination chemotherapy + stem cell transplants 1825 First description of acute leukemia 1950-2000: ~175,000 publications about leukemia
Slide 36: T cells from stem cell transplant donors eliminate residual cancer
T cells from stem cell transplant donors eliminate residual cancer… Riddell & Appelbaum, Graft v. Host Disease, PLOS Medicine, 2007
Slide 37: …but can attack healthy tissues in the patient
…but can attack healthy tissues in the patient Riddell & Appelbaum, Graft v. Host Disease, PLOS Medicine, 2007
Slide 38: Improving immune outcomes of stem cell transplants
Improving immune outcomes of stem cell transplants Can we selectively But not inhibit these... these? Riddell & Appelbaum, Graft v. Host Disease, PLOS Medicine, 2007
Slide 39: From stem cell transplants to personalized immunotherapy
From stem cell transplants to personalized immunotherapy 1960s Combination chemotherapy + stem cell transplants 1825 1990s First description T cells critical for of acute leukemia transplant cures— dramatic increase in success
Slide 40: CAR-T therapy: an overview
CAR-T therapy: an overview) T cell Tumor cell CAR enables T cell to Expression of recognize tumor cell antigen CAR Viral DNA Insertion Antigen Tumor cell apoptosis CAR T cells multiply and release cytokines 40
Slide 41: In vivo killing of cancer cells with CAR-T cells
In vivo killing of cancer cells with CAR-T cells (S. Riddell) Stan Riddell, Fred Hutch
Slide 42: Emily Whitehead: CAR-T Patient #1
Emily Whitehead: CAR-T Patient #1 2022
Slide 43: CAR-T therapy: a breakthrough therapy for lymphoma
CAR-T therapy: a breakthrough therapy for lymphoma 43 Presentation Title
Slide 44: Neelapu SS, et al. N Engl J Med 2017
4 Neelapu SS, et al. N Engl J Med. 2017 Dec 28;377(26):2531-2544. 4
Slide 45: ZUMA-1: Patient Characteristics
ZUMA-1: Patient Characteristics TFL/PMBC DLBCL All Patients Characteristic L (n=73) (n=93) (n=20) Median age (range), years 59 (25-76) 58 (28-76) 59 (25-76) Age ≥60 years, n (%) 36 (49) 9 (45) 45 (48) Male, n (%) 47 (64) 15 (75) 62 (67) ECOG performance status 1, n (%) 48 (66) 8 (40) 56 (60) Median
Slide 46: ZUMA-1 Met Primary Endpoint of ORR in Combined Group
ZUMA-1 Met Primary Endpoint of ORR in Combined Group ZUMA-1 Phase 2 Best DLBCL TFL/PMBCL Combined Response ORR (%) CR (%) ORR (%) CR (%) ORR (%) CR (%) n = 77 n = 24 n = 101 mITTb 82 49 83 71 82 54 aInferential testing when 92 axi-cel–dosed patients had 6 mo of follow-up. ORR 82%, P<0.0001. bmITT (m
Slide 47: Cure of refractory lymphoma with CAR-T therapy (axi-cel)
Cure of refractory lymphoma with CAR-T therapy (axi-cel) Neelapu, et al., NEJM December 2017
Slide 48: CAR-T therapy after six prior lines of therapy
CAR-T therapy after six prior lines of therapy Images by Lazaros Lekakis, MD
Slide 49: Comparable data between the CIBMTR and the pivotal trials: Axi-cel
Comparable data between the CIBMTR and the pivotal trials: Axi-cel Axi-Cel Zuma-1 LTFU Axi-cel PASS - CIBMTR Duration of response Progression- free Survival Jacobson C. et al ASCO 2021, Locke F et al Lancet Oncology 2019 19
Slide 50: Development of the Registry Parallel to Cellular Immunotherapy
The Development of the Registry Parallel to the Expansion of the Field of Cellular Immunotherapy s zi i h tr u n a y tk ria arta c a e ya ecm arv Kym es c f Te f B A b fC NCI funded o f o l of ofY al o al al o val v v CT Registry ova val ro pr o ro v pr o Pilot pr ro p p p p p p Ap A Ap A A Ap 2015
Slide 51: Cellular Immunotherapy Registry at a Glance
Cellular Immunotherapy Registry at a Glance N=7,166 recipients N=7,545 infusions 51
Slide 52: What about earlier lines of lymphoma therapy?
What about earlier lines of lymphoma therapy? 52 Presentation Title
Slide 53: CD19 CAR T-cells in DLBCL: Earlier Lines
CD19 CAR T-cells in DLBCL: Earlier Lines High Risk DLBCL: • Refractory to 1st line ZUMA-7 therapy CAR T Axi-cel • Relapsed within 12m of 1st line therapy BELINDA Tisa-cel TRANSFORM Salvage/ Liso-cel Auto
Slide 54: Is CAR-T therapy the 2nd line DLBCL standard?
Is CAR-T therapy the 2nd line DLBCL standard? § Two of three RCTs favored CAR-T therapy in the second line setting (ZUMA-7 and TRANSFORM) § RCTs demonstrated traditional salvage therapies are suboptimally effective (<40% achieved PR and had AutoSCT) § Additional RCTs would be helpful (but are unlike
Slide 55: What about fourth line? First line?
What about fourth line? First line? § Long-term results of all three commercial products suggest only 30- 40% cure rates § Trials of second CAR-T infusions (including targeting CD19/22 or CD19/20) demonstrate ≤30% ORR § We need better therapies following CAR-T failure, including those that target di
Slide 56: Emerging data in myeloma
Emerging data in myeloma 56 Presentation Title
Slide 57: Ide-cel is superior to SOC in R/R myeloma, but not curative
Ide-cel is superior to SOC in R/R myeloma, but not curative T h e n e w e ng l a n d j o u r na l o f m e dic i n e 1.0 Probability of Progression-free Survival 0.9 0.8 0.73 Median Progression-free 0.7 Survival (95% CI) 0.6 mo 0.55 0.5 Ide-cel 13.3 (11.8–16.1) Standard Regimen 4.4 (3.4–5.9) 0.4 0.40
Slide 58: RCT of ide-cel vs. standard regimens in R/R myeloma
RCT of ide-cel vs. standard regimens in R/R myeloma § Overall, ide-cel outperformed other SOC regimens in this population § However, no plateau suggesting curative potential evident in PFS curves § When progression did occur, BCMA (target) downregulation was NOT seen, in contrast to frequent target
Slide 59: Can we predict cellular therapy failures?
Can we predict cellular therapy failures? 59 Presentation Title
Slide 60: Localized relapse of refractory lymphoma after CAR-T therapy
Localized relapse of refractory lymphoma after CAR-T therapy December 2015 February 2016 July 2016 August 2016 Image courtesy of Lazaros Lekakis, MD., University of Miami
Slide 61: Most patients receiving CD19+ CAR-T therapy relapse
response Most patients receiving CD19+ CAR-T therapy relapse Progression- free Survival Jacobson C. et al ASCO 2021, Locke F et al Lancet Oncology 2019 19
Slide 62: Mechanisms of relapse after CD19 CAR-T therapy
Mechanisms of relapse after CD19 CAR-T therapy
Slide 63: Optimizing CAR-T Therapy: Model by Spiegel and Miklos
Optimizing CAR-T Therapy: Model by Spiegel and Miklos Tumor Biology: - Tumor Antigen Density - Tumor microenvironment Patient CAR-T Product Apheresis Transfection Infusion # of cells CAR-T Product Fitness: Day 0 7 14 21 28 60 90 180 270 360 - Patient T cell fitness - CAR-T construct CAR-T Pharmacoki
Slide 64: Solid tumor T cell therapies: challenges
Solid tumor T cell therapies: challenges 64 Presentation Title
Slide 65: Solid tumor targets
Table 1 Most targeted antigen in clinical trials in solid tumor CAR T cell therapy Antigen Cancer Phase ID EGFR Lung, liver, stomach Phase 1/2 NCT03179007, NCT03525782 HER2 Central nervous system tumor, pediatric glioma Phase 1 NCT03500991 EGFR806 Central nervous system tumor, pediatric glioma Phase
Slide 66: Challenges to CAR-T cell efficacy/safety in solid tumors
Challenges to CAR-T cell efficacy/safety in solid tumors adapted from slide by Julia Carnevale, MD, UCSF
Slide 67: Improving targeting of solid tumor targeted T cells
Improving targeting of solid tumor targeted T cells CAR-T cell chemokines tumor Chemokine • Chemokine receptor receptors • Target tumor stroma/vasculature adapted from slide by Julia Carnevale, MD, UCSF
Slide 68: Strategies to improve tumor persistence and proliferation
Strategies to improve tumor persistence and proliferation • Co-stim domains • Dual targeting • TRAC KI • Gene editing (counter exhaustion, metabolic reprogramming) adapted from slide by Julia Carnevale, MD, UCSF
Slide 69: Overcoming the challenge of tumor heterogeneity
Overcoming the challenge of tumor heterogeneity AND Gating OR Gating • Bivalent CARs • Combinatorial antigen recognition with circuits/logic gating adapted from slide by Julia Carnevale, MD, UCSF Hyrenius-Wittsten et al. Sci Transl Med, 2021.
Slide 70: Overcoming local immunosuppression
Overcoming local immunosuppression Armored CAR Switch Receptor • Switch receptors • Armored CARs • Remodel TME • Gene editing to ignore suppression or withstand metabolic derangements adapted from slide by Julia Carnevale, MD, UCSF
Slide 71: Solid tumor T cell therapies: directions
Solid tumor T cell therapies: directions § CAR-T cells can induce meaningful radiographic, biochemical, and clinical responses in solid tumors, but are relatively short-lived § Safety remains an additional barrier to the success of these therapies as non-dispensable cell types (e.g., B cells) are ta
Slide 72: Conclusions and future directions
Conclusions and future directions
Slide 73: Next steps in T cell therapies
Next steps in T cell therapies § CAR-T therapies have been transformative for patients with relapsed/refractory pediatric ALL, lymphoma and myeloma; solid tumor successes lie ahead § Hematology: broader targets, improved manufacturing, allogeneic products § Solid tumors: Novel strategies to optimize
Slide 74: Improving T cell therapy outcomes
Improving T cell therapy outcomes Better educate Streamline and patients and scale referring manufacturing physicians Measure Develop value, new and advocate for better lower cost therapies Komanduri, J Clinical Oncology, 2021
Slide 75: Evolution of cancer therapy eras
Better Stem Cell chemotherapies, No effective therapies ➙ Chemotherapy ➙ Transplant era (Combinations of ➙ advanced stem cell era transplants and more chemotherapy, effective immunotherapy) immunotherapies 1960s Combination 2017 chemotherapy + Approval of engineered stem cell transplants T cell ther
Slide 76: Acknowledgements
Acknowledgements Slides: Jay Spiegel (UM/Sylvester) Marcelo Pasquini (MCW/CIDR) Miguel Perales (MSKCC) Julia Carnevale (UCSF) Faculty, Staff and Patients at the University of Miami and UCSF 76 Presentation Title
Slide 77: AVA6000 Phase 1a Clinical Study Update – ALS-6000-101
AVA6000 Phase 1a Clinical Study Update – ALS-6000-101 Dr Andrew Saunders, Medical Advisor 23 February 2023
Slide 78: AVA6000: A FAP-Targeted Next Generation Doxorubicin
AVA6000: A FAP-Targeted Next Generation Doxorubicin Exploiting FAP specificity within the Doxorubicin is a very successful chemotherapy tumour by selectively cleaving AVA6000 & due to its efficacy in fighting a wide range of activating doxorubicin at tumour sites to… cancers….but it has limitations
Slide 79: Phase 1 & 2 Study Designs
Phase 1 & 2 Study Designs AVA6000 in Patients with Advanced, Metastatic Solid Tumours Phase 1a: Dose Escalation Phase 1b: Dose Expansion Phase 2 Cohort 6 Phase 1a (mg/m2) Key Eligibility Criteria Cohort 5 • Locally Advanced, (mg/m2) Metastatic Selected 200 mg/m2 RP2D Solid Tumours AVA6000 (135mg/m2)
Slide 80: Overview of Clinical Study ALS-600-101
Overview of Clinical Study ALS-600-101 Phase 1 Dose Escalation of AVA6000 across a range of solid tumours known to be FAP +ve Interim Data Supports AVA6000 Mechanism AVA6000 Dose Regimen - 3 weekly cycles (Doxorubicin Equivalent Dose) • 19 patients dosed across 4 AVA6000 cohorts Cohort 6 • Median (r
Slide 81: Patient Demographics & Baseline Characteristics
Patient Demographics & Baseline Characteristics Study ALS -6000-101 80mg/m2 120mg/m2 160mg/m2 200mg/m2 (n=4) (n=6) (n=6) (n=3) Median Age (range), years 58 (56-71) 58 (30-76) 63 (50-73) 63 (53-72) Female, n (%) 3 (75) 2 (33) 0 (0) 1 (33) Male, n (%) 1 (25) 4 (66) 6 (100) 2 (66) Race, n (%) White 3 (
Slide 82: AVA6000 Safety Profile (80-200 mg/m2 Q3W)
AVA6000 Safety Profile (80-200 mg/m2 Q3W) Treatment-Related Adverse Events Cohort 1 Cohort 2 Cohort 3 Cohort 4 Total 80mg/m2 120mg/m2 160mg/m2 200mg/m2 • Overall AVA6000 has a modest and predictable (N = 4) (N = 6) (N = 6) (N =3) (N=19) safety profile Dose Limiting Toxicity 0 1 0 0 1 (5%) • 2 patien
Slide 83: Safety Profile: AVA6000 vs Doxorubicin
Safety Profile: AVA6000 vs Doxorubicin 1 AVA6000 (80-200mg/m2 Q3W) 2 Doxorubicin (75mg/m2 Q3W) N = 19 N = 249 • No Dose related increase in frequency or severity Treatment-Emergent Median No. Cycles = 2 (Range 1-8) Median No. Cycles = 7 (Range 1-8) of AVA6000 TEAEs with increasing dose (80, 120, 160
Slide 84: Tumour Biopsy Data
Tumour Biopsy Data Plasma vs Biopsy Doxorubicin Concentrations DOX DOX AVA6000 Plasma Biopsy @24h DOX Ratio** Biopsy Cohort (Dox Dose) Patient @24h Biopsy:Plasma Source mg/m2 ng/g nM ng/ml 101-006 (1st) 4.9 135 248nM 28:1 Liver Cohort 1 80 (54) 101-006 (2nd) 4.9 43 79nM 9:1 Liver 103-021* 4.4 376 69
Slide 85: AVA6000: Phase Ib Study
AVA6000: Phase Ib Study Clinical Development in Soft-Tissue Sarcoma (Phase 1 to 2) Development Rationale in Soft Tissue Sarcoma (STS) • Advanced, Metastatic STS tumours • Doxorubicin is the only therapy indicated for first-line monotherapy in advanced STS • No current or near future competition for
Slide 86: Soft Tissue Sarcoma Drugs in Development
Soft Tissue Sarcoma Drugs in Development • Modest number of products in clinical development for STS with majority of R&D activity in early stage • KOLs indicate no serious competition in Soft Tissue Sarcoma indication for 1st Line Therapy Product Company Mechanism Status/Indication Comment Doxorubi
Slide 87: Market Potential for AVA6000
Market Potential for AVA6000 There is huge potential for an improved next generation doxorubicin product considering: • The market value being generated by current doxorubicin therapies and the expectation that doxorubicin- based therapies will continue to be a key approach for oncology treatment •
Slide 88: AVA6000 Conclusions
AVA6000 Conclusions Dose Escalation • AVA6000 has a modest and predictable safety profile across the dose range (80-200mg/m2) • PK data for released doxorubicin highlights a positive profile • Doxorubicin Exposure (AUC) & Maximal Concentrations (Cmax) substantially reduced across doses • Doxorubicin
Slide 89: Investigators
Investigators United Kingdom United States Professor Chris Twelves, Chief Investigator Dr William D. Tap Leeds Teaching Hospitals NHS Trust, Leeds Memorial Sloan Kettering Cancer Centre, New York Professor Udai Banerji Dr Lee D. Cranmer Fred Hutchinson Cancer Centre, Seattle The Royal Marsden NHS Fo
Slide 90: Current & Future Treatment Strategies for Soft Tissue Sarcoma
Current & Future Treatment Strategies for Soft Tissue Sarcoma William Tap, MD Chief, Sarcoma Medical Oncology Service Co-Director Stuart Center for AYA Medicine Memorial Sloan Kettering Cancer Center
Slide 91: Sarcoma
Sarcoma Heterogeneous group of malignancies – Arise from the bone and soft tissue of individuals of all ages – 16,000 new cases diagnosed in the United States per year • (similar to testicular cancer, esophageal cancer – well defined treatment strategies) – 100 (?) different subtypes bone and soft t
Slide 92: Simplest Conceptual Level
Simplest Conceptual Level Ewing’s Sarcoma Osteosarcoma Rhabdomyosarcoma Liposarcoma Synovial Sarcoma Myxofibrosarcoma DFSP Leiomyosarcoma Myxoid Round Cell Liposarcoma Angiosarcoma ASPS Undifferentiated Pleomorphic GIST
Slide 93: 2020 WHO Classification of Soft Tissue Sarcoma
2020 WHO Classification of Soft Tissue Sarcoma Twitter
Slide 94: Hormonal blockade CDK4i/PARPi/LSDi/bi-specifics Splice Switch/GAMPER Oligos
Hormonal blockade CDK4i/PARPi/LSDi/bi-specifics PDGFRB inhibitors Splice Switch/GAMPER Oligos RANKL inhibitors CHK1i FGFR4 inhibitors? cMET/HGF inhibitor VEGF/METi/PD-1i TKIs/Trabectedin CSF inhibitors Trabectidin/PI3Ki/NYESO/MAGE(ACT)/ mTOR/TEAD Eribulin TKIs/MEK inhibitors EZH2i ALK inhibitors MDM
Slide 95: Clinical sequencing of soft tissue and bone sarcomas
Clinical sequencing of soft tissue and bone 2 DPS te Me, At99 sessbae ees: BASE sarcomas delineates diverse genomic landscapes and potential therapeutic targets Aerjamin A. NacevO '23°, Francisco Sanches-Vega O™5,Shaligh A Smith, ist R.Antonesca ©, Evan Roserboum!2, Hengyu Shi, Cerise Tang®S, Nichol
Slide 96: Changing Tide…
Changing Tide… • Genetic diversity attractive drug development • Open field application new technology and scientific advancement • Influx of new agents and trials • Subtype and disease specific - Potential registration tracts • Sarcoma as a bridge to other malignancies/markets • Discovery into mese
Slide 97: Subclassifications of Sarcoma Based on Treatment
Subclassifications of Sarcoma Based on Treatment Sarcomas with… • Genomic alterations with a definitive target and therapy and not responsive to chemo (minority) – GIST (KIT/PDGFRA), PEComa (TSC1/2), Chondrosarcoma (IDH1) • Genomic alterations with target but chemo remains front line – Epithelioid s
Slide 98: What is First Line?
What is First Line? Pharmacokinetics and metabolism of adriamycin in man Clinical Pharmacology and Therapeutics A pharmacokinetic evaluation of adriamycin and its metabolites was undertaken in cancer patients treated according to an intermittent single high-dosage schedule. The long plasma half-life
Slide 99: Adria vs Adria/Ifos
2003-2010 – published 2014 Adria vs Adria/Ifos OS • 455 patients 38 centers; Age </= 60yo; 7 years to enroll • Adria 75mg/m2 (6 cycles – 4.2 months); Ifos 10grams/m2 • OS primary endpoint • Median f/u 56 months PFS • Median OS 12.8 vs. 14.3 HR 0.83 p=0.76 • Median PFS: Adria 4.6 mos; AI 7.4 months –
Slide 100: Front line setting: TH302 (evofosfamide) single agent
Front line setting Adria x 6, 18 weeks (4.2 Months) TH302 (evofosfamide) single agent
Slide 101: Adriamycin 8 cycles (600mg/m2)
Adriamycin 8 cycles (600mg/m2) ; Any line of treatment PFS 4.2m vs 6.6m OS 14.7m vs 26.5m
Slide 102: Contemporary Data Set – Doxorubicin Front Line Setting
Not blinded; OS primary endpoint 1st line stetting Evo maintenance component 640 patients 28 months Contemporary Data Set – Doxorubicin – Front line Setting
Slide 103: Contemporary Data Set of Doxorubicin Front Line
Contemporary Data Set of Doxorubicin Front Line • Median 6 Cycles – 4.2 months • 45% of patients required a dose modification • 10% pts had decrease LVEF >10% or more (EF <55%) • 30-35% patients had a serious adverse event (neutropenia and anemia) • 6 months PFS • 19 months OS • ORR 18%
Slide 104: Cardiac tox related to cumulative doxorubicin dose
Cardiac tox related to cumulative doxorubicin dose • No Difference in median OS, PFS, or RR, ≥ 65yo (209 patients) • Significantly more hematological and Grade ≥ 3 AEs • No significant difference in cardiotoxicity • More likely to stop treatment early
Slide 105: Olaratumab trial results
Blinded/Placebo; OS primary endpoint 1st/2nd line stetting 624 patients Dual Primary endpoint (STS:LMS) 10 months Olara maintenance component OS 20.4 v 19.7 STS OS 21.6 vs 21.9 LMS PFS 5.4 v 6.8 STS PFS 4.3 vs 6.9 LMS
Slide 106: Contemporary Data Set of Doxorubicin 1st/2nd Line
Contemporary Data Set of Doxorubicin 1st/2nd Line • Median 7 Cycles – 5.3 months; median cumulative dose 483mg/m2 • 6.8 months PFS; 20 months OS; ORR 18% Median cumulative dose total population - 450mg/m2 (504 pts; 43% (219) received 8 cycles) Median follow-up of cardiac AEs was 28 weeks Dexrazoxane
Slide 107: How Many Variables Confound a Trial?
How Many Variables Confound a Trial? 620-640 randomized participants 80-99 sites, 12+ countries 40+ Disease Entities; intra-subtype variability Locally Advanced/Metastatic Variations in clincial behavior Trial Endpoints, Overall Survival? Practice/subsequent treatment variability Maintenance Therapy
Slide 108: Subtype specific trials
Subtype specific trials • Subtype specific – true understanding subtype – Often new disease entities, recently genetically defined – Natural history of the disease poorly understood/defined – Genomic and clinical variability not ordered – Clinical needs patient population need to be defined/measured
Slide 109: Scramble to understand the disease and develop drug correctly
Part 2 Extension, six cohorts: 1) Mucoepidermal carcinoma salivary gland 2) Tenosynovial giant cell tumor 3) Gastrointestinal stromal tumor 4) Anaplastic thyroid carcinoma 5) Solid tumors with documented malignant pleural or peritoneal effusions, and 6) Miscellaneous tumor types, with scientific evi
Slide 110: Tenosynovial Giant Cell Tumor (TGCT)
Tenosynovial Giant Cell Tumor (TGCT) Clinical features: Gross features: • Usually single joint: • Collagen • Swelling deposition • Pain • Subchondral • ↓ range of motion bone erosions • Stiffness • Repeat hemarthrosis • Functional impairment • Narcotic use • Disability West, et al. (2006) PNAS, USA
Slide 111: CSF1 receptor inhibition of tenosynovial giant cell tumor
CSF1 receptor inhibition of tenosynovial giant cell tumor using novel disease-specific MRI measures of tumor burden harles Peterty*®, Yan Chen', Peter Countryman’, Bartosz Chmielowski”, Stephen P lanthony?3, John H Healey*, Zev A Wainberg’, Allen L Cohn’, Geoffrey | Shapiro’, Vicki L ‘eedy®, Arun Si
Slide 112: Unresectable/Complicated cases
Unresectable/Complicated cases Referralto center of excellence NOR ees Oho Oncloaix of joint issue ‘Mean change in pain NRS TGCT Treatment + Arthroscopic surgery + Supportive care (pain management, physical therapy) Removal of nodules Los Angeles Als Repeat TKA Return toOR for {anterior) AS Open Los
Slide 113: Need for Placebo? Outcome assumptions?
Need for Placebo? Outcome assumptions? Based on ORR P1 Doing too much? Data Missingness Reordered endpoints Rare but dangerous cholestatic hepatotoxicity Vanishing Bile Duct Syndrome PMID: 33197285 ODAC and REMS
Slide 114: Molecular and Clinical Variation in Chondrosarcoma
NCCN Compendium listed • Molecular and Clinical Variation in Chondrosarcoma – Conventional vs De-differentiated – Variable Natural History in Conventional (PFS/OS) – Large Boney Components (difficult to Image) – Lack of Utility with RECIST • Novel Imaging Technique vs Molecular/Metabolic based outco
Slide 115: ORR 39%, mPFS 10 months, mOS 40.8 months
ORR 39% mDOR NR (2.5 years f/u) mPFS 10 months mOS 40.8 months
Slide 116: Tazemetostat plus doxorubicin trial
mPFS 5.5 mOS 19 months ORR 15% A Phase 1b/3 trial of tazemetostat plus mDOR NR (13.8 month f/u) FDA ODAC December 18, 2019 doxorubicin in the 1st line setting 11-0 for Accelerated Approval
Slide 117: Clinical Need and Opportunity in Sarcoma
“The Pit and the Pendulum” Clinical Need and Opportunity in Sarcoma Clinical Trial Design in Sarcoma –Need to start with early FOCUSED development •Single diseases, homogenous presentations –Understand historical response patterns/outcomes –Objective measures of disease behavior and impact –Applicab
Slide 118: THANK YOU
THANK YOU
Slide 119: Targeted Oncology 2030 Panel Discussion
Targeted Oncology 2030 Panel Discussion
Slide 120: Closing Remarks
Avacta Closing Remarks