Circio Holding Asa · OSL:CRNA
Circio Holding Asa — Targovax — RAS Targeted Drug Discovery Summit 2019
34 slides from Circio Holding Asa's conference presentation, Sep 18, 2019
Slide 1: Activating the immune system to fight cancer
TG mutant RAS Activating the neoantigen vaccine immune Dr. Erik Digman Wiklund, CBO system to RAS Targeted Drug Discovery Summit Company presentation fight cancer Boston, 18 September 2019 August 2018
Slide 2: Important Notice and Disclaimer
IMPORTANT NOTICE AND DISCLAIMER This report contains certain forward-looking statements based on uncertainty, since they relate to events and depend on circumstances that will occur in future and which, by their nature, will have an impact on the results of operations and the financial condition of
Slide 3: Introduction
Introduction 2. A vaccine approach to target mutant RAS 3. TG clinical data 4. Summary & conclusions 3
Slide 4: Targovax aims to activate the patient's own immune system to fight cancer
TARGOVAX AIMS TO ACTIVATE THE PATIENT’S OWN IMMUNE SYSTEM TO FIGHT CANCER Targovax focus Immune Immune activators modulators Oncolytic viruses, Checkpoint vaccines inhibitors Surgery - Radio - Chemo Immune Targeted boosters therapy CAR-Ts, TCRs TKIs, PARPs, etc. 4
Slide 5: Targovax has two clinical stage immune activator programs
TARGOVAX HAS TWO CLINICAL STAGE IMMUNE ACTIVATOR PROGRAMS o Genetically armed adenovirus o Turns cold tumors hot o Induces tumor specific T-cells o Single agent phase I completed Activates the ONCOS immune system o 4 ongoing combination trials Oncolytic virus Triggers patient- specific responses o S
Slide 6: A vaccine approach to target mutant RAS
A vaccine approach to target mutant RAS 3. TG clinical data 4. Summary & conclusions
Slide 7: The RAS gene is mutated in 25-30% of all cancers
THE RAS GENE IS MUTATED IN 25-30% OF ALL CANCERS Including 90% of pancreatic and 40% of colorectal cancers Frequency of RAS mutations Global cancer incidents per 10,000 (xx) = no. of cancer patients o RAS is the most frequently 100% occurring driver mutation Pancreas (340,000) o RAS is a clinically
Slide 8: RAS "the undruggable target"
RAS “THE UNDRUGGABLE TARGET” Oncogenic RAS mutations are key drivers behind uncontrolled cell division Why is RAS such an elusive target? o Very high similarity between mutant and wild-type RAS Balanced Skewed equilibrium equilibrium o Multiple point mutation mut variants o Smooth protein surface an
Slide 9: RAS is potentially an excellent target for an off-the-shelf cancer vaccine approach
RAS is potentially an excellent target for an off-the-shelf cancer vaccine approach o RAS is the most frequently mutated oncogene family across all cancers Neoantigen prevalence o RAS is a true driver mutation, present on all sub-clones of RAS driven cancers o RAS produces distinct, recognizable Neo
Slide 10: Mutant RAS T-cells can form spontaneously in patients, and recognize and destroy tumors
Mutant RAS T-cells can form spontaneously in patients, and recognize and destroy tumors Rosenberg, A. et. al, (2016), New England Journal of Medicine: T-cell transfer therapy targeting mutant KRAS in cancer Endogenous CD8+ tumor- infiltrating lymphocytes (TIL) recognizing the G12D RAS mutation were
Slide 11: The RAS development landscape
THE RAS DEVELOPMENT LANDSCAPE Company Asset/ Program Mechanism of Action Highest Phase GI-4000/Tarmogen Heat-inactivated yeast expressing target RAS mutations Phase II (halted) TG01 / TG02 Peptide vaccine targeting 7/8 codon 12 & 13 RAS mutations Phase II siG12D-LODER RNAi (siRNA) targeting mutant R
Slide 12: Targovax TG vaccine is a peptide cocktail designed to induce T-cell responses to RAS
Targovax TG vaccine is a peptide cocktail designed to induce T-cell responses to RAS driver mutations 1. Activate immune system 2. Induce mutRAS T-cells 3. Attack the cancer o TG peptide cocktail o Mutant RAS T-cells o mutRAS T-cells identify injected intradermally activated by DCs in and destroy mu
Slide 13: The TG peptide cocktail covers ~99% of all codon 12 and 13 RAS mutations
The TG peptide cocktail covers ~99% of all codon 12 and 13 RAS mutations Oncogenic codon 12 & 13 RAS mutations TG product characteristics o Two clinical stage products − TG01: 7 peptides covering ~99% of Wild-type RAS amino acid sequence, with mutation sites in red RAS mutations in pancreatic cancer
Slide 14: TG Clinical data
TG Clinical data 4. Summary & conclusions
Slide 15: TG clinical program overview
TG CLINICAL PROGRAM OVERVIEW Colorectal cancer o Mechanism of action, biomarker TG02 monotherapy and safety trial Phase I o 2nd gen TG vaccine first-in-man 6 patients Metastatic Pancreas o US based trial, collaboration Phase I & II - Phase I/II with Parker Institute and CRI Pancreas Resected pancrea
Slide 16: TG clinical program overview
TG CLINICAL PROGRAM OVERVIEW Colorectal cancer o Mechanism of action, biomarker TG02 monotherapy and safety trial Phase I o 2nd gen TG vaccine first-in-man 6 patients Metastatic Pancreas o US based trial, collaboration Phase I & II - Phase I/II with Parker Institute and CRI Pancreas Resected pancrea
Slide 17: TG vaccination induced CD4+ and CD8+ mutant RAS T-cell responses validated in patients
TG vaccination induced CD4+ and CD8+ mutant RAS T-cell responses has been validated in patients mutRAS specific CD4+ T-cells mutRAS specific CD8+ T-cells mutRAS specific T-cell clones isolated from vaccinated patient isolated from vaccinated patient identified both in blood and tumor o CD4+ T-cell c
Slide 18: Improved survival for mutRAS immune responders in advanced pancreatic cancer
Improved survival for mutRAS immune responders observed in advanced pancreatic cancer patients Clinical study in advanced pancreatic cancer (36 patients); Cocktail of 4 (of 7) TG01 peptides Surviving fraction A: No detectable immune response B: Detectable immune response 19 of 36 (52%) patients had
Slide 19: Phase I monotherapy survival data
PHASE I MONOTHERAPY SURVIVAL DATA TG vaccination showed 20% 10 year survival in resected pancreatic cancer 10 year survival in historical TG trials in resected pancreatic cancer1 n=20, resected patients from two clinical trials, TG monotherapy 100 o 25% (5/20) 5-year survival 90 o 20% (4/20) 10-year
Slide 20: TG clinical program overview
TG CLINICAL PROGRAM OVERVIEW Colorectal cancer o Mechanism of action, biomarker TG02 monotherapy and safety trial Phase I o 2nd gen TG vaccine first-in-man 6 patients Metastatic Pancreas o US based trial, collaboration Phase I & II - Phase I/II with Parker Institute and CRI Pancreas Resected pancrea
Slide 21: TG01 – Resected pancreas study schema
TG01 – RESECTED PANCREAS STUDY SCHEMA Phase I/II trial combining TG01 with adjuvant gemcitabine, 32 patients Patient Resected adenocarcinoma of the pancreas TG01 / GM-CSF (up to 2 years) Treatment population and candidates for adjuvant chemotherapy Gemcitabine (6 cycles) Assess safety, mutant RAS im
Slide 22: 30/32 patients in the trial were confirmed as mutant RAS
30/32 patients in the trial were confirmed as mutant RAS, with most showing presence of multiple point mutations Patient RAS status Number of different RAS mutations detected wt/mut genetic RAS 1 qPCR detection of RAS point mutations in cfDNA 11 Multiple RAS mutations were detected in 30 17/21 (81%)
Slide 23: 12D and 12V were the most frequently occurring RAS mutations
12D and 12V were the most frequently occurring RAS mutations found in the patients Frequency of individual RAS point mutations detected in cfDNA1 Number of patients (%) with mutation confirmed in cfDNA for at least one time point in study (n=21) 18 (86%) 17 (81%) o 12D and 12V mutations co- occurred
Slide 24: Top-line data summary TG01 + gemcitabine
TOP-LINE DATA SUMMARY TG01 + GEMCITABINE as adjuvant combination treatment in resected pancreatic cancer RAS-specific Median disease free Median overall 1 2 3 survival, months immune activation survival, months 33.1 34.3 27,6 19,5 15,2 13,9 94% 30/32 pts ESPAC 4 First Second ESPAC 4 First Second coh
Slide 25: RAS specific immune response confirmed in 30 out of 32 patients
1 RAS specific immune response confirmed in 30 out of 32 patients 1st Cohort 2nd Cohort Overall Parameters (n=19) (n=13) (N=32) Immune responder* 18 (95 %) 12 (92 %) 30 (94 %) DTH Positive 18 (95 %) 8 (62 %) 26 (81 %) (skin hypersensitivity test) mutRAS Specific T-cells 14 (74 %) 12 (92 %) 26 (81 %)
Slide 26: Robust levels of DTH and PBMC mutant RAS immune responses in study
1 Robust levels of DTH and PBMC mutant RAS immune responses in study Overall positive DTH responses during study Overall positive PBMC responses during study number of patients per group number of patients per group 26/32 total positives 26/30 total positives 11 15 81% 87% 10 7 5 6 4 4 2 No 1 2 3 or
Slide 27: DTH and PBMC mutant RAS immune responses increased over time
1 DTH and PBMC mutant RAS immune responses increased over time DTH responses over time PBMC responses over time % of analyzed patients with positive DTH at each time point % of analyzed patients with positive PBMC at each time point 100 100 90 90 80 80 70 70 60 60 50 50 40 40 30 30 20 20 10 10 0 0 B
Slide 28: Disease free survival (DFS) Kaplan-Meier plot
2 Disease free survival (DFS) Kaplan-Meier plot o mDFS 13.9 months in 1st cohort, vs. 15.2 months in ESPAC4 o mDFS 19.5 months in 2nd cohort, vs. 15.2months in ESPAC4 Censored= No progression on latest scan collected DFS was measured from surgery 28 Company data, unpublished
Slide 29: Kaplan-Meier survival plot for all 32 patients
3 Kaplan-Meier survival plot for all 32 patients - signal of clinical benefit of TG vaccination o 72% 2-year survival rate (23/32) vs 53% for ESPAC4 trial o mOS 33.3 months vs. 27.6 months for ESPAC4 historical control (measured from surgery) o 8 long-term survivors, still alive at 3-year cut-off po
Slide 30: TG01 resected pancreas trial - swimmer plot of individual patient outcomes
3 TG01 resected pancreas trial - swimmer plot showing individual patient outcomes * * DFS OS Case examples on following slide * RAS wild type (2/32 patients) All measurements in months from surgery 30 Company data, unpublished
Slide 31: Multiple RAS mutations detected in cfDNA and evidence of clonal clearance
3 Multiple RAS mutations detected in cfDNA in most patients, and evidence of clonal clearance following TG vaccination Mutant RAS mutation Immune response Clinical outcome Mutant RAS cfDNA analysis Possible mutant Wild-type 12D 12V 12A 12R 12S 12C 6 detected DTH: R0 resection - Not determined Baseli
Slide 32: Summary & conclusions
Summary & conclusions ° targovax °
Slide 33: Summary – TG mutant RAS vaccine
SUMMARY – TG MUTANT RAS VACCINE Targets all RAS mutations with one product Covers 99% of codon 12 and 13 oncogenic RAS mutations Patients frequently have multiple RAS mutation clones present Promising immune response and efficacy data Signal of survival benefit in resected pancreatic cancer Mutant R
Slide 34: Activating the patient's immune system to fight cancer
ACTIVATING THE PATIENT`S IMMUNE SYSTEM to fight cancer Oncolytic virus Mutant RAS Innovative vaccine pipeline Strong single agent data Robust immune activation Next generation viruses in pre-clinical testing Re-activation of anti-PD1 Signal of clinical benefit resistant tumors Novel RAS targeting co