Circio Holding Asa · OSL:CRNA
Circio Holding Asa — Targovax — Investor Day (June 2017)
74 slides from Circio Holding Asa's investor day presentation, Jun 8, 2017
Slide 1: Arming the immune system to fight cancer
Arming the immune system to fight cancer Capital Markets Update June 8th 2017 www.targovax.com
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: Capital Markets Update - Agenda
Capital Markets Update - Agenda Introduction – CEO, Øystein Soug Targovax’s technology and trials – CMO, Dr Magnus Jäderberg A physician’s view on pancreatic cancer – Dr Svein Dueland Financial update – CFO, Erik Wiklund Q&A Lunch www.targovax.com 3
Slide 4: Targovax develops two novel cancer immunotherapy drugs
Targovax develops two novel cancer immunotherapy drugs – both with promising phase I/II data TG01 ONCOS-102 Cancer vaccine Oncolytic virus Therapeutic vaccine Injected into the tumor Mimics antigens Releases antigens Stimulates “killer” white blood Stimulates “killer” white blood cells (
Slide 5: Immunotherapy market expected to reach 30-50b USD by 2025
Immunotherapy is considered to have enormous potential, and the market is expected to reach 30-50b USD by 2025 Estimated market size ($Bn)* ~15% p.a. o 8 products currently on the market o Market estimated to reach 40b USD in 2025 o Estimated that 2/3 of cancers will be treated with immunotherapy by
Slide 6: Targovax history
Targovax history 2012-2013 1st ph I trial 2007-2012 2013-2014 115 pts treated in ATAP 3 Orphan Designations 2 collaborations Mesothelioma trial initated 2007 2009 2012 2013 2014 Melanoma trial initated Oncos founded ONCOS-102 IND 2015 2016 2017 1st TG01 trial Orphan Designation Oncos and IPO TG01 da
Slide 7: Two platforms and six clinical trials in total
Two platforms and six clinical trials in total ensures a diversified program with frequent data readouts Cancer Combined 2017 2018 2019 indication with H1 H2 H1 H2 H1 Melanoma CPI Phase l ONCOS-102 Mesothelioma Chemo* Orphan ind. Phase lb/ll Ovarian & Orphan ind. CPI Phase l/ll Colorectal Sponsor: L
Slide 8: Capital Markets Update - Agenda
Capital Markets Update - Agenda Introduction – CEO, Øystein Soug Targovax’s technology and trials – CMO, Dr Magnus Jäderberg A physician’s view on pancreatic cancer – Dr Svein Dueland Financial update – CFO, Erik Wiklund Q&A Lunch www.targovax.com 8
Slide 9: Agenda
Agenda Introduction to immunotherapy ONCOS-102 oncolytic virus platform TG RAS-peptide vaccine platform Targovax clinical program overview www.targovax.com 9
Slide 10: Immunotherapy is revolutionizing the way we treat cancer
IMMUNOTHERAPY Immunotherapy is revolutionizing the way we treat cancer, in some cases curing previously thought incurable patients Case example – Patient in a Yervoy checkpoint inhibitor trial Prior to Yervoy* 4 weeks 8 weeks Week 72: complete remission Week 108: complete remission 20 weeks 8 months
Slide 11: Boosting the natural cancer immunity cycle
IMMUNOTHERAPY The aim of cancer immunotherapy is to boost the natural cancer immunity cycle T-cell T-cell trafficking activation T-cell tumor infiltration Cancer antigen presentation Cancer cell identification Release of cancer Destruction of antigens cancer cells www.targovax.com 11
Slide 12: Immunotherapies target different aspects of the cancer immunity cycle
IMMUNOTHERAPY Immunotherapies target different aspects of the cancer immunity cycle DC-therapy: Provenge T-cell therapy: CAR-T (not yet approved) Checkpoint Inhibitors (CPIs) CTLA-4 blockade: Yervoy Oncolytic virus: PD-1 blockade: PD-L1 blockade: Imlygic Keytruda Tecentriq Opdivo Imfinzi Bavencio ww
Slide 13: Two novel proprietary immunotherapy platforms
IMMUNOTHERAPY Targovax is developing two novel proprietary immunotherapy platforms, with promising phase I/II data o Genetically tailored Adenovirus ONCOS-102 o Selectively infects and lyses cancer cells Oncolytic virus o Releases cancer antigens o Triggers immune response o Cocktail of 7 synthetic
Slide 14: TG01 and ONCOS-102 distinct targeting mechanisms
IMMUNOTHERAPY TG01 and ONCOS-102 have distinct targeting mechanisms in the cancer immunity cycle TG01 Peptide vaccine ONCOS-102 Oncolytic virus www.targovax.com 14
Slide 15: Combining immunotherapies to modulate multiple aspects of immunity cycle
IMMUNOTHERAPY By combining immunotherapies multiple aspects of the cancer immunity cycle can be modulated in parallel Wake up the Train cancer T-cells attack Disarm cancer Immuno-oncology mechanisms immune system specific T-cells the cancer defence Switch on GPS– Press the gas Ignite engine Release
Slide 16: Turning cancer into a manageable chronic disease
IMMUNOTHERAPY The goal is to turn cancer into a manageable chronic disease by combining immuno-oncology therapies Lifting the curve The main benefit is seen in long term overall survival Proportion alive Immunotherapy combination Immunotherapy monotherapy Chemotherapy / TKI Untreated Time from treat
Slide 17: Agenda
Agenda Introduction to immunotherapy ONCOS-102 oncolytic virus platform TG RAS-peptide vaccine platform Targovax clinical program overview www.targovax.com 17
Slide 18: How ONCOS-102 works
ONCOS TG ONCOS-102 works by making cancer antigens visible to the immune system, thus generating tumor specific T-cells Activate immune system: Train T-cells: Attack the cancer: o Virus injected directly into o APCs present tumor o Tumor specific T-cells the tumor / peritoneum specific antigens at l
Slide 19: Most patients do not respond to checkpoint inhibitors
ONCOS TG Most patients do not respond to check point inhibitors (CPIs), due to lack of T-cells in the tumor microenvironment Response rate to checkpoint inhibitors (CPIs) Melanoma ~40% Renal Cell carcinoma ~70% Complimentary Triple Negative Breast ~70%-80% immune priming medicines may make tumors re
Slide 20: ONCOS-102 phase I: increased tumor infiltrating CD8+ T-cells
ONCOS TG ONCOS-102 phase I: Increased tumor infiltrating CD8+ T-cells in 11 of 12 cancer patients with a range of solid tumors 10000 1000 Fold-change from baseline 100 10 1 0,1 FI1-08 FI1-19 FI1-06 FI1-04 FI1-18 FI1-02 FI1-15 FI1-13 FI1-09 FI1-17 FI1-01 FI1-14 Only 1 patient 6 patients 5 patients sh
Slide 21: Initial Phase I ONCOS-102 immune response
ONCOS TG In the initial Phase I ONCOS-102 trial tumor specific and systemic immune response was observed Evidence that immune system Evidence that T-cells find the Evidence of production of recognizes tumor threat tumor and are cell killing tumor antigen specific T-cells Innate Immune System (biopsy
Slide 22: Broad ONCOS-102 clinical program of four new trials
ONCOS TG The encouraging Phase I results have triggered the initiation of a broad ONCOS-102 clinical program consisting of four new trials o Combination with PD-1 Melanoma CPI in refractory patients Phase I o Proof-of-concept 12 patients o Memorial Sloan Kettering Mesothelioma o Combination with che
Slide 23: Melanoma trial with CPI refractory patients
ONCOS TG Melanoma trial – will CPI refractory patients start responding after immune-priming with ONCOS-102? Advanced malignant melanoma patients not responsing to CPIs Setting Immune activate patients with ONCOS-102, then re-challenge with a CPI (Keytruda@) 12 patients Site Memorial Sloan Kettering
Slide 24: Agenda
Agenda Introduction to immunotherapy ONCOS-102 oncolytic virus platform TG RAS-peptide vaccine platform Targovax clinical program overview www.targovax.com 24
Slide 25: RAS mutated in 20-30% of all cancer patients
ONCOS TG RAS is a key regulator of cell cycle that is mutated in 20-30% of all cancer patients, and >85% of pancreatic cancers Incidence of RAS mutations One of the most common mutations in cancer RAS is one of the most well-defined neoantigens Results in cell division permanently switched on No exi
Slide 26: TG peptides prime the immune system against RAS mutated cells
ONCOS TG The TG peptides prime the immune system to recognize and destroy RAS mutated cancer cells Activate immune system: Train T-cells: Attack the cancer: o TG peptides injected into o APCs migrate to lymph o RAS specific T-cells the skin with GM-CSF nodes and present RAS identify mutated RAS adju
Slide 27: Long-term survival data from earlier TG trials
ONCOS TG These results are backed by encouraging 10 year survival data and immune response correlation from earlier trials Long-term data from earlier TG mono-therapy trials – resected pancreatic cancer 100 90 80 70 4/20 (20%) patients Survival (%) 60 > 10 years survival 50 (resected patients) 40 30
Slide 28: Working to replicate and expand encouraging clinical results
ONCOS TG We are currently working to replicate and expand on these encouraging clinical results Historical trials Completing trial Planned / recruiting trials Resected pancreas o Randomized controlled trial Phase II/III (tbd) o Aim to reach registration Phase I Phase I/II Resected & Resected non-res
Slide 29: Agenda
Agenda Introduction to immunotherapy ONCOS-102 oncolytic virus platform TG RAS-peptide vaccine platform Targovax clinical program overview www.targovax.com 29
Slide 30: Two platforms and six clinical trials in total
ONCOS TG Two platforms and six clinical trials in total ensures a diversified program with frequent data readouts Cancer Combined 2017 2018 2019 indication with H1 H2 H1 H2 H1 Melanoma CPI Phase l ONCOS-102 Mesothelioma Chemo* Orphan ind. Phase lb/ll Ovarian & Orphan ind. CPI Phase l/ll Colorectal S
Slide 31: Capital Markets Update - Agenda
Capital Markets Update - Agenda Introduction – CEO, Øystein Soug Targovax’s technology and trials – CMO, Dr Magnus Jäderberg A physician’s view on pancreatic cancer – Dr Svein Dueland Financial update – CFO, Erik Wiklund Q&A Lunch www.targovax.com 31
Slide 32: Targovax - Svein Dueland
Targovax Svein Dueland MD, Ph.D Oslo June 8th 2017
Slide 33: Cancer in Norway
Relative survival and conditional relative survival (9%) 110 Cancer in Norway Figure 101: Pancreas (ICD-10 C25) Relative survival by sex and conditional 5-year relative survival by sex Relative survival by age 1104 ‘Age at diagnosis 1004 o-49 50-59 90 —— 60-69 —. 10-79 = 804 = 80+ 3 70- = 604 2 504
Slide 34: Cancer in Norway
Rates per 100.000 (Norwegian standard) Cancer in Norway Males Figure 11-1: Pancreas (ICD-10 C25) 25.05 22.575 20.0 7.55 15.0- 12.55 10.07 755 5.07 2.54 —_—— 0.05 1965 1970 1975 1980 1985 1990 1995 2000 2005 2010 2015 ——— Incidence Mortality —— Survival 5-year relative survival (%) Rates per 100 000
Slide 35: Cancer in Norway
Cancer in Norway New cases in 2015: 415 males and 410 females Deaths in 2014: 349 males and 364 females 5 year survival after diagnosed with pancreatic cancer is 6-8% Pancreatic cancer 4th most common cause of cancer related death both for males and females 10-20% of patients resectable 35
Slide 36: Metastatic disease
Metastatic disease The NEW ENGLAND JOURNAL of MEDICINE ORIGINAL ARTICLE FOLFIRINOX versus Gemcitabine for Metastatic Pancreatic Cancer Thierry Conroy, M.D., Francoise Desseigne, M.D., Marc Ychou, M.D., Ph.D., Olivier Bouché, M.D., Ph.D., Rosine Guimbaud, M.D., Ph.D., Yves Bécouarn, M.D., Antoine Ade
Slide 37: Folfirinox vs Gemcitabine median OS
Folfirinox, median OS 11,1 moths Gemcitabine, median OS 6,8 months 37
Slide 38: ESPAC-1 study
ESPAC-1 study The NEW ENGLAND JOURNAL of MEDICINE | ORIGINAL ARTICLE | A Randomized Trial of Chemoradiotherapy and Chemotherapy after Resection of Pancreatic Cancer John P. Neoptolemos, M.D., Deborah D. Stocken, M.Sc., Helmut Friess, M.D., Claudio Bassi, M.D., Janet A. Dunn, M.Sc., Helen Hickey, B.S
Slide 39: ESPAC-1 study
Survival (%) No. at Risk No chemotherapy Chemotherapy ESPAC-1 study nN un a ee oe ee No chemotherapy Chemotherapy 0 a 0 12 24 36 48 60 Months 142 89 41 18 11 z 147 99 56 38 22 11 39
Slide 40: Conko-001 study
Conko-001 study Oettle et al. JAMA 2007 40
Slide 41: Conko-001 study
Conko-001 study Figure 2. Disease-Free and Overall Survival (Intent-to-Treat Analysis) Disease-Free Survival Overall Survival 100-4 100 Gemcitabine —— Observation g 804 g 804 & 8 5 5 g 604 Log-Rank P <.001 8 60-4 Log-Rank P=.06 a a @ © 2 & § 404 BS 404 3 3 i= € A PI O 205 O 204 ; : T T T J 0 T T T T
Slide 42: ESPAC-3
ESPAC-3 Neoptolemos et al. JAMA 2010 42
Slide 43: ESPAC-3
ESPAC-3 Figure 2. Survival Results by Randomized Treatment Overall survival Progression-free survival 1005 10075 Fluorouracil 75-4 + folinic acid 754 Log-rank 4° = 0.40; P= 3; i i rn eee Gemcitabine 2 HR, 0.96 (95% Cl; 0.84-1.10) S 504 8 504 fa fa > > 7) a 25- . 254 Log-rank ¥2 = 0.74; P=.39; = Soe
Slide 44: ESPAC-4
ESPAC-4 Comparison of adjuvant gemcitabine and capecitabine with gemcitabine monotherapy in patients with resected pancreatic cancer (ESPAC-4): a multicentre, open-label, randomised, phase 3 trial John P Neoptolemos, Daniel H Palmer, Paula Ghaneh, Eftychia E Psarelli, Juan W Valle, Christopher M Hal
Slide 45: ESPAC-4 overall survival
Number at risk Gemcitabine Gemcitabine plus capecitabine Overall survival (%) w o 1 ESPAC-4 overall survival — Gemcitabine — Gemcitabine plus capecitabine Median survival time=28-0 months (95% Cl 23-5-31-5) Hazard ratio for death: 0-82 (95% Cl, 0-68-0-98); stratified log-rank p=0-032 Median survival
Slide 46: ESPAC-4
ESPAC-4 • All 6 cycles of chemotherapy were given to 65% of patients in the gemcitabine group and 54% of patients in the gemcitabine+capecitabine group 46
Slide 47: ESPAC-1, ESPAC-3, Conko-001 and ESPAC-4 survival comparison
Median OS 5 yr OS ESPAC-1 Control 16.1mo 8.0% 5-FU 19.7mo 21.1% ESPAC-3 Gemcitabine 23.6mo 17.5% 5-FU 23.0mo 15.9% Conko-001 Control 20.2mo 11.5% Gemcitabine 22.1mo 22.5% ESPAC-4 Gemcitabine 25.5mo 16.3% Gemcitabine+Capecit 28.0mo 28.8% abine 47
Slide 48: Acta Oncologica 2016 article
Acta Oncologica, 2016; 55: 265-277 Taylor & Francis a ORIGINAL ARTICLE Impact of early disease progression and surgical complications on adjuvant chemotherapy completion rates and survival in patients undergoing the surgery first approach for resectable pancreatic ductal adenocarcinoma - A populatio
Slide 49: Surgery first approach for resectable pancreatic cancer
Surgery first approach for resectable pancreatic cancer Surgery first 203 patients Completion of adjuvant Failure in completion of No adjuvant chemotherapy chemotherapy adjuvant chemotherapy 85 patients (41.9%) 41 patients (20.2%) T7 patients (37.9%) ——_.. Early progression Early progression 29 pati
Slide 50: Overall survival by chemotherapy completion
OS All 17.0 months Started 20.0 months Completed 25.0 Not completed 12.0 months 50
Slide 51: Overall survival, completed adjuvant chemotherapy
(b) Overall survival 1.05 —— Noor incomplete AC —— Complete AC 08 06 04 027 0.0 T T T T 0 12 24 6 48 60 Time after surgery (months) Completed 25.0 months si
Slide 52: Phase I/II trial of TG01/GM-CSF and gemcitabine
Arming the immune system to fight cancer A Phase I/II trial of TG01/GM-CSF and gemcitabine as adjuvant therapy for treating patients with resected RAS-mutant adenocarcinoma of the pancreas www.targovax.com
Slide 53: TG01-01 Background
TG01-01 Background injectable antigen-specific cancer immunotherapy TG01 targeted to treat patients with RAS mutation - found in more than 85% of pancreatic adenocarcinomas a mixture of 7 synthetic peptides - representing 7 of the most common 12 & 13 mutations in RAS assoc. with human cancer induces
Slide 54: TG01-01 Study design
TG01-01 Study design Modified cohort is ongoing (n=13). Last patient last visit May 2018
Slide 55: TG01-01 Study objectives
TG01-01 Study objectives Primary • To assess the safety of GM-CSF/TG01 vaccination and adjuvant chemotherapy • To assess the immune response to GM-CSF/TG01 and the effect of adjuvant chemotherapy in patients receiving GM-CSF/TG01 after primary resection of pancreatic adenocarcinoma Secondary • To as
Slide 56: TG01-01 Endpoints
TG01-01 Endpoints Primary – Safety • Adverse events • Laboratory assessments – Immune response • DTH responses • Proliferative T-cell responses Secondary – Disease free survival at 2 years – Overall survival at 2 years Exploratory – Relationship between KRAS status in resected primary tumour and rec
Slide 57: TG01-01 Immunological assessment
TG01-01 Immunological assessment Two different antigen specific assays were used to asses the immunological response to TG01: – Delayed Type Hypersensitivity (DTH) skin test • A delayed hypersensitivity test (DTH) is an immune function test measuring the presence of activated T cell s that recognize
Slide 58: TG01-01 Patient disposition main cohort
TG01-01 Patient disposition main cohort Number of patients (N=19) Treated patients 19 (100%) Patients completed study 1 (5%) Patients prematurely 18 (95%) discontinued Reason for withdrawal: Consent withdrawn 3 (16%) Adverse event 4 (21%) Death 2 (11%)* Investigator decision 2 (11%) Disease recurren
Slide 59: TG01-01 Baseline characteristics main cohort
TG01-01 Baseline characteristics main cohort
Slide 60: TG01-01 Efficacy (survival rate from resection)
TG01-01 Efficacy (survival rate from resection) 1 year* 2 years* Assessed from resection 17/19 (90%) 13/19 (68%) (8 weeks before first IMP) *This rate compares favorably with the available published historical two-year survival rates of resected cancer patients treated with gemcitabine alone of betw
Slide 61: TG01-01 Overall survival (from resection)
TG01-01 Overall survival (from resection) In a recently published study (ESPAC-4) the OS in patients receiving gemcitabine alone was 27.6 months from resection (Neoptolemos JP et al.; The Lancet; 389:1011-1024 (2017))
Slide 62: Targovax patient
Targovax patient • Surgery 08.01.2014, N+ (1/8 lymph nodes), R1 resection • 1. Gemcitabine treatment 18.03.2014 • CT thorax scan 20.06.2014 unspecific pulmonary lesions 5mm in size • Last adjuvant gemcitabine treatment 19.08.2014 • CT thorax scan 06.07.2015 lesions increased in size to 15 mm, severa
Slide 63: TG01-01 Immune response
TG01-01 Immune response Immune response by week 11 and entire study period (N=19) *Three patients (week 11) and two patients (entire study period) without blood samples for analysis Immune response after week 11 (n=11)
Slide 64: TG01-01 Overall survival and immune response
TG01-01 Overall survival and immune response
Slide 65: TG01-01 Safety profile (N=19)
TG01-01 Safety profile (N=19)
Slide 66: TG01-01 Safety profile (N=19)
TG01-01 Safety profile (N=19) Grade 3/4 treatment emergent Adverse Events
Slide 67: Toxicity
Toxicity Gemcitabine (n=366) Gemcitabine plus capecitabine (n=359) pvalue grade 12 pvalue grade 3-4 Grade 1-2 Grade 3-4 Grade 5 Grade 1-2 Grade 3-4 Grade 5 Anaemia 213 (58%) 14 (4%) C) 201 (56%) 8 (2%) 0 0-549 0.279 Diarrhoea 151 (41%) 6 (2%) 0 161(45%) 19 (5%) 0 0-331 0-008 Fatigue 241 (66%) 19 (5%
Slide 68: TG01-01 Conclusions
TG01-01 Conclusions TG01/GM-CSF generated early immune responses in 89% of patients with R0/R1 resected pancreatic cancer. This demonstrate that TG01 vaccination activate mutant RAS specific T cells. The regimen was generally well tolerated although some late, manageable allergic reactions were seen
Slide 69: Capital Markets Update - Agenda
Capital Markets Update - Agenda Introduction – CEO, Øystein Soug Targovax’s technology and trials – CMO, Dr Magnus Jäderberg A physician’s view on pancreatic cancer – Dr Svein Dueland Financial update – CFO, Erik Wiklund Q&A Lunch www.targovax.com 69
Slide 70: Financial summary – end of Q1 2017
FINANCIALS Financial summary – end of Q1 2017 Operations Cash NOK 147m USD 17m End of Q1 2017 Net cash flow NOK -24m USD -3m Total Q1 Annual run rate NOK 104m USD 12m Last four quarters Annual opex NOK 116m USD 13m Last four quarters The share OSE: TRVX Market Cap NOK ~1bn USD ~120m At share price N
Slide 71: TRVX upgraded to main list on OSE
FINANCIALS TRVX was upgraded to the main list on OSE in March, and has showed a positive trend in share turnover in 2017 Development in daily average share turnover (NOK million / day) • NOK ~1.2b 20 market cap • NOK 9m NOK avg. daily turnover in 15 last 3 months • NOK 850m total turnover in Q1 10 •
Slide 72: Strong shareholder base as per May 2017
FINANCIALS Strong shareholder base as per May 2017 Shareholder Estimated ownership Shares m Relative HealthCap Sweden 11,2 26,4 % 42.2m ordinary shares RadForsk Norway 4,1 9,7 % • Management ownership: 2.1% Nordea Norway 3,0 7,0 % Nordnet Livsforsikring Norway 1,5 3,5 % • 3,792 shareholders KLP Norw
Slide 73: Multiple near term value inflection points
FINANCIALS Multiple near term value inflection points ONCOS-102 Initiate phase l Ovarian/colorectal ONCOS-102 Initiate phase l/ll melanoma TG02 Initiate phase Ib in colorectal TG01 ONCOS-102 Oslo Stock Exchange ONCOS-102 Initiate phase l/ll Listing on OSE main Initiate phase l phase ll initiated mes
Slide 74: Capital Markets Update - Agenda
Capital Markets Update - Agenda Introduction – CEO, Øystein Soug Targovax’s technology and trials – CMO, Dr Magnus Jäderberg A physician’s view on pancreatic cancer – Dr Svein Dueland Financial update – CFO, Erik Wiklund Q&A Lunch www.targovax.com 74