Oncos Therapeutics: ONCOS THERAPEUTICS Personalized Cancer Immunotherapy. March Antti Vuolanto, COO and co-founder

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1 Oncos Therapeutics: Personalized Cancer Immunotherapy ONCOS THERAPEUTICS Personalized Cancer Immunotherapy March 2015 Antti Vuolanto, COO and co-founder 1

2 History of Oncos Therapeutics Research group at Helsinki University starts development and non-clinical testing of oncolytic viruses Advanced Therapy Access Program (ATAP) starts at Docrates cancer center; 290 patients treated in the program Oncos is founded IP acquired from inventors Lead vaccine ONCOS-102 is selected from 10 vaccines used in ATAP 2010 Series A financing raised from HealthCap Finnish Technology Agency, Tekes, supports Oncos 2012 First patient enrolled in Ph I clinical study C1 Clinical manufacturing completed Ph I clinical study completed Mechanism of Action of lead vaccine elucidated 2

3 ONCOS cancer immunotherapy platform is based on a purposefully engineered human adenovirus (Ad5) Improved infectivity of cancer cells Selective replication in cancer cells inducing immunogenic cancer cell death 24 bp 6.7K/gp19K Ad5 knob E1A E3 Fiber knob ITR transgene Ad3 knob ITR A powerful transgene enhances stimulation of the immune system GM-CSF transgene in ONCOS-102, CD40L-transgene in ONCOS-402 3

4 ONCOS-102 educates the immune system to kill tumor cells Alerting the immune system Education of T cells Immune attack Innate Immune System Adaptive Immune System Anti-tumor Immune Response ONCOS-102 by metastasis T cell activation T cell attack tumor tumor Multiple mechanisms of activation: Viral replication Release of tumor antigens TLR stimulation (primarily TLR 9) Pro-inflammatory cytokines Local GM-CSF expression Targeted anti-tumor immune response: ONCOS-102 teaches the immune system to recognize the unique cancer cells of each patient Local ONCOS-102 treatment induces a unique, systemic anti-tumor immune response in every patient = in situ vaccination 4

5 Intralesional administration superior to systemic Systemic oncolytic MoA Intralesional approach of Oncos Main anti-tumor activity is expected to be caused by direct oncolytic cell killing Systemic spread of active virus from tumor-to-tumor is assumed -> Virus is therefore modified for immune system evasion and enhanced oncolysis Little effect on tumor immunotolerance Main anti-tumor activity is systemic tumor specific CD8+ T cell attack Breaks tumor immunotolerance Local administration utilizes natural immunogenicity of virus Immunostimulation enhanced by transgene Immunological memory provides long term protection Potentially sensitizes tumors to other therapies T T T T TT T T T T T T T T T T T T 5

6 Adenovirus is an optimal vector for cancer immunotherapy Adenovirus can both prime and boost immune responses 1 Adenovirus primarily activates CD8+ T-cells (via TLR 9 and via TLR independent mechanisms) optimal for cancer immunotherapy Adenoviruses are easy to engineer and produce Other viruses are suboptimal for cancer immunotherapy Vaccinia is less effective in priming T-cell responses than adenovirus 2 HSV has evolved multiple immune evasion strategies including inhibition of T cell responses 3,5 ; TLR activation profile not optimal (TLR 2 and 4) 4 ; neurotropism may pose safety concerns RNA viruses are difficult to engineer 1. Draper and Heeney 2010 Nat Rev Microbiol 2. Bart et al 2014 J Clin Invest 3. Raftery et al 1999 J Exp Med 4. Villalba et al 2012 Med Microbiol Immunol 5. Barcy et al 2001 J Immunol 6

7 ONCOS C1 Phase I Study Main objective: safety and dose finding for ONCOS last-line 100% chemo refractory cancer patients with 7 different solid tumors 3 cohorts with 3 dose levels (n=3+3+6): 3 x VP 1 x VP 3 x VP Total of 9 intra-tumoral administrations over 6 months Monitoring of disease progression by CT/PET scans in 10 patients Collection of biopsies and blood samples No DLT, mostly grade 1-2 adverse events with grade 3 adverse events seen in 6 patients, and no grade 4-5 adverse events 7

8 40% of evaluable patients showed stabilization of disease after 3 months Patients Median 2.5 years since diagnosis 100% chemo refractory (up to 16 courses) 66% had prior surgery 50% had prior radiotherapy Patient RECIST (3 months) FI1-01 Ovarian SD FI1-02 Colon SD FI1-04 Colon PD FI1-06 Liver PD FI1-08 Lung PD FI1-09 Mesothelioma PD FI1-13 Rectum PD FI1-14 Mesothelioma SD FI1-17 STS PD FI1-19 Ovarian SD SD =Stable disease, PD =Progressive disease Alive for >22 months 8

9 Ovarian cancer patient FI1-19 (38-year old female) Rapidly progressing carcinoma with stage 3 metastases Debulking surgery and 7 different chemotherapies Received 9 injections of ONCOS-102 ONCOS-102 was well tolerated Responded to chemotherapy following ONCOS-102 treatment CONFIDENTIAL 9

10 Patient FI1-19: Strong immune activation signal Patient is alive, 22 months after start of treatment Baseline 1 month 2 months CD8+ Killer T cells 1. Tumor microenvironment became less immunosuppressive Co-localization of CD8+ T cells (killer phenotype) and B cells in tumors posttreament marker of good prognosis B cells Th1 type immune response Induction of systemic anti-tumor immune response Induction of multiple tumor specific CD8+ T cell populations No tumor-specific antigens detected prior to treatment At 1 month several tumor antigen specific T cells detected in peripheral blood: Mesothelin, NY-ESO-1, MAGE-A1, MAGE-A3 Baseline Weeks 1-12 IFN gamma ELISpot data / Mesothelin specific T cells 10

11 Mesothelioma patient FI1-14 (68-year old male) Asbestos-related condition Rapidly progressing disease despite radiotherapy and chemotherapy (cisplatin, pemetrexed, docetaxel) treatment for one year Received 9 injections of ONCOS-102 ONCOS-102 was well tolerated CONFIDENTIAL 11

12 Mesothelioma patient FI1-14: Immune activation and late response 1. Induction of systemic antitumor immune response 2. 47% reduction in total tumor burden 6 months 7.5 months Before Weeks 1-12 MAGE-A3 specific CD8+ cells were induced by ONCOS-102 (IFN-gamma ELISPOT) 12

13 Oncos aims at improving outcomes and expanding cancer immunotherapy into new cancer types 1. Compelling rationale for combining with check point inhibitors (CPIs): ONCOS-102 induces a systemic tumor-specific CD8+ T-cell response Potentially enhances outcomes in current CPI target indications and expand into new cancer types Combination studies with CPIs are being prepared 2. Clinical and preclinical data also support combining with Standard-of- Care chemotherapies: Mesothelioma*, ovarian cancer*, soft tissue sarcoma* *Orphan Drug Designation granted for ONCOS-102 in US and EU 13

14 ONCOS-102 induce anti-tumor T cells; PD-(L)1 inhibitors remove T cell immune suppression PD-(L)1 inhibitor products Keytruda, anti-pd-1 (Merck) US approval in melanoma Opdivo, anti-pd-1 (BMS) US approval in melanoma, non-small cell lung cancer MPDL3280A, anti-pd-l1 (Roche) breakthrough designation (FDA) in bladder, nonsmall cell lung cancer Tumors express PD-L1 to prevent tumor cell killing by CD8+ T cells PD-(L)1 non-responders constitute the majority of patients Only 20 40% of patients respond (depending on the indication) High CD8+ T cell density in tumors and PD-L1 expression are markers for response (Merck, Roche) ONCOS-102 creates anti-tumor immune reaction Induction of anti-tumor CD8+ T cells CD8+ T cell infiltration Preliminary indication of increased PD-L1 expression 14