Polaris Group 0925/2017

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1 Polaris Group 0925/2017

2 Polaris Group What has Polaris done in 2017 What have we learned in 2017 What is next for 2017 and beyond

3 Polaris Group What has Polaris done in 2017 Clinical studies Pre-clinical research & discovery Publications and presentations Intellectual property cgmp facility and production

4 Ongoing Clinical Studies Tumor Phase Study Site Treatment Type Current Status HCC I/IB Memorial Sloan Kettering Taiwan Combination (+ 5 -Fu; Oxaliplatin) Enrolling patient Pancreatic I/IB Memorial Sloan Kettering Mesothelioma II/III Global Combination (+ Gemcitabine; nab-paclitaxel) Patient enrollment complete Combination (+ Pemetrexed; Cisplatin) Enrolling patient s into Phase II Mesothelioma/NSCLC/Uveal melanoma/glioma I/IB United Kingdom Combination (+ Pemetrexed; Cisplatin) Enrolling patient for sarcomatoid cancers and NSCLC Leukemia (AML) I/IB Taiwan Advanced Solid tumors I/IB Taiwan Combination (+ Cytarabine) Enrolling patient Combination (+ Keytruda) Enrolling patient

5 ADI-PEG 20 + FOLFOX Phase I/II Study for HCC Current Status: 26 patients treated at MSKCC and 6 sites in Taiwan 12/26 patients were second line therapy: 1/12 PR (6.7%) 14/26 patients were third line or later: 4/14 PR (28.6%) Duration of response (DoR) for the third line or later: 5.6m, 5.8m+, 10.4m, 24m Key considerations for Polaris: Accelerated approval Single arm study ORR as the primary end point Agreement to keep all current eligible patients in the final analysis

6 ADI-PEG 20 + FOLFOX Phase I/II Study for HCC Original proposal: Agreement for Accelerated Approval Single arm study Second line or later therapy ORR as primary end point With projected 15% ORR, 169 patients total Agreement after the meeting: Accelerated approval Single arm study Third line or later therapy ORR as the primary end point The lower boundary of the Confidence Interval to be 15% 22% ORR, 225 patients total, need to have 46/225 response Agreement to keep all current eligible patients

7 Polaris Group What has Polaris done in 2017 Clinical studies Pre-clinical research & discovery Publications and presentations Intellectual property cgmp facility and production

8 Second Generation ADI: New Species The ADIs from 38 different organisms have been synthesized and tested 4 unique ADI enzymes have been identified One of the numerous properties evaluated is improved enzymatic activity both prior to and after PEGylation Organism Native Enzyme Specific Activity (IU/mg) Kcat (s-1) Km (um) PEGylated Enzyme Specific Activity (IU/mg) Kcat (s-1) Km (um) M. hominis < <10 M. gal < <10 M. ine < <10 M. col < <10 M. mel < <10

9 Stabilization of Hexameric Second Generation ADI

10 Casein Kinase 2 Project Polaris Compounds Are Synergistic with Approved Drugs Ovarian cancer Pancreatic cancer Colon cancer A2780 cell line % R eduction In R elative V iability BxPC3 Cell Line % Reduction In Relative Viability Colo 205 cell line % R eduction In R elative V iability % 40 % 40 % nm PL µ M C isplatin 123 nm PL µ M C isplatin nm PL µ M E rlotinib 370nM PL µ M Erlotinib nm PL µ M Sutinib 370 nm PL µ M S utinib Completed PK (Pharmacokinetics) analyses of selected CK2 compounds Conducting Kinase paneling analyses to access SPECIFICITY To initiate animal tumor model experiments

11 Combination With Immunotherapy ADI-PEG 20 And Anti-PD-1 mab in Sa1/N Model Data from P.Szlosarek, Barts Cancer Institute, UK

12 Checkpoint Small Molecule Inhibitor Project Potent lead series identified Block PD-L1/PD-1 interaction Non-toxic in vitro Metabolically stable Provisional patent filed BMS Compounds Polaris Compounds Compound IC50s in Interaction Assay, mm Half Life In The Presence of Human Liver Microsomes, min Toxic to cells at 10 mm Biochemical Cell-based A >120 No B >120 No C >120 Yes D ~48 No E >120 No F >120 Yes New compounds in the series showed >10X binding affinity to PD-L1 Second series of PD-L1 inhibitors designed, cureently being tested Modeling and design for additional checkpoint targets initiated

13 Polaris Group What has Polaris done in 2017 Clinical studies Pre-clinical research & discovery Publications and presentations Intellectual property cgmp facility and production

14 Polaris Presentations in Hepatocellular Carcinoma (HCC) 1. Harding J, et al. A phase I study of mfolfox6 and ADI-PEG-20 in patients (pts) with advanced hepatocellular carcinoma (HCC) and other gastrointestinal (GI) malignancies (ASCO Gastrointestinal Cancers 2017) Melanoma 2. Khadeir R, et al. The impact of ADI-PEG20 on PDL1 expression in ASS1 deficient uveal melanoma (AACR 2017) Mesothelioma (MPM) and Lung Cancer 3. Szlosarek PW et al. ATOMIC-Meso: A randomized phase 2/3 trial of ADI-PEG20 or placebo with pemetrexed and cisplatin in patients with argininosuccinate synthetase 1-deficient nonepithelioid mesothelioma (ASCO 2017) 4. Phillips M, et al. Expansion study of ADI-PEG 20, pemetrexed and cisplatin in patients with ASS1-deficient malignant pleural mesothelioma (TRAP) (ASCO 2017) Pancreatic Cancer 5. Lowery MA, et al. Phase 1B trial of ADI-PEG 20 (A) plus nab-paclitaxel (nab-p) and gemcitabine (gem) in subjects with advanced pancreatic cancer (APC) (ASCO Gastrointestinal Cancers 2017)

15 Polaris Publications in 2017 (1) Review: ADI-PEG 20 and Argininosuccinate Synthetase Deficiency 1. Kremer J, et al. Arginine Deprivation Inhibits the Warburg Effect and Upregulates Glutamine Anaplerosis and Serine Biosynthesis in ASS1-Deficient Cancers Cell Rep 18: (2017) 2. Kremer J, et al. Therapeutic arginine starvation in ASS1-deficient cancers inhibits the Warburg effect Mol Cell Oncol Mar 1;4(3):e (2017) 3. Long Y, et al. Argininosuccinate synthetase 1 (ASS1) is a common metabolic marker of chemosensitivity for targeted arginine- and glutamine-starvation therapy Cancer Lett 388:54-63 (2017) 4. Fung M, et al. Drug-induced amino acid deprivation as strategy for cancer therapy J Hematol Oncol. (2017) 10(1) Tsai W-B, et al. Chromatin remodeling system p300-hdac2-sin3a is involved in Arginine Starvation- Induced HIF-1α Degradation at the ASS1 promoter for ASS1 Derepression Scientific Reports 7, (2017) AML 6. Tsai HJ, A phase II study of arginine deiminase (ADI-PEG20) in relapsed/refractory or poor-risk acute myeloid leukemia patients Scientific Reports 7, (2017) Hepatocellular Carcinoma (HCC) 7. Thongkum A, et al. The combination of arginine deprivation and 5-fluorouracil improves therapeutic efficacy in argininosuccinate synthetase negative hepatocellular carcinoma Int J Mol Sci Jun 1;18(6) (2017)

16 Polaris Publications in 2017 (2) Immune Function 1. Brin E, et al. Pegylated arginine deiminase can modulate tumor immune microenvironment by affecting immune checkpoint expression, decreasing regulatory T cell accumulation and inducing tumor T cell infiltration Oncotarget 8: (2017) Mesothelioma (MPM) and Lung Cancer 2. Szlosarek PW, et al, Arginine Deprivation with Pegylated Arginine Deiminase in Patients with ASS1- Deficient Malignant Pleural Mesothelioma: A Randomized Clinical Trial JAMA Oncol 3:58-66 (2017) 3. Beddowes E, et al. Phase 1 dose-escalation study of pegylated arginine deiminase, cisplatin and pemetrexed in patients with argininosuccinate synthetase 1-deficient thoracic cancers J Clin Oncol 35: (2017) Pancreatic Cancer 4. Lowery MA, et al. Phase 1B trial of ADI-PEG 20 (A) plus nab-paclitaxel (nab-p) and gemcitabine (gem) in subjects with advanced pancreatic cancer (APC) (Cancer-in press 2017) 5. Liu Q, et al. Reduced expression of argininosuccinate synthetase 1 has a negative impact in patients with pancreatic ductal carcinoma PLoS One, DOI: , February 10 (2017) Bladder Cancer 6. Sahu D, et al. Argininosuccinate Synthetase 1 Loss in Invasive Bladder Cancer Regulates Survival through General Control Nonderepressible 2 Kinase-Mediated Eukaryotic Initiation Factor 2α Activity and Is Targetable by Pegylated Arginine Deiminase. Am J Pathol 187: (2017)

17 Polaris Group What was accomplished in 2017 Clinical studies Pre-clinical research & discovery Publications and presentations Intellectual property cgmp facility and production

18 Polaris Intellectual Property Applications in 2017 Patents Issued During 2016 Pharmaceutical composition of ADI-PEG 20 with histidine buffer (allow for storage at -20 o C) Issued in the United States (May 2016), Taiwan (December 2016), Australia (July 2016) and Korea (July 2016) Pending in other jurisdictions Applications Filed During 2016 Lyophilized formulations of pegylated ADI (November 2016) (allow for storage at 4 o C) Cancer treatments through combining ADI-PEG 20 with immunotherapies (July 2016) Next-generation CK2 inhibitor (June 2016) Small-molecule immune checkpoint inhibitor (September 2016)

19 Polaris Group What has Polaris done in 2017 Clinical studies Pre-clinical research & discovery Publications and presentations Intellectual property cgmp facility and production

20 DRX- USA cgmp Commercial Launch Facility: Production 300L Fermentor Centrifuge: harvest cells Microfluidizer: break cells Mixing Tanks Protein Purification Station Filtration Station Preparing for production in the commercial scale facility in October Currently increase the production by approximately 10X per batch

21 Polaris Group What has Polaris done in 2017 What have we learned in 2017 What is next for 2017 and beyond

22 Combination Therapy Significantly Increased Efficacy of ADI-PEG 20 in Multiple Cancers HCC: ADI-PEG 20 + FOLFOX Mesothelioma: ADI-PEG 20 + pemetrexed + cisplatin Pancreatic cancer: ADI-PEG 20 + gemcitabine + nab-paclitaxel AML: ADI-PEG 20 + cytarabine Glioblastoma: ADI-PEG 20 + pemetrexed + cisplatin Uveal melanoma: ADI-PEG 20 + pemetrexed + cisplatin Solid tumors: ADI-PEG 20 + Keytruda

23 Polaris Group What was accomplished in 2017 What was learned in 2017 What is the plan for 2017

24 Polaris Plans for 2017 And Beyond Clinical development of ADI-PEG 20 and other projects Pivotal Phase II/III mesothelioma study will opened in Europe in Q2 2017, following US and Taiwan. Anticipate patient enrollment to complete by Q4 2018, Pivotal Phase I/II studies for HCC ongoing Continue to explore the synergy between ADI-PEG 20 and immunotherapies Continue to develop the small molecule checkpoint inhibitors, aim to initiate clinical study in months Business development plans Continue dialogs with major pharmaceutical companies for potential co-development, licensing, and/or acquisition of ADI-PEG 20 Identify strategic partners to speed up the development of small molecule projects Secure funding via a combination of public fund raising, private placement, strategic partnering, licensing and acquisition to sustain corporate development Prepared, Attentive, Aggressive, Creative, Patient

25 THANK YOU