16 th Annual Needham Health Care Conference April 5, 2017

Transcription

1 16 th Annual Needham Health Care Conference April 5, 2017

2 This presentation may contain forward-looking statements, which reflect Trillium's current expectation regarding future events. These forward-looking statements involve risks and uncertainties that may cause actual results, events or developments to be materially different from any future results, events or developments expressed or implied by such forward-looking statements. Such factors include, but are not limited to, Trillium's ability to obtain financing to advance the products in its development portfolio; changing market conditions; the successful and timely completion of preclinical and clinical studies; the establishment of corporate alliances; the impact of competitive products and pricing; new product development risks; uncertainties related to the regulatory approval process or the ability to obtain drug product in sufficient quantity or at standards acceptable to health regulatory authorities to complete clinical trials or to meet commercial demand; and other risks detailed from time to time in Trillium's ongoing quarterly and annual reporting. Forward-looking statements are made only as of the date of this presentation and except as required by applicable securities laws, Trillium undertakes no obligation to publicly update or revise any forward-looking statements, whether as a result of new information, future events or otherwise. 2

3 Investment Highlights Immuno-oncology company developing a next generation checkpoint inhibitor, engaging multiple arms of the immune system Lead programs targets CD47, a do not eat signal tumor cells exploit to escape destruction by the immune system Phase 1a trial in patients with relapsed/refractory lymphomas completed; Phase 1b enrolling 10 cohorts of advanced hematologic malignancies Second trial in solid tumors is currently recruiting and additional trials planned Proprietary fluorine-based medicinal chemistry platform generating a pipeline of pre-clinical oncology assets 3

4 Trillium Pipeline: A Clinical Focus on CD47 Blockade with a Platform for Generating New Oncology Assets SIRPαFc (CD47 Blockade) Discovery Preclinical Phase 1 Phase 2 TTI-621 (Systemic) TTI-621 (Intratumoral) TTI-622 Hematological malignancies Solid tumors + mycosis fungoides Combination therapy Fluorine Med Chem Platform Bromodomain Inhibitor EGFR Inhibitor TBD High brain penetration for glioblastoma & brain mets Undisclosed Targets 4

5 Many Tumor Cells Use the CD47 Do Not Eat Signal to Inhibit Macrophage Phagocytosis Tumors known to express high levels of CD47 Acute myeloid leukemia Acute lymphoblastic leukemia Chronic lymphocytic leukemia Chronic myeloid leukemia Diffuse large B cell lymphoma Follicular lymphoma Mantle cell lymphoma Marginal zone lymphoma Multiple myeloma Myelodysplastic syndrome In many cases high CD47 expression correlates with aggressive disease and poor clinical outcomes Bladder cancer Breast cancer Colon cancer Esophageal cancer Gastric cancer Glioblastoma Glioma Kidney cancer Leiomyosarcoma Liver cancer Lung cancer Melanoma Ovarian cancer Pancreatic cancer Prostate cancer 5

6 TTI-621: A Dual Function SIRPαFc Decoy Receptor CD47 binding domain of human SIRPα Blocks the DO NOT EAT signal from CD47 Human IgG1 Fc Delivers an EAT signal to macrophages through FcγRs TTI-621 is a dual function decoy receptor that blocks the suppressive CD47 signal while engaging activating Fc receptors 6

7 SIRPaFc TTI-621 Activates (TTI-621): Both Inducing the Innate Anti-Tumor and Adaptive Responses Immune Through Blockade Systems of the CD47 Do Not Eat Signal Audra Geras 7

8 TTI-621 Enables Macrophages to Phagocytose A Broad Array of Human Tumor Cells In Vitro Control Fc (1 mm) TTI-621 (1 mm) Representative phagocytosis data (AML target) TTI-621 In Vitro Activity: Dose-dependent increase in phagocytosis Mean EC50 = 10 nm (767 ng/ml) Active against a broad range of hematologic and solid tumors Activates phagocytosis by M1 and M2 macrophages 8

9 TTI-621 is Highly Potent in Vivo TTI-621 In Vivo Activity: Active across a range of xenograft models Activity in the AML xenograft model at 0.05 mg/kg/wk HED* Similar potency observed with a mouse surrogate SIRPaFc (in presence of antigen sink) In non-human primate studies, no severe toxicity occurs up to an HED of 0.3 mg/kg/week Intrafemoral injection of AML patient tumor cells TTI-621 dosed at 0.2 mg/kg IP 3x/wk (0.05 mg/kg/wk HED) for 4 wks starting 14d after engraftment *Human Equivalent Dose Results suggest a potent effect at 0.05 mg/kg HED and the presence of a therapeutic window for efficacy 9

10 CD47 Blockade by TTI-621 Activates Both the Innate and Adaptive Immune Systems Increased tumor cell phagocytosis by TTI-621 leads to enhanced antigen presentation and T cell proliferation using a model (CMV) antigen system 10

11 TTI : Phase 1 Study in Patients with Advanced Hematological Malignancies Phase 1a: Dose Escalation Lymphoma Standard 3+3 dose escalation in lymphoma patients; Expansion across a range of heme malignancies (NCT ) 8 North American sites: Phase 1b: Expansion Acute Myeloid Leukemia Myelodysplastic Syndrome Chronic Lymphocytic Leukemia Hodgkin Lymphoma Indolent B Cell Lymphoma Aggressive B Cell Lymphoma T Cell Lymphoma Multiple Myeloma Myeloproliferative Neoplasms CD20+ Lymphoma with rituximab City of Hope, Duarte CA Cleveland Clinic, Cleveland OH Colorado Blood Cancer Institute, Denver CO Tennessee Oncology, Nashville TN Columbia University, New York NY Mayo Clinic, Rochester MN Memorial Sloan Kettering Cancer Center, New York NY Princess Margaret Cancer Centre, Toronto ON Phase 1b is currently enrolling, additional sites (US and Canada) are now being added Data from Phase 1a (18 patients) provided at ASH 2016; additional pharmacology data presented at ASCO-SITC

12 TTI Phase 1a Update ASH 2016 (n=18) Safety Drug generally well-tolerated No induced anemia Transient, dose-dependent thrombocytopenia (an anticipated, on-target effect) Defined MTD: 0.2 mg/kg/wk (exceeds the minimum efficacious dose in preclinical studies) Pharmacodynamics Achieved receptor occupancy levels that correlate with drug activity in vitro Observed elevations in macrophage-associated chemokines (MIP-1α, MIP-1β) that are associated with TTI-621 activity in vitro Anti-tumor activity One patient (Hodgkin lymphoma) achieved a transient partial response Several patients experienced prolonged progression-free intervals characterized by decreasing tumor volume and decreasing PET activity We believe these data provide preliminary evidence that TTI-621 is active as a monotherapy in patients with relapsed/refractory lymphomas 12

13 Multiple Infusions of TTI-621 Lead to Sustained Receptor Occupancy, Drug Accumulation and Stable Platelet Counts Receptor Occupancy on Circulating Leukemic Blasts Trough Drug Levels and Pre-Dose Platelet Counts These data suggest that we overcome the platelet antigen sink and achieve meaningful TTI-621 exposure while maintaining acceptable platelet counts 13

14 TTI Phase 1b Clinical Update April evaluable patients have been enrolled into the expansion phase to date In the AML cohort, one patient with minimal residual disease (0.7% abnormal blasts at baseline) obtained a complete molecular remission after 4 infusions of TTI-621 and remains in continued remission for 15+ weeks In the rituximab combination cohort, 3 of 6 patients who have had at least one interval PET/CT restaging obtained partial metabolic responses as demonstrated by decreased tumor activity on PET/CT scans - Manageable infusion reactions occurred in most patients after the first infusion of TTI- 621 and the combination has been associated with acceptable outpatient tolerability - Responding patients remain on treatment and progression-free for 19+ (DLBCL), 18+ (transformed lymphoma), and 8+ weeks (follicular lymphoma) in continuing follow-up Although preliminary, we believe that the multiple clinical responses across varied hematologic malignancies seen to date are encouraging 14

15 TTI : Phase 1 Study in Patients with Solid Tumors and Mycosis Fungoides (T cell lymphoma) Phase 1 study of intratumoral TTI-621 in patients with percutaneously accessible solid tumors or mycosis fungoides (NCT ) Rationale for intratumoral route of administration: Compelling preclinical efficacy in xenograft models Achieve high local target saturation Can perform serial, on-treatment biopsies to characterize the effects of TTI-621 on the tumor microenvironment (e.g., macrophages, T cells) First patient dosed in Q1/2017 Plan to provide update 2H/2017 DLBCL (Toledo) xenograft model TTI-621 intratumoral injections (0.2 mg/mouse, arrowheads) 15

16 Expanding our CD47 Pipeline with TTI-622 TTI-621 Human SIRPα TTI-622 Human IgG1 Fc Human IgG4 Fc Blocks CD47 and delivers a strong activating signal through FcγRs Blocks CD47 and delivers a modest activating signal through FcγRs TTI-621 is the most potent SIRPαFc format TTI-622 is less likely to deplete platelets, enabling higher exposures Both agents may have unique combination opportunities Both agents are differentiated from antibodies by a lack of binding to human erythrocytes 16

17 SIRPαFc Broad Clinical Effort in Multiple Malignancies TTI Trial: Continue assessment of 0.2 mg/kg weekly dose across a range of hematologic malignancies (additional cohorts expected) Explore combinations with monoclonal antibodies and other anti-cancer agents Determine if greater exposures can be achieved through alternative dosing strategies TTI Trial: Probe the biological effects of TTI-621 on the tumor microenvironment following intratumoral administration Explore combinations with monoclonal antibodies and other anti-cancer agents TTI-622: Submit IND by year end

18 Trillium s Innovative Chemistry Platform Creating Differentiated New Medicines with Fluorine Approximately 25% of all marketed drugs contain fluorine Block sites of metabolism to increase halflife and reduce toxicity Electronegativity alters chemical properties to improve binding & potency Lipophilicity improves oral absorption and blood-brain-barrier (BBB) penetration Innovative proprietary chemistry allows access to an unprecedented class of novel fluorinated molecules 18

19 EGFR is a Drug Target in Brain Cancer Epidermal growth factor receptor (EGFR) is a receptor tyrosine kinase involved in the pathogenesis of many cancers Amplification of EGFR locus is the most common genetic aberration in glioblastoma (GBM) 1 Aberrant receptor expression correlates with poor clinical prognosis for GBM patients 2 Pharmacological inactivation of EGFR and mutant variants inhibits tumor growth in GBM models 3 1 Parsons et al. Science Shinojima et al. Cancer Res Primary Brain Tumors >50% of GBMs have amplified/mutated EGFR Brain Metastasis Lung and CRC metastasize to brain 3 Johns et al. Clin Cancer Res. 2007; Karpel-Massler et al. Mol Cancer Res

20 Approved EGFR Inhibitors Exhibit Poor CNS Penetration EGFR-targeted drugs approved by FDA There are numerous EGFR-targeted drugs on the market; none are FDA approved for CNS tumors Clinical testing of EGFR inhibitors in brain cancers has yielded mixed results Poor blood-brain barrier (BBB) penetration (<5%) limits efficacy of existing agents There is an urgent unmet medical need for novel BBB-penetrant EGFR inhibitors HNSCC: head and neck squamous cell carcinoma 20

21 A U C (h *n g /m L ) C m a x (n g /m L ) TTI-2341 Exhibits Superior BBB Penetration vs. Afatinib Brain Exposure Following a Single 20 mg/kg Oral Dose in Male SD Rats (n=4) B ra in A U C B r a in C m a x T T I Afa tin ib 0 T T I Afa tin ib TTI-2341 brain AUC and Cmax values are 6-fold higher than afatinib TTI-2341 (but not afatinib) was quantifiable in the brain up to 24 hours post 7-day repeat dosing TTI-2341 has >10-fold higher Kpuu (unbound drug brain-to-plasma ratio) than afatinib 21

22 Summary TTI-2341 as a Potential Best-in-class Brainpenetrant Covalent EGFR Inhibitor TTI-2341 is a novel covalent inhibitor of wild type and mutant EGFR developed with Trillium s proprietary fluorine chemistry Compared to the benchmark compound afatinib, TTI-2341 exhibits: Similar in vitro potency Superior in vitro ADME properties Greater oral bioavailability Enhanced BBB penetration TTI-2341 is amenable to radiolabeling with 18 F for use as a PET imaging probe Future development steps have been identified, IND submission can be achieved in approximately 18 months with appropriate resources 22

23 Projected 12-month Catalysts Present initial clinical data from the TTI-621 heme Phase 1a trial Q4/2016 Presentation of additional preclinical combination data (Q2/2017) Guidance on the bromodomain inhibitor program 1H/2017 Update on the EGFR inhibitor program 1H/2017 Initial clinical data from the TTI-621 solid tumor trial 2H/2017 Additional clinical data from the TTI-621 heme Phase 1b trial expansion cohorts 2H/

24 Experienced Leadership & Veteran Board of Directors MANAGEMENT Executive Title Joined Trillium Dr. Niclas Stiernholm President & Chief Executive Officer 2002 Dr. Robert Uger Chief Scientific Officer 2003 Dr. Eric Sievers Chief Medical Officer 2015 Dr. Penka Petrova Chief Development Officer 2003 Mr. James Parsons Chief Financial Officer 2003 Dr. Malik Slassi Senior Vice President, Discovery Research 2016 BOARD OF DIRECTORS Executive Recent Affiliation Executive Recent Affiliation Dr. Calvin Stiller, Chair Chair Dr. Robert Kirkman CEO Dr. Henry Friesen Chair Dr. Thomas Reynolds CMO Dr. Niclas Stiernholm CEO Mr. Luke Beshar CFO Dr. Michael Moore CEO 24

25 Capitalization and Intellectual Property SHARES OUTSTANDING 10.7M Common & Preferred CURRENT CASH $50.5M CAD as of December 31, 2016 INSTITUTIONAL OWNERSHIP ~70% INTELLECTUAL PROPERTY Two SIRPaFc patent families covering method of use and composition of matter through 2030 and 2033 Eleven patent families covering fluorine small molecule therapeutics and medical uses through 2035 and beyond 25

26 Investment Highlights Immuno-oncology company developing a next generation checkpoint inhibitor, engaging multiple arms of the immune system Lead programs targets CD47, a do not eat signal tumor cells exploit to escape destruction by the immune system Phase 1a trial in patients with relapsed/refractory lymphomas completed; Phase 1b enrolling 10 cohorts of advanced hematologic malignancies Second trial in solid tumors is currently recruiting and additional trials planned Proprietary fluorine-based medicinal chemistry platform generating a pipeline of pre-clinical oncology assets 26