corporate presentation q3, 2017s2.q4cdn.com/.../doc_presentations/2017/corporate-pr… · ·...
TRANSCRIPT
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 pre-
clinical 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.
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Investment Highlights
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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 1b enrolling 13 cohorts of advanced hematologic malignancies and select solid tumors; Second trial in solid tumors and mycosis fungoides is currently recruiting
Multiple anti-tumor responses observed across both myeloid and lymphoid malignancies
Proprietary fluorine-based medicinal chemistry platform generating a pipeline of pre-clinical oncology assets
Trillium Pipeline: A Clinical Focus on CD47 Blockade with a Platform for Generating New Oncology Assets
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Discovery Preclinical Phase 1 Phase 2
TTI-621 (Systemic)
TTI-621 (Intratumoral)
Bromodomain Inhibitor
EGFR Inhibitor
Hematologicmalignancies + selectsolid tumors
Solid tumors +mycosis fungoides
High brain penetrationfor glioblastoma & brain mets
TBD
SIRPαFc (CD47 Blockade)
Fluorine Med Chem Platform
Undisclosed IO Targets
TTI-622 Combination therapy
Many Tumor Cells Use the CD47 “Do Not Eat” Signal to Inhibit Macrophage Phagocytosis
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High CD47 expression often correlates with aggressive disease and poor clinical outcomes
Many hematologic and solid tumors express high levels of CD47
CD47 delivers an inhibitory “do not eat” signal to macrophages through SIRPα
TTI-621: A Dual Function SIRPαFc Decoy Receptor that is Differentiated from Other CD47 Blocking Agents
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Blocks the DO NOT EAT signal from CD47but does not bind CD47+ red blood cells
Delivers an EAT signal to macrophages through FcγRs; differentiated from IgG4 antibodies
CD47 binding domain of
human SIRPα
Human IgG1 Fc
TTI-621 is a dual function decoy receptor that blocks the suppressive CD47 signal while engaging activating Fc receptors
SIRPaFc (TTI-621): Inducing Anti-Tumor Responses Through Blockade of the CD47 “Do Not Eat” Signal
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TTI-621 Activates Both the Innate and Adaptive Immune Systems
©Audra Geras
TTI-621 Enables Macrophages to Phagocytose A Broad Array of Human Tumor Cells In Vitro
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Control Fc (1 mM) TTI-621 (1 mM)
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
macrophagesRepresentative phagocytosis data (AML target)
TTI-621 is Highly Potent in Vivo
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TTI-621 dosed at 0.2 mg/kg IP 3x/wk (0.05 mg/kg/wk HED) for 4 wks starting 14d after engraftment
Intrafemoral injection of AML patient tumor cells
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
Results suggest a potent effect at 0.05 mg/kg HED and the presence of a therapeutic window for efficacy
*Human Equivalent Dose
CD47 Blockade by TTI-621 Activates Both the Innate and Adaptive Immune Systems
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Increased tumor cell phagocytosis by TTI-621 leads to enhanced antigen presentation and T cell proliferation using a model (CMV) antigen system
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Standard 3+3 dose escalation in lymphoma patients completed
Expansion across a range of hematological malignancies and small cell lung cancer
10 North American sites:
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 Seattle Cancer Care Alliance, Seattle WA BC Cancer Agency, Vancouver BC
Clinicaltrials.gov: NCT02663518
TTI-621-01: Phase 1 Study in Patients with Advanced Hematologic Malignancies and Selected Solid Tumors
Phase 1b Expansion Cohorts
MonotherapyMyeloid Malignancies
Acute Myeloid LeukemiaMyelodysplastic Syndrome
Myeloproliferative NeoplasmsLymphoid Malignancies
Acute Lymphoblastic LeukemiaChronic Lymphocytic Leukemia
Hodgkin LymphomaIndolent B Cell Lymphoma
Aggressive B Cell LymphomaT Cell Lymphoma
Multiple MyelomaSolid Tumors
Small Cell Lung Cancer
Combination TherapyCD20+ Lymphoma with rituximab
Hodgkin Lymphoma with nivolumab
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First dose is associated with manageable infusion reactions (similar to rituximab)
No induced anemia, consistent with lack of appreciable drug binding to human erythrocytes
Transient, dose-dependent thrombocytopenia observed
Attenuated after the first infusion
Pre-dose platelet levels remain relatively constant as circulating drug levels increase
MTD cautiously defined at 0.2 mg/kg; case by case dose intensification underway to determine if patients tolerate and benefit from higher exposure
TTI-621-01 Safety: TTI-621 is Well-Tolerated in an Outpatient Setting
Platelet Nadirs after Multiple Infusions
Trough Drug Levels and Pre-Dose Platelet Counts
MIP-1α MIP-1β TNF-α
IFN-γ CXCL10 GM-CSF
IL-6 IL-8 IL-10
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After 6 infusions the half-life is ~ 4 days, consistent with other Fc fusion proteins
Receptor occupancy approaching 50% observed on circulating leukemic cells; levels correlate with preclinical activity
Increases in serum cytokines/chemokines associated with macrophage activation observed:
Several chemokines (e.g., MIP-1α) are associated with TTI-621 activity in preclinical models
Profile suggests rapid engagement of the innate immune system
TTI-621-01 PK/PD: Target Binding Leads to Rapid Engagement of the Innate Immune System
Receptor Occupancy on Circulating Leukemic Blasts
Serum Cytokines Post-Infusion
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B cell lymphoma: one Hodgkin lymphoma patient with a transient partial response; several lymphoma patients with prolonged progression-free intervals characterized by decreasing volume disease and decreased PET avidity
AML: 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
Rituximab combination: 3 of 6 lymphoma 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
TTI-621-01 Anti-tumor Activity: Clinical Responses Observed Across Myeloid and Lymphoid Malignancies
Although preliminary, we believe that the multiple clinical responses across varied hematologic malignancies seen to date are encouraging
TTI-621-02: Phase 1 Study in Patients with Solid Tumorsand Mycosis Fungoides (T cell lymphoma)
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Phase 1 study of intratumoral TTI-621 in patients with percutaneously accessible solid tumors or mycosis fungoides (NCT02890368)
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)
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Expanding our CD47 Pipeline with TTI-622
TTI-621 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
Human SIRPα
SIRPαFc – Broad Clinical Effort in Multiple Malignancies
TTI-621-01 Trial:
Focus on emerging signals of clinical activity and signal seek in additional hematologic malignancies and selected solid tumors
Explore combinations with monoclonal antibodies and other anti-cancer agents
Determine if dose intensification can lead to greater receptor occupancy and ultimately, greater clinical benefit
TTI-621-02 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 2017
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Trillium’s Innovative Chemistry Platform –Creating Differentiated New Medicines with Fluorine
Block sites of metabolism to increase half-life and reduce toxicity
Electronegativity alters chemical properties to improve binding & potency
Lipophilicity improves oral absorption and blood-brain-barrier (BBB) penetration
Approximately 25% of all marketed drugs contain fluorine
Innovative proprietary chemistry allows access to an unprecedented class of novel fluorinated molecules
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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 patients2
Pharmacological inactivation of EGFR and mutant variants inhibit tumor growth in GBM patients3
EGFR is a Drug Target in Brain Cancer
1Parsons et al. Science. 20082Shinojima et al. Cancer Res. 20033Johns et al. Clin Cancer Res. 2007; Karpel-Massler et al. Mol Cancer Res. 2009
Brain Metastasis
Lung and CRC metastasize to brain
Primary Brain Tumors
>50% of GBMs have amplified/mutated EGFR
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Approved EGFR Inhibitors Exhibit Poor CNS Penetration
EGFR-targeted drugs approved by FDA
HNSCC: head and neck squamous cell carcinoma
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
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TTI-2341 Exhibits Superior BBB Penetration vs. Afatinib
Brain Exposure Following a Single 20 mg/kg Oral Dose in Male SD Rats (n=4)
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
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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 18F 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
Summary – TTI-2341 as a Potential Best-in-class Brain-penetrant Covalent EGFR Inhibitor
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/2017
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Experienced Leadership & Veteran Board of Directors
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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
MANAGEMENT
BOARD OF DIRECTORS
Executive Recent Affiliation
Dr. Calvin Stiller, Chair Chair
Dr. Henry Friesen Chair
Dr. Niclas Stiernholm CEO
Dr. Michael Moore CEO
Executive Recent Affiliation
Dr. Robert Kirkman CEO
Dr. Thomas Reynolds CMO
Mr. Luke Beshar CFO
Capitalization and Intellectual Property
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SHARES OUTSTANDING
CASH AND MARKETABLE SECURITIES
INSTITUTIONALOWNERSHIP
INTELLECTUAL PROPERTY
16.7M Common & Preferred
$41.3M CAD as of March 31, 2017; $30M USD raised June 2017 (~$40M CAD)
~70%
• 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
Investment Highlights
26
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 1b enrolling 13 cohorts of advanced hematologic malignancies and select solid tumors; Second trial in solid tumors and mycosis fungoides is currently recruiting
Multiple anti-tumor responses observed across both myeloid and lymphoid malignancies
Proprietary fluorine-based medicinal chemistry platform generating a pipeline of pre-clinical oncology assets