Targeting the CD47 “Do Not Eat” Signal with TTI-621 (SIRPα-IgG1 Fc)

September 28, 2018 | Bob Uger, PhD

Discovery on Target:Targeting Tumor Myeloid Cells

This presentation may contain forward-looking statements, which reflect Trillium's current expectationregarding future events. These forward-looking statements involve risks and uncertainties that may causeactual results, events or developments to be materially different from any future results, events ordevelopments expressed or implied by such forward-looking statements. Such factors include, but are notlimited to, Trillium's ability to obtain financing to advance the products in its development portfolio; changingmarket conditions; the successful and timely completion of pre-clinical and clinical studies; the establishmentof 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 sufficientquantity or at standards acceptable to health regulatory authorities to complete clinical trials or to meetcommercial demand; and other risks detailed from time to time in Trillium's ongoing quarterly and annualreporting. Forward-looking statements are made only as of the date of this presentation and except as requiredby applicable securities laws, Trillium undertakes no obligation to publicly update or revise any forward-lookingstatements, whether as a result of new information, future events or otherwise.

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Many Tumor Cells Use the CD47 “Do Not Eat” Signal to Inhibit Macrophage Phagocytosis

CD47 delivers an inhibitory “do not eat” signal to macrophages through SIRPα

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Many hematologic and solid tumors express high levels of CD47

High CD47 expression often correlates with aggressive disease and poor clinical outcomes

TTI-621: A Dual Function SIRPαFc Decoy Receptor that Blocks CD47 and Delivers an Activating Signal

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Blocks the CD47 DO NOT EAT signal

Delivers an EAT signal through FcγRs

TTI-621 Activates Both the Innate and Adaptive Immune Systems

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TTI-621 Is Efficacious In Vitro and In Vivo

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Petrova et al. Clin. Cancer Res. 2017

Lin et al. AACR 2017

AML Xenograft Model – Systemic Administration

DLBCL Xenograft Model – Local Administration

Phagocytosis Visualized by Confocal Microscopy

In Vitro Activity – Primary Heme Samples

Differentiating TTI-621 From Other CD47 Blocking Agents1. TTI-621 IgG1 Fc delivers a potent “eat” signal

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CD47 Blocker* (Company) Isotype

TTI-621 (Trillium) IgG1

TTI-622 (Trillium) IgG4

Hu5F9 (Forty Seven) IgG4

CC-90002 (Celgene) IgG4

SRF231 (Surface Oncology) IgG4

ALX148 (ALX Oncology) Inert IgG1

Petrova et al. Clin. Cancer Res. 2017

*Clinical stage compounds

Advantages of an IgG1 Fc:• Maximizes potency by delivering an activating signal to

macrophages through Fc receptors• Higher likelihood of monotherapy activity - not dependent

upon a combination with another IgG1 antibody• Could be used to treat tumors where no anti-cancer

antibody is available

Differentiating TTI-621 From Other CD47 Blocking Agents2. TTI-621 Does Not Bind Human RBCs

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Petrova et al. Clin. Cancer Res. 2017

CD47 is associated with the Rh Ag complexand anchored to the cytoskeleton in RBCs TTI-621 does not bind human RBCs TTI-621 does not agglutinate human RBCs

Salomao et al. PNAS 2008

Why does TTI-621 not bind RBCs?• Moderate binding affinity – need bivalent interaction• Lack of CD47 mobility in the RBC membrane prevents

clustering and limits bivalent binding

Advantages of non-RBC binding:• Minimizes likelihood of anemia• Avoids drug removal by the “antigen sink”• Avoids interference with transfusion medicine testing

CD47 Clinical Programs

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Phase 1/2a(POC)Preclinical

Phase 2b/3(Pivotal)Indication

Intratumoral

Intratumoral

Intravenous

Intravenous

Intravenous

Monotherapy

Combination(IFNα, PD-1/PD-L1)

Monotherapy

Combination(Rituximab, Nivolumab)

Monotherapy,Combination

Monotherapy/CombinationRoute

CTCL, Solid tumors

CTCL

DLBCL, CTCL, PTCL

DLBCL, HL

Lymphoma, myeloma

Candidate

TTI-622(SIRPα-IgG4 Fc)

TTI-621(SIRPα-IgG1 Fc)

TTI-621(SIRPα-IgG1 Fc)

Intratumoral Administration Study (TTI-621-02)

Multicenter, open-label phase 1 study of direct intratumoral injection of TTI-621 in patients with relapsed/refractory mycosis fungoides (MF) or percutaneously accessible solid tumors (NCT02890368)

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*10 mg 3x/wk for 2 wks then 10 mg weekly

^Combinations: IFN-α, anti-PD-1/PD-L1, T-vec (melanoma only), radiation (plasmacytoma only)

Single injection(1, 3 or 10 mg)

Multiple Injection(10 mg 3x/wkfor 1 or 2 wks)

Induction*+ continuation

(monotherapy or combinations^)

ASH 2017

Ongoing

• Advantages of direct injection:• Obtain very high local drug

concentrations

• Avoid systemic antigen sink

• Rapid responses

Update recently reported at EORTC 2018

Intralesional TTI-621 Injections Were Well Tolerated in CTCL Patients

• Related adverse events (AEs) all Grade 1 or 2; no Grade ≥3 AEs

• Common related AEs include chills, injection site pain, and fatigue

• No related serious adverse events or dose-limiting toxicity

11Querfeld et al. EORTC CLTF 2018 Data Cut-off: August 3, 2018

CAILS Reductions in Injected Lesions Were Observed in the Majority of Patients

18 patients have available CAILS scores*

• 16 (89%) with decreased CAILS

• 8 (44%) with ≥50% reduction in CAILS

• CAILS decreases:

• Occurred at all dose levels

• Following single and multiple injections

• In all stages IA to IVB

12Querfeld et al. EORTC CLTF 2018 Data Cut-off: August 3, 2018

*Composite Assessment of Index Lesion Severity, a measure of local lesion responses

CAILS Responses Occurred Rapidly Within the 2-Week Induction Period

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* Patients received maximally 2 weeks of study treatment (induction phase)† Response assessments beyond day 14 are provided if patients have not progressed or continued onto another therapy# The first patient treated obtained a CR of the injected lesion that is ongoing after 52+ weeks

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Data Cut-off: August 3, 2018Querfeld et al. EORTC CLTF 2018

Examples of Rapid Tumor Regression in MF Patients

A) 85M with stage IIB MF with large cell transformation received a single 10 mg injection of TTI-621 into the proximal lesion on the left foot

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Baseline Baseline

Day 3

Week 4

Day 3

Week 18

Day 3

Week 12

Baseline

A) B) C)

B) 72M with stage IIB MF with large celltransformation received a single 1 mginjection of TTI-621 into the lesion on thedorsal surface of the left foot

C) CD4 staining of skin biopsies frompatient in B).

Querfeld et al. ASH 2017

Local-Regional Responses Were Observed in Non-Injected, Adjacent Control Lesions

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All CAILS scores: Injected vs Non-Injected Control Lesions

Injected

Control

Data Cut-off: August 3, 2018Querfeld et al. EORTC CLTF 2018

• 7 patients with reduced CAILS had a paired CAILS assessments in an adjacent non-injected lesion

• Injected lesion CAILS decreased -14% to -67% in all patients

• Non-injected lesions CAILS decreased -12% to -67% in 6/7 patients

• Median distance between paired injected and non-injected lesions is estimated to be 5.3 cm (range 0.2 - 15 cm)

Abscopal (Systemic) Effects Were Observed in One of Two Patients Receiving Continuation Monotherapy

16Data Cut-off: August 3, 2018Querfeld et al. EORTC CLTF 2018

Rapid resolution of lesions on abdomen (lower panel), left flank/back and arms (not shown) following TTI-621 injections of target lesions on left calf (upper panel), left ankle and right foot

Screening

Injected Lesion – T01 (Left Calf)

Distal Non-Injected Lesion – Abdomen

Screening Week 2 Week 9

Week 2 Week 11Week 7

Week 2

Peripheral Responses Were Observed Following Local Injections

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Screening Day 8

P r e - T r e a t m e n t D a y 8

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Screening Day 8Screening Day 8

Single 1 mg Injection Single 1 mg Injection Single 3 mg Injection

P r e - T r e a t m e n t D a y 3 D a y 8

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Querfeld et al. EORTC CLTF 2018

Intravenous Administration Study (TTI-621-01)

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Multicenter, open-label phase 1 study in patients with relapsed/refractory hematologic malignancies (NCT02663518)

Dose Escalation(0.05, 0.1, 0.2, 0.3 mg/kg)

MonotherapyIndications

Identified first dose MTD(0.2 mg/kg)

ASH 2016

Lymphoma

None

0.2 mg/kg (mono)0.1 mg/kg (combo)

Heme Malignancies

CD20+ (Rituximab)

0.2 mg/kg + higher(Dose Intensification)

CTCL, PTCL, ALL

CD20+ (Rituximab)cHL (Nivolumab)

Dosing

CombinationIndications

ASH 2017 Ongoing

Expanded Safety DataPreliminary DLBCL Efficacy Data

Intravenous TTI-621 is Well Tolerated

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Cohort(s): All

Grade 1-2 Grade ≥3

Infusion Related Reaction 64 (42) 3 (2) 67 (44)

≥ 15% Thrombocytopenia 8 (5) 29 (19) 37 (24)

Chills 30 (20) 30 (20)

Fatigue 24 (16) 24 (16)

Nausea 20 (13) 20 (13)

Diarrhoea 16 (10) 1 (1) 17 (11)

Anaemia 5 (3) 11 (7) 16 (10)

Pyrexia 16 (10) 16 (10)

Vomiting 14 (9) 1 (1) 15 (10)

≥ 5% Headache 13 (8) 13 (8)

Neutropenia 11 (7) 11 (7)

Hypotension 6 (4) 2 (1) 8 (5)

Decreased Appetite 7 (5) 7 (5)

Epistaxis 5 (3) 2 (1) 7 (5)

Related Adverse Events

n(%)Adverse Event Grades

Total

n=153

0 25 50 75 100

AE Reports (%)

Grade 1-2

Grade ≥3

* Patients with at least one reported AE were included in the analysis

*

Based on Data Snapshot of Aug 10, 2018

• Most frequent AEs were low-grade infusion reactions, clinically managed by pre-medication and close monitoring

• ≥ Grade 3 thrombocytopenia occurred in 19% patients

• Diverse patient population from the following expansion cohorts: AML, MDS, MPN, B-NHL, T-NHL, HL, MM, CLL, SCLC

The following data summaries are based on interim data and thus should be regarded as preliminary

Transient Thrombocytopenia Not Associated with Increased Risk of Bleeding

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• Thrombocytopenia is likely an on-target effect resulting from CD47 blockade and the TTI-621 IgG1 Fc

• Thrombocytopenia is reversible within a week

• Pre-dose platelet levels remain relatively stable over the course of the study

• Transient platelet decreases did not lead to an increased risk of bleeding

• Platelet decreases did not impact drug delivery – 1/163 patients had dosing discontinued due to thrombocytopenia

Median Platelet Levels in All Subjects During Week 1 (N=163)

Pre-dose Platelet Levels in All Subjects Over Study Course (N=163)

Bleeding Adverse Events in All Subjects (N=163)

Based on Data Snapshot of Apr 10, 2018

All Related All Related All Related All Related

Epistaxis 6 (4) 2 (1) 1 (1) 1 (1) 7 (4) 3 (2)

Anal hemorrhage 2 (1) 2 (1)

Contusion 2 (1) 1 (1) 1 (1) 2 (1) 1 (1)

Ecchymosis 1 (1) 1 (1)

Gastric hemorrhage 2 (1) 2 (1)

Hematoma 1 (1) 1 (1)

Hematuria 1 (1) 1 (1) 1 (1) 1 (1)

Menorrhagia 1 (1) 1 (1) 1 (1) 1 (1)

Petechiae 1 (1) 1 (1)

Purpura 1 (1) 1 (1) 1 (1) 1 (1)

Total 13 (8) 5 (3) 2 (1) 1 (1) 3 (2) 1 (1) 17 (10) 7 (4)

Based on April 2018 CSV

Bleeding Adverse Events

n (%)

Grade 1 Grade 2 Grade 3 Total

Hemoglobin is Not Significantly Impacted

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0 0 1 (1) 0 0 0 0 0 0

117 114 115 115.5 115 117 115 114.5 115

1 8 15 22 29 36 43 50 58

137 124 117 100 75 95 65 30 10

0

40

80

120

160

200

g/L

Dose Days

Subjects (n)

Gr4 n (%)

Median Hemoglobin Levels Through Day 58Dose Cohort(s): All Excluding AML/MDS

Dose Level(s): All

0 0 1 (1) 0 0 0 0 0 0

117 114 115 115.5 115 117 115 114.5 115

1 8 15 22 29 36 43 50 58

137 124 117 100 75 95 65 30 10

0

20

40

60

80

100

Patien

ts (

%)

Dose Days

Nml Grade 1 Grade 2 Grade 3 Grade 4

Subjects (n)

Median Hgb

Gr 4 n (%)

Pre-Dose Hemoglobin Grades Through Day 58Dose Cohort(s): All Excluding AML/MDS

Dose Level(s): All

Data Cut-off: July 24, 2018

Median Hemoglobin Levels Through Day 58(All Patients Excluding AML/MDS)

Pre-dose Hemoglobin Grades Through Day 58(All Patients Excluding AML/MDS)

Doses Higher than the MTD Are Tolerated in Dose Intensified Patients

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• Dose intensification at Investigator’s discretion allowed per protocol; later standardized in Amendment 8

• 16 patients dose intensified to 0.5 mg/kg and maintained at 0.5 mg/kg for 1-27 weeks (range)

• No patients escalated to 0.5 mg/kg have been discontinued due AEs

Based on Data Snapshot of Aug 10, 2018

IV TTI-621 Has Single Agent Activity in T-Cell Lymphoma Patients

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• Monotherapy ORR: 19% in MF, 25% in PTCL

• 5/7 responses observed in patients receiving weekly doses of 0.2 mg/kg

Based on Data Snapshot of Jul 24, 2018

Response

n (%)

Objective Response

median days (range)

CR PR SD ORR Time to Resp Tmt Duration

Mycosis Fungoides 21 --- 4 (19) 6 (29) 4 (19) 37 (16-51) 103 (41-281)

Sezary Syndrome 5 --- --- 3 (60) --- --- ---

Peripheral TCL 12 --- 3 (25) 2 (17) 3 (25) 79 (20-81) 143 (85-288)

Total / Overall 38 --- 7 (18) 11 (29) 7 (18) 50 (16-81) 135 (41-288)

TTI-621-01: T-Cell

LymphomaN

IV TTI-621 Has Activity as Monotherapy and in Combination with Rituximab in DLBCL Patients

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• DLBCL efficacy:• 25% ORR monotherapy• 25% ORR rituximab

combo

• Majority of responses were observed in patients receiving weekly doses of 0.2 mg/kg (monotherapy, 2/2 pts) or 0.1 mg/kg (combination, 8/9 pts)

TTI-621 Monotherapy TTI-621 + Rituximab Combination Therapy

Based on Data Snapshot of Jul 24, 2018

Response

n (%)

Objective Response

median days (range)

CR PR SD ORR Time to Resp Tmt Duration

DLBCL 24 1 (4) 5 (21) 10 (42) 6 (25) 62 (21-78) 165 (127-247)

iNHL 4 --- 2 (50) 2 (50) 2 (50) 21 (18-23) 145 (127-162)

MCL 3 --- 1 (33) --- 1 (33) 31 (31-31) 172 (172-172)

Total / Overall 31 1 (3) 8 (26) 12 (39) 9 (29) 31 (18-78) 162 (127-247)

*excludes 3 subjects: ABCL (n=1, SD); PTCL and Other (both NA)

TTI-621-01: B-Cell

NHL Rituximab

Combination*

N

Response

n (%)

Objective Response

median days (range)

CR PR SD ORR Time to Resp Tmt Duration

DLBCL 8 1 (13) 1 (13) 3 (38) 2 (25) 106 (78-133) 139 (134-143)

iNHL 9 --- --- 7 (78) --- --- ---

MCL 1 --- --- --- --- --- ---

Total / Overall 18 1 (6) 1 (6) 10 (56) 2 (11) 106 (78-133) 139 (134-143)

*Excludes ABCL (n=1, PD) and Other (n=2, SD, PD)

TTI-621-01: B-Cell

NHL (ABCL/IBCL)*N

Summary

• TTI-621 is a novel dual function decoy receptor that blocks the CD47 “do not eat” signal and delivers an activating signal through FcRs

• TTI-621 is differentiated from other CD47 blocking agents by its potent IgG1 Fc and lack of RBC binding

• Intratumoral delivery of TTI-621 has been shown to be well tolerated and results in responses in injected and non-injected MF lesions

• Intravenous TTI-621 is well tolerated, activity observed as a single agent in CTCL, PTCL and DLBCL patients and in combination with rituximab in DLBCL patients at relatively low doses; dose intensification ongoing

• Clinical program is moving forward in three distinct areas: • Intratumoral mono- and combination-therapy in CTCL

• IV monotherapy in both CTCL and PTCL

• IV combination therapy in B-cell lymphoma

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Acknowledgements

• Patients and their families

• Staff members who contributed to the TTI-621 clinical studies:• BC Cancer Agency• City of Hope• Cleveland Clinic• Colorado Blood Cancer Institute• Columbia University• Hackensack University Medical Center• Mayo Clinic – Rochester• Mayo Clinic - Jacksonville• Memorial Sloan Kettering Cancer Center• New York University• Oregon Heath & Sciences University• Princess Margaret Hospital• Seattle Cancer Care Alliance• Tennessee Oncology• University of Pittsburg

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