A First-in-class, First-in-human Phase 1 Pharmacokinetic (PK) and Pharmacodynamic (PD) Study of Hu5F9-G4 (5F9), an Anti-CD47 Monoclonal Antibody (mAb), in

Patients with Advanced Solid Tumors

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Branimir I. Sikic1, Nehal Lakhani2, Amita Patnaik3, Sumit Shah1, Sreenivasa Chandana2, Drew Rasco3, A. Dimitrios Colevas1, Timothy O’Rourke2, Kyriakos Papadopoulos3, George A. Fisher1, Victor

Villalobos1, Mark Chao4, Balaji Agoram4, James Y. Chen4, Jenny Huang4, Matthew Axt4, Jens-Peter Volkmer4, Ravindra Majeti5,6, Irving L Weissman6, Chris H. Takimoto4, Mark D. Pegram1, Sukhmani K.

Padda1

1Stanford University School of Medicine, Stanford, CA; 2South Texas Accelerated Therapeutics (START) Midwest, Grand Rapids, MI; 3START San Antonio, TX; 4Forty Seven, Inc., Menlo Park, CA, 5Department of

Medicine, Division of Hematology, Stanford University School of Medicine; and 6Cancer Institute and Institute for Stem Cell Biology and Regenerative Medicine - Stanford University

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Disclosures: B. I. Sikic

o Research Funding: Forty Seven, CellDex Therapeutics, Basilea,Genentech/Roche, Gilead, Ovarian Cancer Research Fund, Novartis, U. S. National Institutes of Health

o Data Monitoring Committees: Pfizer, Immune Design

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CD47 is a Key Regulator of Macrophage Activity and Cancer Evasion

o Cancer cells overexpress CD47, a “don’t eat me” signal, to evade detection by the immune system and subsequent destruction by macrophages.

o CD47 overexpression is common among solid and hematological tumor types and correlated with aggressive disease and poor prognosis.

o 5F9 is a humanized IgG4 that binds to and inhibits CD47 and “takes the brakes off” macrophages, analogous to T cell checkpoint inhibitors.

o In preclinical models, 5F9 is active against a wide range of solid tumors and hematological malignancies as monotherapy and combined with antitumor antibodies and T cell checkpoint inhibitors.

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5F9 is a Novel Macrophage Immune Checkpoint Inhibitor Targeting CD47

Control mAb: No Phagocytosis

Anti-CD47 mAb: Phagocytosis

MacrophagesCancer cells

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Primary and Secondary Objectives

• Primary• Assess safety and tolerability • Determine recommended Phase 2 dose and schedule (RP2DS) for

further trials

• Secondary• Pharmacokinetic profile • Preliminary evidence of antitumor activity• Characterize the tissue penetration of 5F9 in tumor biopsies from

patients in translational expansion cohorts

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SCI-CD47-001 is a First-in-Human Trial of 5F9 in Adults with Relapsed/Refractory Solid Tumors and Lymphoma

o Three-Part Dose Escalation Design using accelerated dose titration/3 + 3

• Part A: Priming dose determination using weekly intravenous (IV) dosing

• Part B: 1 mg/kg priming dose on day 1 followed by weekly maintenance

• Part C: 1 mg/kg priming dose, two loading doses in week 2, and weekly maintenance

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Patient Characteristic NumberMedian age, years (range) 60 (35 to 84)

Gender, n (%)• Male• Female

22 (35%)40 (65%)

Ethnicity, n (%)• Hispanic or Latino• Not Hispanic or Latino

4 (6.5%)58 (93.5%)

Race, n (%)• White• Asian• Black or African American

49 (79.0%)11 (17.7%)

2 (3.2%)Median prior systemic treatments (range) 5 (1 to 18)

Median 5F9 infusions (range) 8 (1 to 72)

Tumor Type Number Colorectal 18 Ovarian 13 Salivary 5Breast 5 Head & neck 4Pancreatic 4 Lung 2 Skin 2Diffuse large B-cell lymphoma 2 Other 7

Patient Characteristics (n = 62)

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Part and Dose Cohort Patients Infusions Patients

with DLTPart A: Weekly Dose (Prime)0.1 mg/kg 1 72 00.3 mg/kg 2 11 01 mg/kg 6 70 03 mg/kg 2 2 2 (a, b)Part B: Prime + Maintenance dose1, 3 mg/kg 4 20 1 (c)1, 10 mg/kg 3 112 01, 20 mg/kg 7 78 1 (b)

Part and Dose Cohort Patients Infusions Patients

with DLTTumor Biopsy Cohort (Prime + Maintenance)1, 20 mg/kg 15 197 0

Part C: Prime + Loading + Maintenance1, 20, 20 mg/kg 7 130 1 (c)

1, 30, 30 mg/kg 9 129 0

1, 45, 45 mg/kg 6 54 0

Total 62 875 5

Treatment Cohorts and Dose Limiting Toxicities (DLTs)

Dose Limiting Toxicities(a) Grade 3 Pain, Right Upper Abdomen(b) Grade 3 Hemagglutination (Grade 2 Headache with Hemagglutination on Peripheral Blood Smear)(c) Grade 3 Elevated Bilirubin(Unconjugated)/Blood bilirubin increased

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Treatment-Related Adverse Events (AE) by Cohort and Dose Level

AE Term *20 mg/kg Maintenance

Dose (n = 29)30 mg/mg Maintenance

Dose (n = 9)45 mg/mg Maintenance

Dose (n = 6)All Grades Grade 3 Grade 4 All Grades Grade 3 Grade 4 All Grades Grade 3 Grade 4

Anemia 19 (66%) 5 (17%) 0 3 (33%) 0 0 3 (50%) 1 (17%) 0

Hemagglutination 12 (41%) 1 (3%) 0 2 (22%) 0 0 2 (33%) 0 0

Hyperbilirubinemia 11 (38%) 3 (10%) 0 0 0 0 1 (17%) 0 0

Thrombocytopenia 5 (17%) 0 0 0 0 0 0 0 0

Lymphocyte count decreased 4 (14%) 4 (14%) 0 3 (33%) 2 (22%) 1 (11%) 1 (17%) 1 (17%) 0

Arthralgia/myalgia 5 (17%) 0 0 2 (22%) 0 0 1 (17%) 0 0

Headache 11 (38%) 0 0 6 (67%) 1 (11%) 0 4 (67%) 0 0

Nausea 3 (10%) 0 0 2 (22%) 0 0 3 (50%) 0 0

Fatigue 18 (62%) 0 0 6 (67%) 0 0 4 (67%) 0 0

Fever 14 (48%) 0 0 4 (44%) 0 0 2 (33%) 0 0

Chills 12 (41%) 0 0 5 (56%) 0 0 3 (50%) 0 0

Infusion-related reaction 7 (24%) 2 (7%) 0 2 (22%) 1 (11%) 0 2 (33%) 1 (17%) 0

*AEs occurring in >15% of patients across all three cohorts listed (n = 44) and selected AEs of interest

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Anemia is Mitigated with a Priming and Maintenance Dosing Regimen

oPriming dose results in an early, temporary decline in hemoglobin

oHemoglobin frequently returns to baseline even with continued treatment with Hu5F9-G4

oAssociated with a reticulocytosis that resolves during the dosing period

1 2 3 4 5 6 7 8

4

6

8

10

12

14

16

0

2

4

6

8

10

Hem

og

lob

in (g

/dL) Reticulo

cytes (%)

Reticulocytes

Hemoglobin

Grade 2 anemia

5F9priming1mg/kg

5F9 maintenance 30mg/kg weekly

Hemoglobin lower limit of normal >11.7-13.5 g/dLReticulocytes upper limit of normal <2.28 %

30 30 30 30 30 30 301Dose (mg/kg)

Week

Anemia with Compensatory Reticulocytosis

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5F9 Achieves Target PK Levels at Clinically Feasible Doses

o5F9 can overcome the CD47 antigen sink at 10 mg/kg or higher

oAntibody half-life is ~13 days

oFree plasma drug levels exceed preclinical activity thresholds identified from PK modeling (>100 to 250 µg/ml)

Week 5 5F9 Pharmacokinetics

0 50 100 150

0.1

1

10

100

1000

Hours after Dose

Hu5F

9-G4

µg/m

l Therapeutic Range in Preclinical Models

30 mg/kg20 mg/kg10 mg/kg

3 mg/kg

1 mg/kg

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Pharmacodynamic Analyses Support the Recommended Dose

o Pharmacodynamic CD47 receptor occupancy assay shows maximal saturation on circulating white blood cells (WBCs) at recommended Phase 2 doses

o Hu5F9-G4 antibody present in the tumor microenvironment at recommended doseso Recommended dose: 1 mg/kg priming followed by 30 mg/kg weekly in Cycle 1 (28 days), then

Q2 weeks in Cycles 2 and beyond

Anti-IgG4 staining to detect 5F9-G4 on axillary lymph node 30 mg/kg 5F9 maintenance given in a patient with ovarian cancer

Pre-Treatment Day 36

0 14 28 42 56 70 840

20

40

60

80

100

Day

WB

C -

CD

47 R

ecep

tor O

ccup

ancy

(%)

WBC Receptor Occupancy

Patients treated at 30 mg/kgweekly (n = 14)

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Preliminary Efficacy for Patients Treated at 20 mg/kg or Higher

o Two ovarian or fallopian tube cancer patients had confirmed partial responses by RECIST

• Both patients heavily pre-treated with more than 6 prior lines of systemic therapy

• Both received weekly maintenance doses at 20 mg/kg

o A patient with DLBCL had shrinkage of target lesions and a mixed response (progressive disease) by Lugano criteria

PR, Clear Cell Ovarian CancerPR, Fallopian Tube CancerMixed response (PD), DLBCL

PR, Partial Response, PD, Progressive disease

* Colorectal cancerO Ovarian cancer

Best Percent Change In Target Lesion in Patients Treated at 20 mg/kg or Higher

Perc

ent C

hang

e Fr

om B

asel

ine

(%)

Patient with clear cell ovarian cancer: Partial Response (~50% reduction)

Patient with with fallopian tube cancerPartial Response (~43.5%)

• Confirmed PR and on treatment for 5.2 months at 20 mg/kg

loading dose then weekly

• CA125 tumor marker drop: 338 to 70 U/mL

• Prior treatment: carboplatin/taxane/pegylated liposomal

doxorubicin, gemcitabine, pemetrexed, bevacizumab,

topotecan, letrozole, cisplatin, and anti-PD-L1 antibody

Baseline Scan 8-Week Scan

21.7mm

27.9mm

Baseline Scan 8-Week Scan

• Confirmed PR and on treatment for 9.2 months at 20 mg/kg

weekly

• CA125 tumor marker drop: 890 to 103 U/mL

• Prior treatment: carboplatin/paclitaxel, topotecan, pegylated

liposomal doxorubicin /bevacizumab,

gemcitabine/bevacizumab, carboplatin/paclitaxel, niraparib (no

prior IO therapy)

17.33mm 9.87mm

Monotherapy Partial Responses Observed in Two Patients with Ovarian Cancer

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Conclusions (1)

o 5F9 is well tolerated using a priming and maintenance dosing strategy

o Expected AEs include transient, predictable anemia

o Doses up to 45 mg/kg weekly were well tolerated (no “MTD”)

o The RP2DS of 1 mg/kg priming on day 1, followed by 30 mg/kg weekly for 3 doses then Q2 weeks achieves exposures that exceed preclinical activity thresholds

o Single-agent activity at 20 mg/kg in two patients with ovarian cancer• Added an expansion cohort in ovarian cancer patients• Combination trials with avelumab (anti-PD-L1) planned

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o Blocking CD47 and enhancing macrophage phagocytosis of tumor cells with 5F9 is a promising new therapeutic strategy• FDA Fast Track designation in DLBCL and Follicular Lymphoma

o Translational studies analyzing the tumor microenvironment are pending

o Oral Presentation: Activity of the first-in-class anti-CD47 antibody Hu5F9-G4 with rituximab in relapsed/refractory non-Hodgkin lymphoma: Initial Phase 1b/2 results

• Sunday Jun 3, 2018, 9:45 am-12:45 pm by R. Advani, • Abstract 7504

o Poster Presentation: Pharmacokinetics of Hu5F9-G4, a first-in-class anti-CD47 antibody, in patients with solid tumors and lymphomas

• Monday, June 4, 2018, 8:00 am-11:30 am, by B. Agoram, Poster Board: #351 • Abstract 2525

Conclusions (1)

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Our grateful acknowledgements to:o The patients who volunteered and their relatives and friends who

supported them

o The physicians who referred their patients and worked with us to participate in their care

o The research nurses and clinical research associates who contributed greatly to the performance of this study

o The California Institute for Regenerative Medicine for the CIRM DR3-06965 award to Stanford University for the initiation of this program

o Our collaborators involved in the translational analyses, notably Jim Allison, Pam Sharma and the Immunotherapy Platform at MD Anderson