Phase 1 First-in-Human Trial of AMV564, a Bivalent Bispecific (2:2) CD33/CD3 T-Cell Engager, in Patients with Relapsed/Refractory

Acute Myeloid Leukemia (AML)

Peter Westervelt, MD, PhD1, Jorge E. Cortes, MD2, Jessica K. Altman3, Meixiao Long, MD4, Vivian G.Oehler, MD5,6, Ivana Gojo, MD7, Jeanmarie Guenot, PhD8, Patrick Chun, MD8 and Gail J. Roboz, MD9

1Division of Oncology, Washington University School of Medicine, Saint Louis, MO; 2Georgia Cancer Center, Augusta University, Augusta, GA;

3Northwestern University, Chicago, IL; 4Division of Hematology, Department of Internal Medicine, Ohio State University Hospital, Columbus, OH;

5Division of Hematology, Department of Medicine, University of Washington, Seattle, WA; 6Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA;

7Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, MD; 8Amphivena Therapeutics, Inc, South San Francisco, CA;

9Division of Hematology and Oncology, Weill Cornell Medical College of Cornell University, New York

ASH 61st Annual Meeting and ExpositionDecember 7-10, 2019. Orlando, FL

AMV564: A Bivalent, Bispecific CD33/CD3 T-cell Engager

AMV564: Binding Sites & Mechanism of Action

• CD33 Expressed on AML blasts

• EC50 4 - 8 pM for target-dependent killing of AML cell lines

AMV564: Selectivity

2 CD33 Binding Sites

2 CD3 Binding Sites

1Amphivena Therapeutics, Inc. https://amphivena.com/amv564/2Chen X, et al. Induction of myelodysplasia by myeloid-derived suppressor cells. J Clin Invest. 2013;123(11):4595-611.

AMV564Selectivity for CD33-signaling/clustered

Monovalent T-cells engagerscannot distinguish cell types

0.5 – 50 mcg

100 mcg

150 mcg

200 mcg

250 mcg

3+3 DESIGN(14 Days Continuous IV Infusion on a 28 Day cycle)

AMV564-101 Phase 1 Clinical Study Design: Relapsed/Refractory AML

450 mcg

300 mcg

Key Eligibility Criteria • Age ≥ 18 years• Relapsed or refractory

disease• 1-3 prior induction/salvage

regimens • Secondary AML • ECOG 0-2• Normal renal/hepatic

function

Status at cutoff date of 11/1/2019• 41 patients dosed• 11 dose cohorts

explored to date• Lead-in dosing for

450mcg cohort: 15mcg 30mcg 100mcg150mcg 300mcg target dose

AMV564-101 Phase 1 Clinical Study Design: Relapsed/Refractory AML

• Key Objectives− To characterize the safety and tolerability, including dose-limiting toxicity (DLT), of

AMV564 administered by CIV infusion− To identify the maximum tolerated dose (MTD) and recommended Phase 2 dose

(RP2D) of AMV564− To evaluate preliminary efficacy of AMV564 administered at the RP2D

• Additional objectives− To characterize the pharmacokinetics (PK), pharmacodynamics (PD), and

immunogenicity of AMV564 when administered by CIV infusion− To evaluate predictive biomarkers of response or resistance to AMV564 − To investigate the immunoregulatory activity of AMV564, including measures of T-

cell function and profiling of T-cell subpopulations

AMV564-101: DemographicsPatient Demographics N=41Median age, year (range), n (%)Age >65

71.3 (24.2 to 84.6)28 (68.3)

ECOG score, n (%)012

7 (17.1)29 (70.7)5 (12.2)

AML Classification, n (%)AML with Myelodysplasia Related ChangesAML, Not Otherwise SpecifiedAML with Recurrent Genetic AbnormalitiesTherapy Related Myeloid Neoplasm

20 (48.8)12 (29.3)7 (17.1)2 (4.9)

Number of prior AML regimen, n (%)a

123 >3

13 (31.7)12 (30.0)9 (22.5)6 (15.0)

Prior AML TherapyAnthracyline based therapyHypomethylating agent therapyPrior high dose cytarabine (≥1000 mg/m2)a, n (%)

20 (50.0)25 (62.5)13 (31.7)

Prior allogeneic transplant, n (%) 3 (7.3)MRC cytogenetic risk group, n (%)UnfavorableIntermediateFavorable

22 (53.7)17 (41.5)1 (2.4)

aN=40

AMV564-101 Treatment-Emergent Adverse Events (> 20% Patients) and Grade 3+ AEs

Adverse Event, n (%) Total Safety Evaluable, (N=41)TEAE > 20% Grade 3+

Pyrexia 20 (48.8) 1 (2.4)Nausea 19 (46.3)Oedema peripheral 18 (43.9) 1 (2.4)Cytokine release syndrome 16 (39.0)Headache 15 (36.6) 1 (2.4)Diarrhoea 14 (34.1) 3 (7.3)Cough 14 (34.1)Febrile neutropenia 13 (31.7) 11 (26.8)Fatigue 12 (29.3)Constipation 12 (29.3)Vomiting 12 (29.3)Hypokalaemia 10 (24.4) 2 (4.9)Hypotension 10 (24.4) 3 (7.3)Rash 9 (22.0)Hypomagnesaemia 9 (22.0)Insomnia 9 (22.0)

• No Dose-Limiting Toxicity through 450 mcg/day• Infusion related Adverse Events (n=2; Grade 2)• AEs leading to discontinuation (n=2): septic shock (n=1; 150 mcg/d) and myocarditis (n=1; 250 mcg/d)

AMV564-101: Cytokine Release Syndrome (CRS)• CRS events were Grade 1 and Grade 2 in severity• Pre-medication: antihistamine, antipyretic, H2-antagonist, and antiemetic• Management includes early recognition, supportive care, tocilizumab, and

corticosteroids as per investigator discretion

CRS (N)0.5 mcg –

30 mcgN=14

50 mcgN=4

100 mcgN=5

150 mcgN=5

200 mcgN=4

250 mcgN=4

300 mcgN=3

450 mcgN=2

TotalN=41

Grade 1 0 1 1 3 0 0 1 1 7

Grade 2 0 1 2 1 2 3 0 0 9

Grade 3+ 0 0 0 0 0 0 0 0 0

AMV564-101: Best Response in Bone Marrow

2 37 32 1 27 33 22 28 19 13 4 5 35 6 34 29 20 25 11 23 12 9 31 3 7 8 14 16 38 30 10 15 17 36 18 26 24 21

92%

67%60%

46% 43%36% 35%

7% 6%0% 0%

-7% -10% -13% -13%-17% -17%

-22% -23% -24%

-33%

-45% -46%-50%

-57% -59%-63%

-67%

-75%

-83% -84% -85% -88% -91% -92%-100%

-80%

-60%

-40%

-20%

0%

20%

40%

60%

80%

100%

2 37 32 1 27 33 22 28 19 13 4 5 6 35 34 29 20 25 11 23 12 9 31 3 7 8 14 16 38 30 10 15 17 36 18 26 24 21

CRi CRp PR CRPR

0.5 mcg

1.5 mcg

5 mcg

15 mcg

50 mcg

100 mcg150 mcg200 mcg250 mcg300 mcg450 mcg

Plot No.

FLT3-ITD

FLT3-TKD

TP53

IDH1

IDH2

DNMT 3A

ASX L1

KMT ZA

EZH

N-RAS

TET-2

32% (n=12)

AMV564-101: Summary of Responses

Patient Age (yrs)

AML Diagnosis (WHO Criteria)

AMV564 Dose Cycle and Response Prior therapy Cytogenetics

(Mutation)

18 71 AML with MRC 200 mcgCycle 1 Day 22: CRCycle 1 Day 29: CRCycle 2 Day 15: CR

Azacitidine --

30 70 AML with MRC 150 mcg Cycle 2 Day 16: CRpCycle 2 Day 29: CRiCycle 3 Day 29: CRp

Cladribine, High Dose Cytarabine

Mitoxantrone --

3 72

AML with Recurrent Genetic

Abnormalities

1.5 mcg Cycle 1 Day 29: CRiCycle 2 Day 29: PD

Cytarabine, Decitabine, Vosaroxin,

Fludarabine, Lirilumab, Azacitidine

KMT ZA

15 75AML with Minimal

Differentiation100 mcg Cycle 1 Day 29: PR

Cytarabine, Daunorubicin,

Decitabine, Ivosidenib--

10 84 AML with MRC 1.5 mcg Cycle 1 Day 15 (EOI): PRCycle 1 Day 29: PR Decitabine

FLT3-ITD, DNMT3A, ASX L1, N-RAS,

TET-2

MRC, Myelodysplastic Related Changes; Response criteria by European LeukemiaNet (ELN) (Dohner H et al. Diagnosis and management of AML in adults: 2017 ELN recommendations from an international expert panel. Blood. 2017;129(4):424-447)

AMV564-101: Duration of Treatment• Completed Cycles

− 95.1% (n = 39) of patients in the study completed Cycle 1

• Duration of Treatment− Median 19.5 days (range: 15 to 204 days)− Median number of cycles = 1

• 5 cycles: n=1 • 6 cycles: n=1

• Dose Adjustments: − No dose reduction or dose delays due to AEs at dose cohorts 0.5 mcg/d to 50 mcg/d

Dose Modification Category(N)

0.5 mcg –50 mcgN=18

100 mcgN=5

150 mcgN=5

200 mcgN=4

250 mcgN=4

300 mcgN=3

450 mcgN=2

Total Dose Escalation

Phase N=41

Dose Reduced

Due to AEs0 0 1 0 1 0 0 2

Dose Delayed Due to Aes 0 1 0 0 2 0 0 3

AMV564-101: Duration of Treatment

141515151515151515151515151516161718

2122

444445

49505051

535656575757

7092

196204

0 14 28 42 56 70 84 98 112 126 140 154 168 182 196 210

47

162

132327283319213212

5372238253631

124

31718

611

98

1015201435342630

CR: Complete RemissionCRi: CR with Incomplete Blood Count Recovery

CRp: CR with Incomplete Platelet RecoveryPR: Partial Remission

0.5 mcg1.5 mcg

5 mcg

15 mcg

50 mcg

100 mcg150 mcg200 mcg250 mcg300 mcg450 mcg

CRp CRi CRp

PR PRPR

CR CRCR CR

CRi

N=37 patients with complete data entered through end-of-treatment

Days

Patie

nt #

AMV564-101: Duration of Treatment: Responders (N=5)

45

50

56

57

204

0 14 28 42 56 70 84 98 112 126 140 154 168 182 196 210

No. 3

No. 18

No. 10

No. 15

No. 30

CR CRCR CR

CRi

CRp CRi CRp

PR PR

1.5 mcg

15 mcg

100 mcg150 mcg200 mcg

CR: Complete RemissionCRi: CR with Incomplete Blood Count Recovery

CRp: CR with Incomplete Platelet RecoveryPR: Partial Remission

PRPatient 15

Patient 10

Patient 18

Patient 3

Patient 30

Days

AMV564-101: Evidence of T Cell Activation

• Margination/redistribution of T cells from the periphery apparent in lead-in doses for most cycles

* Dose interruption# No sampling in cycle 4 dosing interval

0

10

20

30

40

50

Peripheral Blood T Cells

% o

f CD4

5+

CD3+CD4+CD8+

AMV564:

Day: 1 8 15 22 29 36 43 50 57 63 70 77 84 91

* #

0

10

20

30

Bone Marrow T Cells

% o

f CD4

5+

CD3+CD4+CD8+

AMV564:

Day: 1 8 15 22 29 36 43 50 57 63 70 77 84 91

* #

• Evidence of T cell increases in bone marrow in repeat-cycle patients

− No increase in Treg− Example shown: best response CRi

AMV564-101: Conclusions and Future Directions

• AMV564 administered as continuous IV infusion is safe and well-tolerated at doses up to 450 mcg/day in heavily pre-treated relapsed/refractory AML patients

• No Dose-Limiting Toxicities • No Grade 3+ CRS• Low incidence of discontinuation due adverse events• Early evidence of clinical activity• AMV564 activates T-cells and shows anti-leukemic blast activity• Subcutaneous and chronic dosing of AMV564 are being explored

in other clinical trials

Acknowledgments

• Patients and their families

• Investigators, study teams, and site personnel