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, PhD 1 , Jorge E. Cortes, MD 2 , Jessica K. Altman 3 , Meixiao Long, MD 4 , Vivian G. Oehler, MD 5,6 , Ivana Gojo, MD 7 , Jeanmarie Guenot, PhD 8 , Patrick Chun, MD 8 and Gail J. Roboz, MD 9 1 Division of Oncology, Washington University School of Medicine, Saint Louis, MO; 2 Georgia Cancer Center, Augusta University, Augusta, GA; 3 Northwestern University, Chicago, IL; 4 Division of Hematology, Department of Internal Medicine, Ohio State University Hospital, Columbus, OH; 5 Division of Hematology, Department of Medicine, University of Washington, Seattle, WA; 6 Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA; 7 Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, MD; 8 Amphivena Therapeutics, Inc, South San Francisco, CA; 9 Division of Hematology and Oncology, Weill Cornell Medical College of Cornell University, New York ASH 61 st Annual Meeting and Exposition December 7-10, 2019. Orlando, FL
AMV564: A Bivalent, Bispecific CD33/CD3 T-cell Engager AMV564: Binding Sites & Mechanism of Action AMV564: Selectivity AMV564 Selectivity for CD33- signaling/clustered 2 CD33 Binding Sites 2 CD3 Binding Sites • CD33 Expressed on AML blasts • EC 50 4 - 8 pM for target-dependent killing of AML cell lines Monovalent T-cells engagers cannot distinguish cell types 1 Amphivena Therapeutics, Inc. https://amphivena.com/amv564/ 2 Chen X, et al. Induction of myelodysplasia by myeloid-derived suppressor cells. J Clin Invest . 2013;123(11):4595-611.
AMV564-101 Phase 1 Clinical Study Design: Relapsed/Refractory AML 3+3 DESIGN (14 Days Continuous IV Infusion on a 28 Day cycle) 450 mcg Status at cutoff date of Key Eligibility Criteria 11/1/2019 • Age ≥ 18 years 300 mcg • 41 patients dosed • Relapsed or refractory disease 250 mcg • 11 dose cohorts • 1-3 prior induction/salvage explored to date 200 mcg regimens • Lead-in dosing for • Secondary AML 150 mcg 450mcg cohort: • ECOG 0-2 15 mcg 30 mcg 100 mcg 100 mcg • Normal renal/hepatic 150 mcg 300 mcg target function dose 0.5 – 50 mcg
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: Demographics Patient Demographics N=41 Median age, year (range), n (%) 71.3 (24.2 to 84.6) Age >65 28 (68.3) ECOG score, n (%) 0 7 (17.1) 1 29 (70.7) 2 5 (12.2) AML Classification, n (%) AML with Myelodysplasia Related Changes 20 (48.8) AML, Not Otherwise Specified 12 (29.3) AML with Recurrent Genetic Abnormalities 7 (17.1) Therapy Related Myeloid Neoplasm 2 (4.9) Number of prior AML regimen, n (%) a 1 13 (31.7) 2 12 (30.0) 3 9 (22.5) >3 6 (15.0) Prior AML Therapy Anthracyline based therapy 20 (50.0) Hypomethylating agent therapy 25 (62.5) Prior high dose cytarabine (≥1000 mg/m 2 ) a , n (%) 13 (31.7) Prior allogeneic transplant, n (%) 3 (7.3) MRC cytogenetic risk group, n (%) Unfavorable 22 (53.7) Intermediate 17 (41.5) Favorable 1 (2.4) a N=40
AMV564-101 Treatment-Emergent Adverse Events (> 20% Patients) and Grade 3+ AEs Total Safety Evaluable, (N=41) Adverse Event, n (%) 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 0.5 mcg – 50 mcg 100 mcg 150 mcg 200 mcg 250 mcg 300 mcg 450 mcg Total CRS (N) 30 mcg N=4 N=5 N=5 N=4 N=4 N=3 N=2 N=41 N=14 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 100% 92% 100 mcg 0.5 mcg 150 mcg 80% 1.5 mcg 67% 200 mcg 5 mcg 60% 250 mcg 60% 15 mcg 300 mcg 46% 43% 50 mcg 450 mcg 40% 36% 35% 32% (n=12) 20% 7% 6% PR CR 0% 0% CRi CRp PR 0% 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 -7% -10% -20% -13% -13% -17% -17% -22% -23% -24% -40% -33% -45% -46% -50% -60% -57% -59% -63% -67% -80% -75% -83% -84% -85% -88% -91% -92% -100% Plot No. 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 FLT3-ITD FLT3-TKD TP53 IDH1 IDH2 DNMT 3A ASX L1 KMT ZA EZH N-RAS TET-2
AMV564-101: Summary of Responses Age AML Diagnosis AMV564 Cytogenetics Patient Cycle and Response Prior therapy (yrs) (WHO Criteria) Dose (Mutation) Cycle 1 Day 22: CR 18 71 AML with MRC 200 mcg Cycle 1 Day 29: CR Azacitidine -- Cycle 2 Day 15: CR Cycle 2 Day 16: CRp Cladribine, High Dose 150 mcg 30 70 AML with MRC Cycle 2 Day 29: CRi Cytarabine -- Cycle 3 Day 29: CRp Mitoxantrone AML with Cytarabine, Recurrent 1.5 mcg Cycle 1 Day 29: CRi Decitabine, Vosaroxin, 3 72 KMT ZA Genetic Cycle 2 Day 29: PD Fludarabine, Abnormalities Lirilumab, Azacitidine AML with Cytarabine, 15 75 Minimal 100 mcg Cycle 1 Day 29: PR Daunorubicin, -- Differentiation Decitabine, Ivosidenib FLT3-ITD, DNMT3A, Cycle 1 Day 15 (EOI): PR 10 84 AML with MRC 1.5 mcg Decitabine ASX L1, N-RAS, Cycle 1 Day 29: PR 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 Total Dose 0.5 mcg – Modification 100 mcg 150 mcg 200 mcg 250 mcg 300 mcg 450 mcg Escalation 50 mcg Category N=5 N=5 N=4 N=4 N=3 N=2 Phase N=18 (N) N=41 Dose Reduced 0 0 1 0 1 0 0 2 Due to AEs Dose Delayed 0 1 0 0 2 0 0 3 Due to Aes
AMV564-101: Duration of Treatment N=37 patients with complete data entered through end-of-treatment 30 CRp CRi CRp 204 26 196 34 92 35 70 14 57 20 57 15 PR 57 10 PR PR 56 8 56 9 53 0.5 mcg 100 mcg 11 51 1.5 mcg 150 mcg 6 50 18 50 CR CR CR CR 200 mcg 5 mcg 17 49 250 mcg 15 mcg 3 CRi 45 Patient # 300 mcg 24 44 50 mcg 1 44 450 mcg 31 22 36 21 25 18 38 17 22 16 37 16 5 15 12 15 32 15 CR: Complete Remission 21 15 19 15 CRi: CR with Incomplete Blood Count Recovery 33 15 CRp: CR with Incomplete Platelet Recovery 28 15 PR: Partial Remission 27 15 23 15 13 15 2 15 16 15 7 15 4 14 0 14 28 42 56 70 84 98 112 126 140 154 168 182 196 210 Days
AMV564-101: Duration of Treatment: Responders (N=5) Patient 30 No. 30 CRp CRp CRi 204 1.5 mcg Patient 15 No. 15 PR 57 15 mcg 100 mcg 150 mcg Patient 10 No. 10 PR PR 56 200 mcg CR: Complete Remission Patient 18 No. 18 CRi: CR with Incomplete Blood Count Recovery CR CR CR CR 50 CRp: CR with Incomplete Platelet Recovery PR: Partial Remission Patient 3 No. 3 CRi 45 0 14 28 42 56 70 84 98 112 126 140 154 168 182 196 210 Days
AMV564-101: Evidence of T Cell Activation Peripheral Blood T Cells Bone Marrow T Cells AMV564: AMV564: # # * 50 30 * 40 % of CD45+ % of CD45+ 20 30 20 CD3+ CD3+ 10 10 CD4+ CD4+ CD8+ CD8+ 0 0 Day: 1 8 15 22 29 Day: 1 8 15 22 29 36 43 50 57 63 70 77 84 91 36 43 50 57 63 70 77 84 91 • Evidence of T cell increases in bone • Margination/redistribution of T cells marrow in repeat-cycle patients from the periphery apparent in lead- in doses for most cycles − No increase in Treg − Example shown: best response CRi * Dose interruption # No sampling in cycle 4 dosing interval
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