Syndax Pharmaceuticals, Inc. · NASDAQ:SNDX
Syndax Pharmaceuticals — AACR 2020
19 slides from Syndax Pharmaceuticals's conference presentation, May 2020
Slide 1: A first-in-class Menin-MLL1 antagonist for MLL-r and NPM1 mutant leukemias
A first-in-class Menin-MLL1 antagonist for the treatment of MLL-r and NPM1 mutant leukemias Jerry McGeehan PhD Syndax Pharmaceuticals 1
Slide 2: Disclosure
Disclosure I am an employee and shareholder of Syndax Pharmaceuticals, Inc. 2
Slide 3: Forward-looking statements disclosure
Forward-looking statements disclosure This presentation contains forward-looking statements within the meaning of the Private Securities Litigation Reform Act of 1995. Words such as "may," "will," "expect," "plan," "anticipate" and similar expressions (as well as other words or expressions referenci
Slide 4: Overview of MLL-r and NPM1c+ AML
Overview of Mixed Lineage Leukemia-rearranged (MLL-r) and Nucleophosmin Mutant AML (NPM1c+ AML) MLL-r is caused by translocations at the MLL1 locus that create oncogenic MLL-fusion proteins • MLL-r is an acute leukemia that presents as ALL or AML, commonly diagnosed at presentation (FISH) • MLL-rear
Slide 5: Menin-MLL binding inhibition leads to loss of the leukemic transcription program
Menin-MLL binding inhibition leads to loss of the leukemic transcription program in MLLr/NPM1c, causing terminal differentiation of cells SNDX-5613 occupies the MLL1 binding pocket SNDX-5613 inhibits Menin-MLLr interaction on Menin SNDX-5613 CDK9 DOT1L P-TEFb Fusion Menin CBX8 MLL1 Differentiation O
Slide 6: Menin inhibitors change the transcription program by evicting Menin from chromatin
Menin inhibitors cause significant changes in the transcription program by evicting Menin from chromatin Free protein ~ 1 mDa ~ 2 mDa Fraction# 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 MOLM13 (MLL-AF9) DMSO MEN Day 3 VTP MEN 0.3uM Me O S O HN N N O N O N F N SNDX-50469 6
Slide 7: Menin inhibitors have profound single-agent activity in MLL-r PDX models
Menin inhibitors have profound single-agent activity in MLL-r PDX models, producing deep and durable responses • Significant survival benefit in 7/8 PDXs after single 28d treatment with SNDX-469 PDX Dx MLL-fusion MLL-1 ALL t(1;11), MLL-EPS15 • Profound effects on PDX- MLL-2 ALL t(4;11), MLL-AFF1 MLL
Slide 8: Menin inhibitors have profound single-agent activity in NPM1c PDX models
Menin inhibitors also have profound single-agent activity in NPM1c PDX models, producing deep and durable responses % human CD45 engraftment % Survival Days post transplant Days elapsed i.v. Engraft 5-75% PB Leukemia % human CD45 engraftment % Survival ~90 Day Treatment SNDX-50469 formulated in Chow
Slide 9: SNDX-5613 pharmacologic profile shows high potency and specificity
SNDX-5613 pharmacologic profile shows high potency and specificity for Menin – MLL inhibition Et Parameter Summary of findings O S O Binding Ki 0.149 nM HN in vitro / Cell based IC50 10 – 20 nM in vivo profile in vivo (Plasma) IC50 (nM) 53 nM Specificity (>125 enzyme/receptor) No off-target binding
Slide 10: SNDX-5613 provides survival benefit in MOLM-13 disseminated xenografts
SNDX-5613 treatment provides significant survival benefit and leukemic control in aggressive MOLM-13 disseminated xenografts K-M Survival MOLM-13 %hCD45+ PB 100 100 hCD45+ (% live cells) 80 Percent survival 80 60 60 40 40 20 20 i.v. Engraft 5 days Treatment Period 0 0 0 10 20 30 40 50 60 0.025% 0.05
Slide 11: Steady-state plasma PK analysis for leukemic control in MOLM-13 xenografts
Steady-state plasma PK analysis clarifies the drug exposures required for leukemic control in MOLM-13 xenografts ss Plasma Levels MOLM-13 %hCD45+ PB 10000 100 Concentration, ng/mL hCD45+ (% live cells) 80 60 1000 IC95 40 IC90 20 i.v. Engraft 5 days 0 100 6pm 10pm 2am 6am 10am 2pm 0.025% 0.05% 0.1% 0
Slide 12: Projecting pre-clinical PK/PD to target clinical exposure
Projecting pre-clinical PK/PD to target clinical exposure Steady State Plasma Levels 10000 Target PK Profile Requirements Concentration, ng/mL Maintain steady state levels above IC95 1000 (~600 ng/mL) for most of dosing IC95 interval IC90 AND 100 Maintain Cmin level above 6pm 10pm 2am 6am 10am 2pm T
Slide 13: AUGMENT-101: Phase 1/2 trial of SNDX-5613 in acute leukemia
AUGMENT-101: Phase 1/2 trial of SNDX-5613, in patients with acute leukemia Phase 1: Phase 2: Dose escalation Expansion Enrolling R/R acute leukemias* Accel. titration into 3+3 design Adult MLL-r ALL 28-day cycle Starting dose = 113 mg PO BID Adult MLL-r AML Adult NPM1 mut AML Endpoints: Safety, PK,
Slide 14: Patient #1 characteristics and PK
Patient #1: 113 mg PO q12h Day 8 Cmin = 251 ng/mL Patient Characteristics Day 8 est. AUC0-24 = 12,200 ng*h/ml Gender, Age Male, 60 yr old 10000 Concentration of SNDX-5613 3000 Diagnosis Refractory AML 1000 in Plasma (ng/mL) Mutational No MLLr or NPM1 IC95 status mutation IC90 300 Prior lines of 3 (A
Slide 15: Patient #2 characteristics and PK
Patient #2: 226 mg PO q12h Day 8 Cmin = 3030 ng/mL Day 8 est. AUC0-24 = 93,900 ng*h/ml Patient Characteristics 10000 Gender, Age Female, 69 yr old Concentration of SNDX-5613 3000 Diagnosis Refractory MPAL 1000 in Plasma (ng/mL) Mutational status MLL-TET1 fusion IC95 FLT3 ITD 300 IC90 Prior lines of
Slide 16: Response summary to date – Patients not on CYP3A4 Inhibitor
Response summary to date – Patients not on CYP3A4 Inhibitor Pt # Prior Mutational Meets target # Age Tx status Dose PK profile^ DLT period Response Assessment Progressive Disease/ 1 60 3 None* 113 q12 No No DLTs off study MLL-r 3 32 8 226 q12 No No DLTs No Response/ on study t(5;11) 5 pediatric pati
Slide 17: Response summary to date – Patients on Strong CYP3A4 Inhibitor
Response summary to date – Patients on Strong CYP3A4 Inhibitor Pt # Prior Mutational Meets target # Age Tx status Dose PK profile^ DLT period Response Assessment No DLTs MLL-r Day 28 CRi - improved to CR 226 q12 Grade 2 QTc, 2 69 2 t(10;11) Yes FISH neg, Flow neg, 113 q12 resolved with dose FLT3 I
Slide 18: Menin-MLL interaction inhibitors represent a novel, targeted therapy
Menin-MLL interaction inhibitors represent a novel, targeted therapy for Mixed Lineage Leukemia-rearranged (MLL-r) and NPM1 mutant AML SNDX-5613 is a potent, selective, orally available inhibitor of menin-MLL1 • Attractive biopharmaceutical properties • Monotherapy activity in multiple preclinical x
Slide 19: Acknowledgements
Acknowledgements Dana Farber Cancer Institute Vitae Pharmaceuticals Syndax Pharmaceuticals Scott A. Armstrong Deepak Lala Galit Rosen Andrei V. Krivtsov Yi Zhao Susan Brower Yuri Bukhtiyarov Sue Fischer Hannah Uckelmann David Claremon Suniket Fulzele Shankar Venkatraman Shaliny Kushwaha Children’s C