Development and Manufacture of a Novel Drug- Linker: Enabling High DAR ADCs. Michael J Kaufman, Ph.D. Senior Vice President, CMC

Transcription

1 Development and Manufacture of a Novel Drug- Linker: Enabling High DAR ADCs Michael J Kaufman, Ph.D. Senior Vice President, CMC

2 Legal Disclaimer This presentation contains forward-looking statements that are within the meaning of federal securities laws and are based on our management s beliefs and assumptions and on information currently available to management. Forward-looking statements include information concerning our possible or assumed future results of operations, business strategies, financing plans, competitive position, industry environment, potential growth opportunities, potential market opportunities and the effects of competition. Forward-looking statements include all statements that are not historical facts and can be identified by terms such as anticipates, believes, could, seeks, estimates, intends, may, plans, potential, predicts, projects, should, will, would or similar expressions and the negatives of those terms. Forward-looking statements represent our management s beliefs and assumptions only as of the date of this presentation. Our operations involve risks and uncertainties, many of which are outside our control, and any one of which, or combination of which, could materially affect our results of operations and whether the forward-looking statements ultimately prove to be correct. Factors that may materially affect our results of operations include, among other things preclinical testing may not be predictive of the results or success of ongoing or later preclinical and clinical trials and that the development of our product candidates will take longer and/or cost more than planned, as well as, those listed in our Quarterly Report on Form 10-Q filed on August 11, 2017 with the Securities and Exchange Commission ( SEC ). Except as required by law, we assume no obligation to update these forward-looking statements publicly, or to update the reasons actual results could differ materially from those anticipated in the forward-looking statements, even if new information becomes available in the future. You may get copies of our Quarterly Report on Form 10-Q and our other SEC filings for free by visiting EDGAR on the SEC website at

3 Therapeutic Index of a Conventional ADC is a Compromise of Multiple Design Parameters Component Option Efficacy Tolerability Direct conjugation approach Drug Drug-Antibody Ratio (DAR) Linker Cell Permeability Target Expression Level in tumor Anti-tubulin (eg. MMAE) DNA Damaging (e.g. PBD) < 4 > 4 cleavable non-cleavable permeable (bystander) non-permeable (no bystander) high - low - Challenge: Optimizing ADC parameters for efficacy and tolerability at the same time

4 Established and Emerging ADC Platforms Linker Payload Mechanism Payload Permeability DAR SGEN vcmmae Cleavable Anti-tubulin Bystander ~3.5 SGEN mcmmaf Non-cleavable Anti-tubulin No bystander ~3.5 IMGN SMCC-DM1 IMGN SPDB-DM4 Synthon vc-duocarmycin Non-cleavable Anti-tubulin No bystander ~3.4 Cleavable Anti-tubulin Bystander ~3.4 Cleavable DNA damaging Bystander ~2.8 Daiichi Sankyo Exatecan Cleavable Topoisomerase Bystander ~8 Mersana Dolaflexin Cleavable Anti-tubulin Dual; timedependent ~12-15 Reference: de Goeij and Lambert, Curr. Op. Immunol. 2016, 40:

5 The Dolaflexin ADC Platform Designed to Improve Efficacy and Tolerability Stable polymer-antibody linker Non-cleavable Facile bioconjugation to hinge region cysteines DolaLock Payload with controlled bystander effect proprietary auristatin with unique pharmacology anti-tubulin; selectively toxic to dividing cells drugs per antibody Fleximer polymer extremely water soluble biocompatible and biodegradable homogeneous environment which protects payload molecules in circulation provides optimal PK and drug-like properties Proprietary polymer-drug linker Highly stable in circulation; < 0.05% of drug released in plasma Readily and efficiently cleaved inside tumor cell 5

6 XMT-1522 Features Proprietary Auristatin Payload with Unique Pharmacology Metabolic Conversion in Tumor Auristatin F-HPA (AF-HPA) Bystander Killing Auristatin F (AF) No Bystander Killing Yes Crosses Cell Membrane No ++++ Cell Killing Potency If Released Outside Cell Cell Killing Potency if Released Inside Cell ++++ MTD Effect in Rats at 0.1 mg/kg Dose NOEL

7 XMT-1522 Dolaflexin-based anti-her2 ADC potent in low HER2-expressing tumors Novel anti-her2 Antibody (XMT-1519) Antibody Mersana proprietary Fully human Result of screening for optimal antibody for ADC development Binds to distinct epitope from trastuzumab or pertuzumab DAR Being evaluated in Phase I dose escalation study TM TM Proprietary Auristatin Payload (DolaLock) Fleximer

8 Tumor Volume (mm 3 ) Tumor Volume (mm 3 ) Tumor Volume (mm 3 ) XMT-1522 Achieves Durable Complete Regressions Across Models with Range of HER2 Expression Levels HIGH N87 Gastric Cancer 800,000 HER2/cell HER2 3+ MEDIUM JIMT-1 Breast Cancer 80,000 HER2/cell HER2 2+ LOW SNU5 Gastric Cancer 22,000 HER2/cell HER2 0/ Vehicle Day (Dosing on Day 1) Vehicle IgG1-dolaflexin (3 mg/kg) T-DM1 (10 mg/kg) XMT-1522 (1 mg/kg) Day (Dosing on Day 1) IgG1-dolaflexin (2 mg/kg) T-DM1 (20 mg/kg) XMT-1522 (2 mg/kg) 800 Vehicle 400 IgG1-dolaflexin (5 mg/kg) T-DM1 (10 mg/kg) XMT-1522 (0.67 mg/kg) Day (Dosing on Day 1)

9 Dolaflexin Process Development Controlling Dolaflexin Heterogeneity 9

10 Dolaflexin Structure 10

11 Sources of Heterogeneity in Dolaflexin ADCs Heterogeneity arising from the polymer Molecular weight Polydispersity β-alanine Regiochemistry 11

12 Sources of Heterogeneity in Dolaflexin ADCs Heterogeneity due to regiochemistry and loading factors: Unit 1: 2 4 mole% (~ 2 units/polymer) Unit 4: 8 9 mole% (3 4 warheads/polymer) Unit 3: 20 mole% (10 12 units/polymer) Unit 2: 70 mole% (~ units/polymer) 12

13 Heterogeneity in Practice: SEC Analysis 13

14 Dolaflexin GMP Manufacturing Process -Over view 14

15 Step 1: Creating the Linear Polymer Control of Polymer MW and Polydispersity XMT-1501 Batch # Dextran Input kg Output Kg Yield % Mw by SEC kda N/A PDI KF %

16 Step 2: Introduce the β-alanine Handle Control β-alanine Loading XMT-1502 Batch # XMT-1501 Input -kg XMT-1502 Output -kg Yield* % Mw by SEC kda PDI Loading %

17 β-alanine Loading is Controlled by Preparative WAX 17

18 β-alanine Loading is Determined by 1 H-NMR 18

19 MW Determined by SEC January 17 19

20 Fractions Carefully Selected for Further Processing Fraction BA Loading (%) MW (Dalton) Acceptance criteria for both BA Loading and MW are applied 20

21 Crude Dolaflexin is Prepared in a 1-Pot Reaction 21

22 Purified Dolaflexin Obtained via Prep HPLC 22

23 Selected Batch Data Batch # Attribute MW PDI Drug Load % Free Drug % Linker Load % Hydrolyzed Linker % nd 35 nd Endotoxin EU/mg nd nd

24 Controlling Dolaflexin Heterogeneity Conclusions Heterogeneity in Dolaflexin can be minimized and controlled by: Control of raw material properties (e.g. Dextran MW) Precise control and monitoring of reaction conditions Chromatographic fractionations with established pooling criteria Dolaflexin Critical Quality Attributes have shown good batchto-batch reproducibility 24

25 ADC Purification Controlling ADC Heterogeneity 25

26 Bioconjugation Process Overview Buffer Exchange of Antibody Reduction of Antibody Conjugation and Quench Formulation and Bottling Buffer Exchange of ADC Purification by Chromatography 26

27 Cation Exchange Chromatography is Useful as Both a Preparative and Analytical Method 27

28 Development of a SCX Purification Method A1-A7 B1-B5 C1-C4 Pool A1-A5 Pool A1-A7 Pool B1-B2 Pool B1-B3 Pool B4-B5 Pool C1-C2 28

29 Chromatographic Fractionation Determines DAR 29

30 Development of a SCX Purification Method 30

31 Comparison of Crude and Purified ADC Unconjugated XMT-1519 mab 31

32 icief for Monitoring Charge Variants in Dola ADCs WCX of ADC icief of ADC WCX is featureless, makes comparability and quantitation of charge variants challenging icief elctropherogram is fingerprint-like, facilitating comparability and enabling quantitation 32

33 Comparability of ADC Batches 33

34 Final Process Provides Excellent Batch-to-Batch Consistency Tox Batch GMP #1 GMP #2 DAR Drug:Polymer Polymer:mAb Main Fraction (WCX) Free Payload % 0.01 nd nd Free mab % HER2 Binding (Elisa) Cell-Based Potency

35 Conclusions A clinical-scale manufacturing process for Dolaflexin and Dolaflexin-containing ADCs has been developed Heterogeneity inherent in the Dolaflexin platform is measurable and controllable The manufacturing process has produced Dolaflexin and ADCs with excellent batch-to-batch consistency The clinical profile of Mersana s first Dolaflexin ADC XMT-1522 is being explored in ongoing Phase 1 trials 35

36 Acknowledgements Venu Reddy Reddy Bollu Jacques LeBlanc Tom Wagler Dave Lee Dmitry Gumerov Susan Clardy Mark Nazzaro Alex Johnson Yuanyuan Li Mao Yin Lei Zhu Dorin Toader Tim Lowinger Corporate Partners: Takeda Merck KGA CDMO Partners MilliporeSigma Johnson Matthey 36