Creating Highly Efficacious ADCs for Low-Expression Targets While Improving Therapeutic Index TIM LOWINGER, PHD

Transcription

1 Creating Highly Efficacious ADCs for Low-Expression Targets While Improving Therapeutic Index TIM LOWINGER, PHD CSO

2 Mersana Therapeutics VC-backed Biotech in Cambridge, MA Investors: NEA, Pfizer, Fidelity, Proquest, Rho Proprietary Fleximer Biodegradable Polymer Conjugation Platform for use in creating Antibody Drug Conjugates Strategic collaborations with select partners Independent, wholly owned pipeline programs 2

3 Creating Effective ADCs is Not Trivial Common Obstacles: Payload hydrophobicity Aggregation Limited capacity (3-4) requires very high potency Detrimental effects on PK with higher loading Limited number of payload classes Microenvironmental influences on stability/release Low antigen expression Safety / tolerability 3

4 Fleximer - Tested, Superior Platform New Composition IP Nonimmunogenic Fully Biodegradable Very Safe (~200 Patients) Multiple Conjugation Sites Highly Soluble, Stable 4

5 Facile CMC and Bioconjugation Fleximer polymer Fleximer-drug conjugate payload drug ORGANIC SOLVENT Very High Aqueous Solubility Isolated, characterized and stored long-term Fleximer Antibody-Drug Conjugate WATER Multiple standard and site-specific bioconjugation chemistries available lysine, cysteine, or site-specific / engineered 5

6 Showcasing the Dolaflexin TM ADC Platform Trastuzumab as representative antibody Proprietary Auristatin-derived payload Conjugation via hinge-region cysteines Drug-Antibody ratio of

7 Dolaflexin ADC Structure CYSTEINE-BASED FLEXIMER-DRUG ANTIBODY CONJUGATION PARTIALLY REDUCED ANTIBODY DOLAFLEXIN ADC mab-cys 7

8 Trastuzumab-Dolaflexin ADC Characteristics PARAMETER ANALYSIS ADC size kda ADC Polydispersity PDI < 1.2 Drug/mAb ratio, (DAR) Fleximer/mAb ratio 3-4 Free drug content, % total <0.5% Free mab content, % total <0.5% Free Dolaflexin, % total drug <1% Aggregation, % <2% Free thiol groups Not detected 8

9 Dolaflexin ADC Uniform, No Aggregation DOLAFLEXIN SIZE AND POLYDISPERSITY ANALYSIS: Peak MW ~200 kda PDI ~1.15 ADC SEC, UV 280 nm mau ADC mab Minutes MINUTES 9

10 Dolaflexin ADCs Maintain Target Affinity Trastuzumab-Dolaflexin Affinity Similar to Trastuzumab and T-DM1 by SPR Sample ADC Type DAR k a (M -1 s -1 ) k d (s -1 ) K D (pm) Trastuzumab n/a n/a 9.90(1)e5 2.60(1)e (1) Kadcyla Lys/DM (2)e5 3.17(9)e (3) ADC1 Cys/Dolaflexin TM (2)e5 2.32(2)e (1) ADC2 Cys/Dolaflexin TM (3)e5 2.60(9)e (3) ADC3 Cys/Dolaflexin TM (3)e5 2.43(1)e (3) ADC4 Cys/Dolaflexin TM (5)e5 2.03(1)e (5) Notes: The number in parentheses represents the error in the last digit. For example, 9.9(1)e5 equals (9.9 ± 0.1) x

11 High DAR Fleximer ADCs Retain Excellent PK Half-life of Conjugated Drug in Mice > 5 Days Trastuzumab-Dolaflexin (DAR20) Mouse PK COMPOUND PLASMA CONCENTRATION, ng/ml Free drug 10,000x lower than conjugated drug Total mab (ELISA) Conjugated Drug Free Drug Time, hours 11

12 Excellent PK Across a Range of High DARs Pharmacokinetics Independent of DAR Conjugated Drug Plasma PK 10, CONC. (ng/ml) 1, TIME (HRS) ADC ID ADC1 ADC2 ADC3 DAR Conjugated Drug T 1/2 (hr) AUC (ug*hr/ml)

13 Trastuzumab-Dolaflexin Highly Active in HER2 (3+) Breast Cancer Model 100% Tumor Free Survivors After Single 5 mg/kg Dose 1200 BT-474 HER2 (3+) Breast Cancer Xenograft 500,000 copies of HER2 / cell TUMOR VOLUME (MM 3 ) Single i.v. Injection Day 1 DAYS Vehicle Trastuzumab Dolaflexin 5 mg/kg 10/10 Tumor Free Survivors 13

14 Trastuzumab-Dolaflexin Highly Active in HER2 (3+) Gastric Cancer Model 100% Tumor Free Survivors After Single 3 mg/kg Dose 800 N87 HER2 (3+) Gastric Cancer Xenograft > 500,000 copies of HER2 / cell Vehicle MEAN TUMOR VOLUME (MM 3 ) DAY (DOSING ON DAY 1) Trastuzumab- Dolaflexin 0.67 mg/kg Trastuzumab Dolaflexin 3 mg/kg 10/10 Tumor Free Survivors Single i.v. Injection Day 1 14

15 Fleximer ADCs Increase Delivery Efficiency and Cell Kill for Low Antigen Expression Cells High DAR Fleximer ADCs More Readily Achieve Threshold Concentration HIGH EXPRESSION LOW EXPRESSION 15

16 High DAR Significantly More Active in Low Target Expressing Cells 100-Fold Potency Advantage In Vitro JIMT-1 Cells 79,000 copies of HER2 / cell % VIABILITY Trastuzumab-Dolaflexin IC 50 =0.14nM T-DM1 IC 50 = 18 nm LOG Cpd (nm) 16

17 Trastuzumab-Dolaflexin Shows Dramatic Activity in T-DM1 Resistant Low HER2 Model 100% Tumor Free Survivors After Single 2 mg/kg Dose; T-DM1 inactive at 10x Dose JIMT-1 Breast Cancer Xenograft 79,000 copies of HER2 / cell MEAN TUMOR VOLUME (MM 3 ) Rituximab-Dolaflexin 2 mg/kg Vehicle Single i.v. Injection Day 1 DAY (DOSING ON DAY 1) T-DM1 20 mg/kg 0.67 mg/kg Trastuzumab-Dolaflexin 2 mg/kg 10/10 Tumor Free Survivors 17

18 18 Trastuzumab-Dolaflexin Is Well Tolerated in Mice Therapeutic Index of > 15 vs. Single Dose Leading to 100% Tumor Free Survival Trastuzumab-Dolaflexin Mouse Tolerability 20 mg/kg 30 mg/kg 40 mg/kg 0.67 mg/kg TI > 40 2 mg/kg* 3 mg/kg* Trastuzumab-Dolaflexin mouse efficacy* * Sustained regressions in HER2-high and HER2-low models Non-severely toxic dose Severely toxic dose 20 mg/kg 30 mg/kg 40 mg/kg

19 Single Dose Trastuzumab-Dolaflexin NHP Study 0.67 mg/kg 600 μg/m mg/kg 2.68 mg/kg 1200 μg/m μg/m 2 TRASTUZUMAB- DOLAFLEXIN NHP TOX 3 mg/kg 612 μg/m 2 10 mg/kg 30 mg/kg 2040 μg/m μg/m 2 KADCYLA NHP TOX (POON 2013) 1 mg/kg 232 μg/m 2 3 mg/kg 696 μg/m 2 6 mg/kg 1392 μg/m 2 ADCETRIS NHP TOX (BLA REVIEW) Dose of ADC (mg/kg) Dose of payload (μg/m2) Severely toxic dose 19

20 Summary of Findings in Exploratory Toxicology Trastuzumab-Dolaflexin was well-tolerated at all doses tested All animals survived until scheduled necropsy No test article-related changes on gross pathology Adverse findings on clinical pathology were generally consistent with published observations for Kadcyla Greater AST increases than described for Kadcyla, lesser ALT increases No evidence of myelosuppression Microscopic pathology changes were minimal to mild No microscopic pathology changes in HER2-expressing tissues (heart, lungs, gut) Highest non-severely toxic dose of trastuzumab-dolaflexin exceeds 2.68 mg/kg (2400 μg/m 2 toxin dose)

21 21 Trastuzumab-Dolaflexin NHP Plasma PK Very high stability in NHPs Half life for ADC of ca. 5 Days CYNOMOLGUS MONKEY 2.68 MG/KG SINGLE DOSE Total mab (ELISA) ADC Conjugated Drug Free drug

22 AUC of Highest, Well-Tolerated Dose in Cynos Similar to AUC for 100% Tumor Free Survivors in Mice TRASTUZUMAB-DOLAFLEXIN CONJUGATED DRUG EXPOSURE (MOUSE VS. CYNO MONKEY) Conjugated Drug Plasma Concentration, ng/ml MED in mice (0.67 mg/kg) Single Dose for 100% Tumor Free Survivors In Mice 3 mg/kg 2 mg/kg Highest Tested Dose in Cyno 2.68 mg/kg Time, hrs

23 Favorable Therapeutic Index in NHP 0.67 mg/kg 1.34 mg/kg 2.68 mg/kg 600 μg/m μg/m μg/m 2 Trastuzumab- Dolaflexin NHP tox 0.67 mg/kg 2 mg/kg 3 mg/kg TI > μg/m μg/m μg/m 2 Trastuzumab- Dolaflexin efficacy Trastuzumab-dolaflexin has a favorable therapeutic index in HER2-amplified and HER2-low models TI > 16 by allometrically scaled payload dose TI > 3 by exposure 23

24 Asana 5T4-Targeted Dolaflexin Program

25 Superior Efficacy in Head-to-Head Study Efficacy Comparable to A1mcMMAF at 1/10 th the Dose ASN004 1 mg/kg A1mcMMAF 10 mg/kg

26 Mersana s First ADC Product Highly Active in Multiple Cancer Models Single doses also highly active in other tumor models including NSCLC, breast and ovarian MEAN TUMOR VOLUME (mm3) Western-derived Gastric Cancer High Target Expression 0 Mersana product 1 mg/kg 4 PR / 6 CR / 6 TFS Single i.v. Injection Day 1 Vehicle DAY (DOSING ON DAY 1) MEAN TUMOR VOLUME (mm3) Asian-derived Gastric Cancer Low Target Expression (<25,000 receptors per cell) Vehicle Mersana product 0.67 mg/kg 10 CR / 9 TFS DAY (DOSING ON DAY 1) Single i.v. Injection Day 1 IND Planned for

27 27 Fleximer ADC Platform Enables high drug loading without sacrificing PK Provides excellent physicochemical properties Achieves high efficacy against low expression targets Foundation for Mersana s ADC product portfolio Adds significant value to partners ADC pipelines

28 The Mersana Research Team Pictured from Left to Right: Pat, Alex, Mao, Dmitry, Venu, Xianhua, Alex, Radha, Cheri, Natasha, Laura, Peter, Elena, Roberta, Liu, Dennis, Josh, Mike 28

29 Thank you for your attention!