Fleximer ADCs:

Advancing to the Clinic

Timothy Lowinger, PhD - CSO

WORLD ADC SUMMIT, SAN DIEGO

21 OCTOBER 2015

A Differentiated Approach to ADCs

Parameter Direct Conjugation Mersana - Fleximer Advantage

Maximum Drug Capacity

per mAb ≤ 4 20+ Greater efficacy

Target Antigen

Expression

Requirements

High

(e.g. Her-2:

500,000+)

Low

(e.g. Her-2: 20,000) Expanded Target Space

Drug Payload

Requirements IC50 < 1 nM IC50 < 20 nM

Overcome intrinsic and

acquired resistance

Targeting Agent

Requirements Full IgG antibody

Highly flexible – fragments

to full size

Greater solid tumor

penetration

ADCs: Expanding the Therapeutic Index

Maximum Tolerated Dose

Abs, linker stability, payload metabolism

Minimally Efficacious Dose DAR, payload potency, bystander effect

Therapeutic Index

Dolaflexin Intracellular Processing

AF-HPA

Primary release product

sub-nanomolar potency; freely cell permeable

Metabolism Bystander Killing

AF

IC50 > 20 nM

Non cell-permeable

No Bystander Killing

4

Free Drug Tissue Accumulation BT474 Xenograft Bearing SCID Mice, ADC Dose 5 mg/kg, 48 Hrs, N=4

Biodistribution Consistent with

Efficacy & Tolerability

0

10

20

30

40

50

60

70

80

90

100

Tumor Liver Spleen Kidney Muscle Plasma

Co

nc

en

tra

tio

n, n

g/m

L

AF-HPA (bystander killing)

AF (non-cell permeable)

Tissues isolated from non-perfused animals

0 2 4 6 8 10 12

Mersana Product #1 (XMT-1522)

Mersana Product #2(XMT-1535-dolaflexin)

Adcetris(Seattle Genetics)

NaPi2b-vc-MMAE(Genentech)

CD22-vc-MMAE(Genentech)

AGS-5-vc-MMAE(Agensys)

Therapeutic Index*

Therapeutic Index of Dolaflexin ADCs Compare

Favorably to Other Cleavable Auristatin ADCs

* TI = Lowest dose inducing regressions in mouse xenograft (mg/m2)

Highest non-severely toxic dose in NHP (mg/m2)

Source for vc-MMAE data: company presentations; peer reviewed publications; publicly-released FDA documents

Safe, Biodegradable Fleximer Scaffold

Spontaneous

Hydrolysis at

Endosomal / lysosomal pH

glycerol glycolate

Current Product Pipeline

Discovery Preclinical Development Phase 1

XMT-1522

PROGRAM 2

PROGRAM 3

PROGRAM 4

XMT-1522:

A Differentiated Approach to

HER2-Targeted Therapy

Majority of Breast Cancer Patients Express HER2

but are Classified “HER2-negative”

Breast Cancer

0+

HER2-positive

20%

1+ 2+

“HER2-negative” = HER2-Low

55%

3+

Amp

10

XMT-1522: A Custom-designed Her-2 ADC

HT-19 Antibody

Novel human anti-HER2 mAb

Specifically chosen for ADC

properties

Not trastuzumab-based; binds to

unique epitope

Can be combined with

trastuzumab and pertuzumab

Dolaflexin

Mersana Fleximer polymer allows much

higher drug loading: ~ 15 per antibody

Proprietary auristatin payload with

unique pharmacology to enhance

therapeutic index

~ 15 drugs per

antibody

Her-2 Binding

Cell Binding affinity and epitopes

Internalization rate

HER2 signaling, cell proliferation inhibition by mAb

In vitro cytotoxicity of ADC

In vivo efficacy of ADCs head to head

Antibody Selection Process

HT19

> 1500 mAbs

Target-dependent sub-nM cell killing in vitro as low as 25,000 HER2 receptors/cell

ADC Sensitivity (IC50 < 10nM) vs HER2 Expression Level

0.001

0.01

0.1

1

10

100

1,000 10,000 100,000 1,000,000

AD

C P

ote

nc

y (

IC5

0 n

M)

HER2 Receptors/cell

XMT-1522

T-DM1

0.001

0.01

0.1

1

10

100

1,000 10,000 100,000 1,000,000

AD

C P

ote

nc

y (

IC5

0 n

M)

HER2 Receptors/cell

XMT-1522

T-DM1 0.001

0.01

0.1

1

10

100

1,000 10,000 100,000 1,000,000

AD

C P

ote

nc

y (

IC5

0 n

M)

HER2 Receptors/cell

XMT-1522

T-DM1

10 nM

0%

10%

20%

30%

40%

50%

60%

70%

80%

90%

100%

135k-660k (HER2+) 10k-135k 0-10k

Fra

ction

of C

ell

Lin

es S

en

sitiv

e

HER2 Receptor Number/Cell

XMT-1522 Kadcyla13

XMT-1522 is Highly Potent Across Cell Lines

XMT-1522 Highly Active in Her2 3+ Gastric Model

N87 HER2 3+ gastric cancer model; > 500,000 HER2 / cell

XMT-1522: 10/10 animals

tumor free at Day 70

0

200

400

600

800

0 10 20 30 40 50 60

Mean

Tu

mo

r V

olu

me (

mm

3)

Day (Dosing on Day 1)

Vehicle XMT-1522 3 mg/kg Rituximab-dolaflexin 3 mg/kg Kadcyla 10 mg/kg

0

200

400

600

800

1000

1200

1 8 15 22 29 36 43 50 57 64

Tu

mo

r V

olu

me

(m

m3)

Day (Dosing Day 1)

Vehicle Trastuzumab (20 mg/kg)

Kadcyla (20 mg/kg) Rituximab-dolaflexin (2 mg/kg)

XMT-1522 (2 mg/kg)

XMT-1522 Achieves Complete Regressions in a

Trastuzumab and Kadcyla Resistant Model

JIMT-1 HER2 2+ breast cancer model; 79,000 HER2/cell

XMT-1522: 10/10 animals

tumor free at Day 70

0

200

400

600

800

1000

1200

1400

1600

1800

1 8 15 22 29 36 43 50 57 64

Tu

mo

r V

olu

me (m

m3)

Day (Dosing Day 1)

Vehicle Rituxumab-dolaflexin 5 mg/kg

Kadcyla 10 mg/kg XMT-1522 0.67 mg/kg

XMT-1522 Achieves Complete Regressions in a

HER2-Low Gastric Cancer Model

SNU5 HER2 1+ gastric cancer model; 22,000 HER2/cell

XMT-1522: 9/10 animals

tumor free at Day 60

XMT-1522 Shows Synergistic Activity with a

Trastuzumab/Pertuzumab Doublet

XMT-1522 Triplet achieves significantly longer survival and higher tumor regression rate

XMT-1522 0.67 mg/kg on Day 1

Trastuzumab (15 mg/kg) and Pertuzumab (15 mg/kg) dosed weekly x3

0

100

200

300

400

500

600

700

800

900

1000

1 8 15 22 29 36 43 50 57 64 71 78 85 92 99 106 113 120

Tum

or

Volu

me (

mm

3)

Day

Vehicle

XMT-1522 0.67 mg/kg

Trastuzumab + Pertuzumab

XMT-1522 Triplet

XMT-1522 Shows Synergistic Activity with a

Trastuzumab/Pertuzumab Doublet

-100%

-90%

-80%

-70%

-60%

-50%

-40%

-30%

-20%

-10%

0%

trastuzumab +

pertuzumab

15 mg/kg

qwk x 3

XMT-1522

0.67 mg/kg

qd x 1

combined

regimens

(triplet)

1 / 10 PR 2 / 10 PR 10 / 10 PR

XMT-1522 Triplet achieves higher tumor regression responses

0

200

400

600

800

1000

1200

1400

1600

1800

2000

0 10 20 30 40 50 60 70 80 90

Me

an

Tu

mo

r V

olu

me

(m

m3)

Day (Dosing on Day 1)

Vehicle XMT-1522 1 mg/kg Rituximab-dolaflexin 3 mg/kg Kadcyla 10 mg/kg

XMT-1522 Achieves Complete Regressions in a

HER2+ Breast Cancer PDX Resistant to Kadcyla

MAXF-1162 HER2 3+ gene-amplified patient-derived breast cancer model

XMT-1522: 8/9 animals

tumor free at Day 83

XMT-1522 is Highly Active in Kadcyla

Acquired Resistance Model

• Parental model: Kadcyla-sensitive, HER2-amplified N87 gastric model

• Model generated through serial passage in increasing doses of Kadcyla in vitro

• Resistant model >500X less sensitive to Kadcyla, retains HER2 expression

0

200

400

600

800

1000

0 20 40 60 80 100 120

Mean

Tu

mo

r V

olu

me (

mm

3)

Day (Dosing on Day 1)

Vehicle Kadcyla 10 mg/kg XMT-1522 3 mg/kg

Single Dose of XMT-1522 Shrinks Re-growing

Tumors After Treatment with Kadcyla

0

100

200

300

400

500

600

700

800

900

115 125 135 145 155 165 175

Tu

mo

r V

olu

me

(m

m^

3)

Day

Day 119 XMT-1522 3 mg/kg

Mean tumor size 320 mm3

Range: 75-847 mm3

Day 176 Mean tumor size 15 mm3

Range: 4-40 mm3

Confidential

0.1

1

10

100

1000

10000

100000

0 100 200 300 400 500

Co

nce

ntr

ati

on

(n

g/m

L)

Time (h)

Antibody Conjugated AF-HPA Free AF-HPA

XMT-1522 is Very Stable in Plasma Non Human Primate Exploratory Tox Study

>99.98% of drug payload remains antibody conjugated

Lower limit of detection

Summary of Findings in Exploratory Toxicology

Well-tolerated at 2.5 mg/kg in Non-Human Primates

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)

• No signs of eye-related toxicities

0 2 4 6 8 10 12 14 16

N87HER2 3+ Gastric

BT-474HER2 3+ Breast

MAXF-1162HER2 3+ Breast PDX

JIMT-1HER2 2+ Breast

SNU5HER2 1+ Gastric

Therapeutic Index

XMT-1522 Kadcyla

XMT-1522 Has a Favorable Therapeutic Index in

HER2-Positive and HER2-Low models

Kadcyla inactive at a 10 mg/kg dose

Kadcyla inactive at a 20 mg/kg dose

Kadcyla inactive at a 10 mg/kg dose

* TI = Lowest dose inducing regressions in mouse xenograft (mg/m2)

Highest non-severely toxic dose in NHP (mg/m2)

T-DM1 HNSTD = 30 mg/kg; T-DM1 activity based on Mersana data or peer-reviewed literature (BT-474)

Beyond XMT-1522:

Building the Mersana Portfolio

0

200

400

600

800

1000

1200

1400

1 8 15 22 29 36 43

Tu

mo

r V

olu

me

(m

m3)

Day

Vehicle Rituximab-dolaflexin 3 mg/kg qwk

Competitor vcMMAE 3 mg/kg qwk XMT-1535-dolaflexin 3 mg/kg qwk

XMT-1535-dolaflexin 5 mg/kg x1

Mersana Second Program:

Solid Tumor ADC - 2017 IND

Mersana ADC comapres favorably to competitor currently in early clinical development

Ovarian Cancer Xenograft

Mersana has identified a novel mAb (XMT-1535) with superior properties for ADC development

XMT-1535-dolaflexin is well-tolerated in NHP at a 5 mg/kg ADC dose • Payload equivalent of a 15-20 mg/kg vc-MMAE dose

Competitor vc-MMAE

Mersana Third Program:

First-in-Class Solid Tumor ADC - 2018 IND

Immuno-oncology target

Renal Cancer Xenograft

Mersana has discovered a proprietary antibody for ADC development

Broad solid tumor indications: NSCLC, Breast, Gastric, CRC, Ovarian, Renal

0

200

400

600

800

0 10 20 30 40 50 60 70

Mea

n T

um

or

Vo

lum

e (

mm

3)

Day (Dosing on Day 1)

Vehicle MERS3-dolaflexin (3 mg/kg)

MERS3-dolaflexin: 6/10

animals tumor free at Day 69

Current Product Pipeline

28

Discovery Preclinical Development Phase 1

XMT-1522

PROGRAM 2

PROGRAM 3

PROGRAM 4

Pictured from Left to Right: Pat, Alex, Mao, Dmitry, Venu, Xianhua, Alex, Radha, Cheri, Natasha,

Laura, Peter, Elena, Roberta, Liu, Dennis, Josh, Mike

The Mersana Research Team