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1 CONFIDENTIAL Q1 2020 Pioneering the Next Genera3on of Redirected T Cell Engaging Therapeu3cs in Immuno-Oncology

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Page 1: Pioneering the Next Genera3on of Redirected T Cell Engaging … · 2020. 2. 20. · BiTEs significantly enhance immune response to tumors rela3ve to an3body dependent cellular cytotoxicity

1CONFIDENTIAL

Q1 2020

Pioneering the Next Genera3on of

Redirected T Cell Engaging Therapeu3cs in Immuno-Oncology

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2

Agenda

• Corporate Overview: Leader in T Cell Engaging Therapy in Solid Tumors

• The Opportunity: T Cell Engaging Therapy in Solid Tumors – Game Changing

• The Maverick Solution: COBRA™ Therapeutic Platform

• COBRATM Platform Validation: Lead Candidate MVC-101

• Path to Treating Patients: Clinical Strategy & Indications of Interest

• Single Focus on Developing T Cell Engaging Therapies: COBRA™ Pipeline

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mavericktx.com

CORPORATE OVERVIEW

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Maverick TherapeuEcs IntroducEon

• Immuno-Oncology company launched in 2017

• Our Mission: Become the Leader in T Cell Engaging Therapy in Solid Tumors

COBRA™: A novel condiEonally acEve T cell engager

designed to safely target solid tumors with highly

specific and potent acEvity

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5

Partnerships

Focus

Strategic Validation

$125M of Committed Funding

ValidaEon of approach,

scienEfic plaJorm and

programs by key industry

leaders

Develop proprietary,

best-in-class, T cell-engaging

antibody therapeutics

5 year drug development

project based on the promise

of early-stage research

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Leadership Team

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mavericktx.com

T Cell Therapy in Solid Tumors = Game Changing Opportunity

THE OPPORTUNITY

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8

The Promise of Bispecific T Cell Engagers

BiTEs significantly enhance immune response to tumors rela3ve to an3body dependent cellular cytotoxicity (ADCC)

blinatumomab

rituximab100,000 fold

Dreier, et al. (2002), Int. J. Cancer, 100: 690–697

2012: Amgen acquires Micromet for $1.2 billion

2014: FDA grants accelerated approval of blinatumomab (Blincyto®) for the treatment of adult patients

with relapsed or refractory ALL

Sp

eci

fic

Cy

toto

xic

ity

[%

]

Antibody Concentration [ng/ml]

• BiTEs are a class of bispecific an3bodies (bsAbs) used for cancer treatment

• They are a fusion between tumor-targe3ng and T cell engaging recombinant an3body fragments

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The Challenge of bsAbs Beyond Hematological Cancers

• bsAbs redirect T cells to cell surface targets, regardless of whether expressed on the tumor or on healthy 3ssues

• Blinatumomab transiently depletes normal B

cells in hemo-onc patients, which can be

tolerated

• Damage to normal tissues by bsAbs results in

significant toxicity and limits patient response

by lowering the dose that can be safely

administered

The COBRA™ design can manage the limitations of less specific bsAb targets, by taking

advantage of the tumor’s unique proteolytic microenvironment for T cell activation

Normal Tissue Tumor Tissue

T cell

B-cell counts of 20 patients treated with blinatumomab

B-cell Depletion (to ≤1/ μl)

Klinger, et al. (2012), Blood, 119:6226-6233

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I/O Landscape: Enormous Unmet Need in Solid Tumors

Hematological Cancers Solid Tumor Cancers

Cancer Types Lymphoma, leukemia, myeloma

Breast, lung, prostate, colorectal,

melanoma, uterine & ovarian, kidney &

renal, head & neck, pancreas, others

Therapies

• Bispecific T cell engagers

(blinatumomab)

• CAR-T (tisagenlecleucel,

axicabtagene ciloleucel)

• Checkpoint Inhibitors (nivolumab,

pembrolizumab, ipilimumab)

Average Overall

Response Rates40 – 93%** 0.5 – 24%**

# of new cases* 174,000 = ~10% of all cancers 1,561,000 = ~90% of all cancers

* American Cancer Society, 2018

** Based on efficacy data in prescribing information for each therapy listed

There are 900% as many solid tumor cancers as there are hematological cancers

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mavericktx.com

COBRA™: A Novel Conditionally Active Bispecific Antibody

THE MAVERICK SOLUTION

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12

COBRA™ = Conditional Bispecific Redirected ActivationαEGFR sdAb inacEve VLαCD3 VH αEGFR sdAb inactive VHαCD3 VL αHSA sdAb

Protease

Cleavable Linker8 a.a. 8 a.a.

COBRA™ Construct Design and Predicted Folding

Inactivated VH & VL domains pair

with αCD3 VH & VL domains

min2.5 5 7.5 10 12.5 15 17.5 20 22.5

mAU

0

100

200

300

400

500

600

700

DAD1 A, Sig=280,2 Ref=off (JK180703 SEC lot 803 2018-07-03 11-14-55\005-P1-A5-Pro186 lot PL-0803.D)

14

.69

8

17

.00

4

15.7

41

Monomer = 97.5%

AnalyEcal Size Exclusion Chromatography

Predicted COBRA™ Folding

EGFR/MMP9 = MVC-101 = Maverick COBRA™ Program 1

Protein A and Prepara3ve SEC purifica3on

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MVC-101 Ac3ve Dimer

αCD3 agonist (dimer of αCD3 VH and VL )

Binds EGFR

Binds CD3

MVC-101 Cleavage Products

αCD3

VH and VL

inactive

VH and VL

Binds EGFR

Impaired CD3 binding Binds serum albumin

+

MVC-101

Cleaved MVC-101 Dimerizes to Form the Active Molecule

Binds EGFR

Impaired CD3 binding

Binds serum albumin

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CharacterizaEon of COBRA™ Binding

sdAb(monovalent EGFR binding)

MVC-101(bivalent EGFR binding)

Active MVC-101(tetravalent EGFR binding)

αEGFR KD (nM)

αEGFRKD (nM)

αCD3 KD (nM)

αHSAKD (nM)

αEGFRKD (nM)

αCD3 KD (nM)

Human 2.7 0.12 nb 11.3 <0.01 1.7

Cyno 6.3 0.14 nb 10.8 <0.01 2.4

Mouse nb* nb nb 106.3 nb nb

*nb = no binding

Binding kinetics to EGFR, serum albumin and CD3ε were assessed via the Octet system

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COBRA™ Mechanism of AcEon

= MVC-101; = cMVC-101; = inactivating domain; = adMVC-101

Cell Surface

Target Antigen=

Watch our mechanism of action video here:

https://www.mavericktx.com/technology/#our-science

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mavericktx.com

MVC-101: In Vivo Efficacy Data

COBRA™ PLATFORM VALIDATION

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17

Activated MVC-101 Demonstrates Potent In Vitro Activity

HT29 Tumor Cells

E:T 10:1

48 hours

0.001

0.01

0.1 1 10100

1000

0.0

0.5

1.0

T cell Killing Assay

Concentration (pM)

Tu

mo

r ce

lls

- R

LU

MVC-NCL

MVC-101

MVC-101 Pre-Cleaved

200X

(Non-cleavable)

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0 5 10 15 20 25 30 35 40 45

0

500

1000

1500

2000

SCC25

Days post initial dose

0 5 10 15 20 25 30 35

0

500

1000

1500

2000

LoVo

Days post initial dose

Tu

mo

r V

olu

me

(m

m3)

MVC-NCL - 100 µg/kg

MVC-101 - 100 µg/kg

MVC-101 - 20 µg/kg

MVC-101 - 4 µg/kg

0 5 10 15 20 25 30 35

0

500

1000

1500

2000

HT29

Days post initial dose

MVC-101 Regresses Established Solid Tumors in Mice

Dosed every 3 days for 7 doses total

Cell Lines:

8,774 EGFR/cell 33,218 EGFR/cell 239,344 EGFR/cell

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19

0 24 48 72 96 120 144 1680.1

1

10

100

1000

10000

Time (Hours)

Pla

sm

a C

on

c (

ng

/mL

)

Pre-Cleaved MVC-101 - 100 µg/kg

MVC-101 - 100 µg/kg

MVC-NCL - 100 µg/kg

PK in non-tumor bearing mice

Cleaved MVC-101 Clears More Rapidly Than Intact MVC-101

MVC-101

MVC-NCL

MVC-101

Pre-Cleaved

0 5 10 15 20 25 30 35

0

500

1000

1500

2000

LoVo

Days post dose initiation

Tu

mo

r V

olu

me

(m

m3)

MVC-NCL - 100 µg/kg

MVC-101 - 100 µg/kg

Pre-Cleaved MVC-101 - 100 µg/kg

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20

Bio

log

ica

l Re

spo

nse

Le

vel

Log (exposure)

Preclinical Results Predict Increased Therapeutic Window

Efficacious

Dose

Maximum

Tolerated

Dose

MVC-101 exposures at efficacious doses relative to tolerated doses predicts

an increased therapeutic window compared to standard T cell engagers

Standard T Cell Engagers

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21

Bio

log

ica

l Re

spo

nse

Le

vel

Log (exposure)

Preclinical Results Predict Increased Therapeutic Window

Efficacious

Dose

Maximum

Tolerated

Dose

Increased

Therapeutic

Window

MVC-101 exposures at efficacious doses relative to tolerated doses predicts

an increased therapeutic window compared to standard T cell engagers

COBRA™ MVC-101

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22

Clinical Strategy & Indications

PATH TO TREATING PATIENTS

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CONFIDENTIAL 23CONFIDENTIAL

MABEL

Bio

log

ica

l Re

spo

nse

Le

vel

Log (exposure)

COBRA Safety Mechanisms Enable Increased FIH Dose

• FDA requires MABEL* starting dose for standard bispecific T cell engagers

• COBRA safety features & robust pre-clinical safety package combined with

an ex-US strategy allow Maverick to maximize FIH dose

COBRA™ MVC-101

“... [We] would, in principle, accept

the proposed approach based on

the HNSTD, provided that the

Sponsor is confident that the

calculated starEng dose should not

be sub-efficacious in the proposed

pa3ent popula3on”

Star3ng ra

nge based

on feedback

*MABEL = minimum anticipated biological effect level

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CONFIDENTIAL 24CONFIDENTIAL

Clinical Development Strategy

Transition to select

indications and 3+3

design prior to

expansion

1+3 design for

ini3al steps

X μg/kg

X μg/kg

X μg/kgNon-Small Cell

Lung Cancer

N = 15-20

X μg/kg

Colorectal Cancer

N = 15-20X μg/kg

Head & NeckSCC

N = 15-20

• U3lize ex-US regulatory feedback

to maximize star3ng dose

• Dose Escala3on run in Australia

• Begin US IND filing once sufficient

safety data has been collected

• Dose Expansion run in AUS and US

X μg/kg

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CONFIDENTIAL 25CONFIDENTIAL

PaEent PopulaEons of Interest

Head and Neck

Squamous Cell

Carcinoma (HNSCC)

Colorectal Cancer

(CRC)

Non-Small Cell Lung

Cancer (NSCLC)

EGFR Expression

Consistency

High (97%)

constitutively

expressed for all

subtypes1

Constant for both

KRAS mutant and

wildtype2

Most consistent

within EGFR mutant

subtype3

Standard of Care

Efficacy* Bar –

Objective Response

Rate (ORR)

pembrolizumab4

16%

regorafenib5

1%

docetaxel6

15%

*Based on MVC-101 target clinical posi3oning

1. Zimmerman M, et al. (2006), Radiat Oncol, 10.1186/1748-717X-1-11

2. Callisia C, et al. (2015), Journal of Gastrointestinal Oncol, 6(6):660-667

3. Mascaux C, et al. (2011), Clin Cancer Res, 24:7796-807

4. https://www.merck.com/product/usa/pi_circulars/k/keytruda/keytruda_pi.pdf

5. http://labeling.bayerhealthcare.com/html/products/pi/Stivarga_PI.pdf

6. http://uspl.lilly.com/cyramza/cyramza.html

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CONFIDENTIAL 26CONFIDENTIAL

• 98% EGFR positive by IHC

• PD-1 combination: Potential path

to first line for COBRATM

Induc-onTherapy:

1st Line:

Surgery ±

Radiation

Platinum Chemo

+ Radiation

Resectable Unresectable

Anti-PD1

HNSCC Initial

Presentation

Recurrent Unresectable Locally

Advanced or Metasta3c Disease

2nd LineOr Later:

30%

1. World Health Organization

2. National Cancer Institute

3. Australian Institute of Health and Welfare

4. Cetuximab + platinum + fluorouracil

40%

Metastatic

60% 30% 10%

AnE-PD1 moving to

inducEon therapy

EXTREME4

EXTREME42nd Line:

90% 10%

MVC-101

AnE-PD1

16% ORR

Path to Early Line: Head and Neck SCC (HNSCC)

MVC-101+

Worldwide1 US2 AUS3

New Cases per Year 700,000 50,000 5,200

Deaths per Year 380,000 10,000 1,200

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CONFIDENTIAL 27CONFIDENTIAL

• 83% EGFR posi3ve by IHC

“More than 90% of pa?ents with

metasta?c colorectal cancer will

require second-line treatment.”7

1st Line:

2nd/ (3rd) Line:

Ras Mut (30-50%) Ras WT (25-30%) BRAF Mut

Chemo4 + Bev5 Chemo4 +

An3-EGFR6

Chemo4 +

Bev5Regorafenib

MSI-H

Molecular testing

3rd LineOr Later:

Limited Patient

Population

Path to Early Line: Colorectal Cancer (CRC)

MVC-101

Regorafenib MVC-101

4th LineOr Later:

MVC-101

1 % ORR

Unresectable

Metastatic CRC

42%38%

42%

Worldwide1 US2 AUS3

New Cases per Year 1,800,000 145,000 16,400

Deaths per Year 861,000 51,000 5,600

1. World Health Organization

2. National Cancer Institute

3. Australian Institute of Health and Welfare

4. 5-FU + Oxaliplatin + Irinotecan given concurrently (FOLFOXIRI) or sequentially

(irinotecan monotherapy 2nd) 5. Bevacizumab

6. Cetuximab or panitumumab

7. Tanios Bekaii-Saab (2018) Clinical Advances in Hematology & Oncology 16 (9) Supp 18

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CONFIDENTIAL 28

COBRA™ Pipeline

SINGLE FOCUS ON DEVELOPING

T CELL ENGAGING THERAPIES

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CONFIDENTIAL 29CONFIDENTIAL

COBRA™ PlaJorm Pipeline

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30

Maverick Achievements

ü We have designed a conditionally active, highly potent T cell engaging

platform

ü In vitro assays demonstrate protease mediated linker cleavage increases

potency of T cell-mediated killing up to 200-fold

ü Regression of established solid tumors in xenograft-bearing mice is

dependent on tumor mediated activation

ü Half-life extended MVC-101 has a more rapid clearance rate post

proteolytic activation

ü Exploratory tox study validates COBRA mechanism of action and

establishes meaningful therapeutic index

ü First-in-class programs with best-in-class design

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31

Maverick Highlights

UNMET MEDICAL NEEDThe COBRA™ pla{orm is designed to safely target a broad range of solid tumors with

highly specific and potent ac3vity while limi3ng on-target toxici3es in normal 3ssues

TECHNOLOGYProprietary, best-in-class, T cell-engaging antibody therapeutics that are selectively

activated by the tumor microenvironment

INTELLECTUAL PROPERTYPatents issued for T cell engaging and half-life extension domains; multiple patents filed

for conditionally active formats

PEOPLEMaverick is led by a team of leading experts in protein engineering, immunotherapy

and T cell therapeutic research and development

FUNDING/MILESTONES$125M of commi}ed funding through 2021, providing the runway for clinical proof of

concept in pa3ents

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32CONFIDENTIAL

Thank You