june 7 , 2019 - jefferies group · 2019-06-13 · confidential| © 2019confidential| © 2019...

CONFIDENTIAL| © 2019CONFIDENTIAL| © 2019

Compass Therapeutics Jefferies 2019 Global Healthcare Conference

June 7th, 2019

1

CONFIDENTIAL| © 2019

Who We Are

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• Therapeutic focus: immuno-oncology and autoimmunity

• Proprietary antibody discovery platform: First 40+ targets drugged

• Broad pipeline of novel therapeutic candidates targeting multiple targets of the immune system

• Growing biotech with lab/office/vivarium in Cambridge, MA

Key Milestones• Developed comprehensive and deep approach to antibody discovery: novel drug candidates and building

blocks for next-generation bispecific antibodies. StitchMabs™ HT screening platform.

• Nominated our first clinical candidate

• 2018 “Fierce 15” biotech company

• Completed $132 M in series A financing: OrbiMed, F-Prime, Cowen, Borealis, Thiel, Biomatics, Alexandria, BioMed

2019• Enroll Phase 1 Study: CTX-471 – novel CD137 agonist: https://clinicaltrials.gov/ct2/show/NCT03881488

• Begin IND enabling studies for our second candidate: first-in-class NKp30 bispecific

• Nominate a third clinical candidate: two new INDs in 2020

• Series B financing; IPO ready

https://clinicaltrials.gov/ct2/show/NCT03881488


Our Discovery Approach Bridges Innate & Adaptive Immunity

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Tumor

Adaptive Immunity

Macrophage

Neutrophil

CD89

SIRPa

NKCD8+ CTL

MDSC

Treg

Innate ImmunityDC

Ag shedding

Her2BCMACD38CD200CD30

NKG2DCD226NKp30NKp46CD16a2B4

CD137NKG2DCD226CD2PD-1TIGITCD112RCD96

CD94CD2CD137TIGITCD112RCD96

CD89

SIRPa

PD-L1CD155CD112CD113CD47CD277

CD137TIGITTNFR2OX40GITR

PD-L1Gal-1Gal-3IL-6

CD40

VALIDATED ANTIBODY PANELS TO 40+ TARGETS FORM BUILDING BLOCKS FOR COMBINATION & BISPECIFIC SCREENING

OX40GITR


Compass Pipeline: June 2019

Discovery Phase I In Vitro In VivoIND Enabling

Studies

Mac

rop

hag

e T-

Cel

l N

K C

ell

AActivation

ACKPT Blockade

Phase II

CTX-471: Novel CD137 agonist

CTX-471 Combinations

CTX-8371: PD-1 x PD-L1 Bispecific

CTX-8573: BCMA x NKp30 Bispecific

NKp30 x TAA Platform

TGFβ x TIGIT Bispecific

Receptor x TAA Bispecifics

CTX-5861: SIRPα and Combinations

AActivation

ACKPT Blockade

AActivation

ACKPT Blockade TAA: Tumor associated antigen

CKPT: Checkpoint

CONFIDENTIAL| © 2019 5

T-Cells

ActivationCTX-471 - CD137 Agonist

Checkpoint blockadeCTX-8371 - PD1 x PDL1 Bispecific


CTX-471: Best in Class CD137 Agonist

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NOVEL EPITOPE WITH DIFFERENTIATED ACTIVITY SUPPORTED BY EXTENSIVE PRECLINICAL DATA

CTX-471 Summary

Selection

▪ Panel of 70 antibodies

▪ 8 unique epitope bins

▪ Comprehensive in vitro characterization based on binding, signaling, activation, and drug-like properties

▪ 4 leads compared in vivo

Molecular Profile

▪ Fully human, IgG4 agonist

▪ Non-ligand competitive

▪ Differentiated epitope in CRD3/4

▪ Mouse/human/cyno cross-reactive

CTX-471 binds a unique, non-ligand competitive epitope in CRD3-4 of CD137

CD137L

CD137

Urelumab, 3H3

CTX-471

Utomilumab


Raising the Bar for Preclinical Efficacy - High Burden Tumor Models

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Small CT26 tumor: ~75 mm3

➢ Typical size at which treatment begins in mouse efficacy studies

➢ Tumors this small are modestly sensitive to monotherapy with α-PD-1/L1, α-OX40, α-CTLA4, or α-CD137 (3H3)

➢ Small tumors can be eradicated by CTX-471 monotherapy

Large CT26 tumor: ~500 mm3

➢ Treating extremely large tumors of this size is generally considered futile

➢ Tumors this large are highly resistant to monotherapy α-PD-1/L1, α-OX40, α-CTLA4, or α-CD137 (3H3)

➢ Large tumors can also be eradicated by CTX-471 monotherapy


CTX-471 Induces Regression of ~500 mm3 Tumors

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Control CTX-471 CTX-471-AF-1 CTX-471-AF-2

Tu

mo

rV

olu

me

(m

m3

)

Days Post-Treatment Days Post-Treatment Days Post-Treatment Days Post-Treatment

0 20 40 600

500

1000

1500

2000

0 20 40 600

500

1000

1500

2000

0 20 40 600

500

1000

1500

2000

0 20 40 600

500

1000

1500

2000

0/6 4/6 6/6 4/6

✓ Tumors were allowed to grow to ~500 mm3 before treatment began✓ Therapeutic model, not a prevention model✓ Unprecedented Monotherapy activity for an I/O Antibody

CTX-471 AND CTX-471-AF CLONES WERE TESTED IN CT26 THERAPEUTIC IN VIVO MODEL

Low affinity Intermediate affinity High affinity


Generation of Long Term Immunological Response

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* P values from Log-rank test compared to control

P=0.008

P=0.01

P=0.0005

Survival Curve: Re-challenge

0 10 20 30 40

0

20

40

60

80

100

Days Post-Re-Challenge

Pe

rce

nt

surv

ival Isotype/ Naïve

CTX-471 CTX-471 –AF-1

CTX-471 –AF-2

Survival Curve: Monotherapy Treatment

POTENT AND FUNCTIONAL IMMUNOLOGICAL MEMORY – ALL CURED MICE REJECTED THE TUMOR

✓ Monotherapy treatment ✓ At > 8 x t1/2 all mice of Clone #1 and most mice of Parental survived ✓ All surviving mice re-challenged with CT-26 rejected the tumor


CTX-471-AF-1 Induces Comprehensive Reprogramming Within the Tumor Microenvironment

CD45

Sid

e sc

atte

r

18 ± 1 % 62 ± 25 %

Control CTX-471-AF-1

Increased Infiltration of Immune Cells in the TME

Protection/Reversion of T-cell Exhaustion

TIGIT

PD

-1

43 ± 5 % 8 ± 5 %


31 ± 9 % 7 ± 3 %


FOXP-3

CD

25

Treg Reduction in the TME

44 ± 4 % 24 ± 11 %


CD11b

F4/8

0

Tumor Associated Macrophage Reduction in the TME


Combinations are Synergistically Effective In Vivo

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CT26HuHER2 ADOPTIVE TRANSFER MODEL – T-CELL MEDIATED ACTIVITY SHOWN FOR CTX-471

Control

Trastuzumab

Monotherapy

Combination

Combination (No T cells)

Days post-Treatment

Per

cen

t Su

rviv

al

40% survival @ D64

100% survival @ D64

0% survival @ D64

0 20 40 60 800

20

40

60

80

100

Control Her2 Mono CTX-471 MonoT

um

or

Vo

lum

e(m

m3

)

Note: Treatment initiated 6-days post tumor inoculation

0 20 40 600

500

1000

1500

2000

0 20 40 600

500

1000

1500

2000

0 20 40 600

500

1000

1500

2000

Days Post-Treatment Days Post-Treatment Days Post-Treatment

0/80/8 3/8

Parental Clone

Her2 + CTX-471Cocktail

(No T cells)

+

Parental Clone

Her2 + 471Cocktail

+

0 20 40 600

500

1000

1500

2000

0 20 40 600

500

1000

1500

2000

Days Post-Treatment Days Post-Treatment

8/8 0/8


CTX-471-AF causes Profound Tumor Necrosis of Very Large Tumors

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Tumor Rejection by CTX-471-AF is Associated with Increased Frequency and Penetration of CD8+ T Cells

13

Co

ntr

ol

CTX

-47

1-A

F

Day 7 Day 10 Day 14

Anti-CD8 IHC


• Vision: a broad T-Cell and NK-cell activator that has efficacy after PD-1/PD-L1 blockade in the immune-sensitive tumors (‘hot tumors’) and activity in selected cold tumors– Widely expressed on T cells and NK cells

– Activation via CTX-471 leads to efficacy across a broad set of syngeneic tumors in mice

– Demonstrable activity in cold tumors such as colorectal cancer, pancreatic cancer, etc.

• Phase 1 will test the activity of CTX-471 in the relapsed patient population after PD-1 axis blockade– Immunological architecture is required for response: patients can not be refractory to PD-1 blockade

– Once efficacy has been established in the 2L, 3L, we will proceed to front line therapy

• Tumor types: all approved PD-1 and PD-L1 indications– Immunologically responsive based on at least 3 months of stable disease

– High unmet medical need due to limited response to CKPT blockers

– Second line NSCLC is a major commercial opportunity

• Execution– IND open as of 3/2019

– 6-8 Centers in the US: Dana Farber, MGH, Wash. U., Mary Crowley CC, Mt. Sinai, ITOR, Hackensack

– Currently screening patients

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CTX-471 Clinical Development Plan

PD-1 RefractoryCold tumors

Immune competent~50% of PD-1 population

CTX-471


NK-Cells

ActivationCTX-8573 – BCMA x NKp30 BispecificNKp30 Engager Platform

Checkpoint blockadeTIGIT x TGFβ Bispecific


Empirical Identification and Optimization of NK Bispecific Antibodies

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Comprehensive antibody discovery

NK-R

BCMA

IgG1

Panel of BCMA-NKR StitchMabs™ and bispecificsexpressed and purified at 24 well scale

Primary ScreenPrimary NK cellsIgG1 Fc

Secondary screen – Effect of CD16a engagement

Combinatorial library

COMPASS SCREENING WORKFLOW FOR MULTISPECIFIC CONSTRUCTS


Next Generation NK Cell Bispecific Platform Targeting NKp30 Receptor

• First in class bispecific antibody targeting NKp30 activating receptor expressed by NK cells

• Overcomes CD16a deficiency

• Lowers the threshold of NK cell activation and induces NK cell-mediated killing of tumor cells expressing high, medium and low levels of TAAs with >100 fold increased potency compared to mAb

• Induces NK cell proliferation and cytokine release in the presence of target cells

• Wide therapeutic window with no activity in the absence of target antigen

• Leverages Compass common light chain and StitchMabs™

technologiesTumor cell

TAA

NK-Cell

CD16a

NKp30


NKp30 Bispecific Platform Significantly Enhances ADCC Potency of α-BCMA mAb SUPERIOR TUMOR CELL KILLING ACTIVITY MAINTAINED IN THE ABSENCE OF CD16A

NCI-H929 target cells4 hour incubation

BCMA

IgG1

NKp30

IgG1 Fc – CD16a Engagement

0 . 0 0 0 1 0 . 0 0 1 0 . 0 1 0 . 1 1 1 0

0

1 0

2 0

3 0

4 0

C o n c e n t r a t i o n ( n M )

% s

pe

cific

ly

sis

B C M A - N K p 3 0

B C M A m A b

H e r 2 m A b

Aglycosylated Fc – no CD16a

0 . 0 0 0 1 0 . 0 0 1 0 . 0 1 0 . 1 1 1 0

0

1 0

2 0

3 0

4 0


% s

pe

cific

ly

sis

Target cell killing by primary NK cells

0 . 0 0 0 1 0 . 0 0 1 0 . 0 1 0 . 1 1 1 0

0

2 0

4 0

6 0

8 0

1 0 0

t a r g e t s : R P M I - 8 2 2 6


%

sp

ec

if

ic

ly

si

s

C T X 4 4 1 9

B C M A - I g G 1 ( m A b )

H e r 2 - I g G 1

Target cell killing by CD16- KHYG-1 cell line


0. 0

00

1

0. 0

01

0. 0

1

0. 1 1

10

10

0

0

2 0

4 0

6 0

8 0

1 0 0

A n t i b o d y C o n c e n t r a t i o n ( n M )

% S

pe

ci

fi

c

Ly

si

s

H929 MM.1S RPMI 8226 HL-60

Affinity Matured, Afucosylated BCMA x NKp30 Lead CTX-8573 Induces Highly Potent and Selective Lysis of BCMApos Tumor Cells Expressing Different Levels of Antigen

Ag expression level

BCMA negative tumor cells

Methods: Primary NK cells from one donor were cultured for 4 hours with tumor cells.E:T ratio 10:1

>500,000 ~100,000 <30,000

0. 0

00

01

0. 0

00

1

0. 0

01

0. 0

1

0. 1 1

10

10

0

0

2 0

4 0

6 0

8 0

1 0 0


% S

pe

ci

fi

c

Ly

si

s

0. 0

00

01

0. 0

00

1

0. 0

01

0. 0

1

0. 1 1

10

10

0

0

2 0

4 0

6 0

8 0

1 0 0


% S

pe

ci

fi

c

Ly

si

s

0. 0

00

01

0. 0

00

1

0. 0

01

0. 0

1

0. 1 1

10

10

0

0

2 0

4 0

6 0

8 0

1 0 0


% S

pe

ci

fi

c

Ly

si

s

0. 0

00

01

0. 0

00

1

0. 0

01

0. 0

1

0. 1 1

10

10

0

0

2 0

4 0

6 0

8 0

1 0 0


% S

pe

ci

fi

c

Ly

si

s

C T X - 8 5 7 3 [ N K p 3 0 x B C M A a f u c o s y l a t e d ]

C T X - 6 7 6 7 [ N K p 3 0 x B C M A ]

C T X - 7 9 8 6 [ N K p 3 0 x B C M A F c s i l e n t ]

C T X - 6 6 0 5 [ B C M A - I g G 1 m A b ]

I g G 1 i s o t y p e c o n t r o l

n o a n t i b o d y

BCMA copies per cell

8573 – BCMA x NKp30-afucosylated (NKp30/CD16a++)

6767 – BCMA x NKp30 (NKp30/CD16a)

7986 – BCMA x NKp30-aglycosylated (NKp30)

6605 – BCMA mAb (CD16a)

Isotype control

No antibody


Single Dose of 1st Generation BCMA x NKp30 Bispecific Depletes BM Plasma Cells & Expands BM NK-Cells in Cynomolgus Monkeys

Bone marrow plasma cell depletion (ELISpot)

Activation & expansion of bone marrow NK-cells

- 5 5 1 5 2 5 3 5 4 5 5 5

1

1 0

1 0 0

1 0 0 0

1 0 0 0 0

D a y s p o s t t r e a t m e n t

CT

X-4

41

9 (

nM

)

A K 7 4 9 J

B 6 0 1 6

IgG-like PK with 16 day β-phase half-life

30 mg/kg dose

COLLABORATION WITH DR. FRANCOIS VILLINGER AT NEW IBERIA RESEARCH CENTER


BCMA Targeting ProgramsMultiple myeloma and other cancers

Severe Autoimmune Indications driven by

pathological IgGsComments

Anti-BCMA (IgG1) + - Insufficient potency on low BCMA expressing cells

BCMA-ADCs + - Safety

CAR-T + - Safety & cost

BCMA x CD3 (‘BiTE’) + - Safety and product profile

NKp30 x BCMA + +Targets cells expressing high,

medium and low BCMA, PK/PD profile

21

Our NKp30xBCMA is Uniquely Suited to Target Severe Autoimmune Indications

NKp30

BCMA

IgG1

BCMA

IgG1


Indication Prevalence Limitations of Current Treatment Options

Light-chain amyloidosis1 ~40 cases per 1,000,000~12,000 pts in the U.S.

Up to 80% of pts are ineligible for ASCT, and plasma cell directed chemotherapy has been shown to fall short in addressing organ dysfunction caused by amyloid deposition

Myasthenia Gravis2 ~20 cases per 100,000.~60,000 pts in the U.S.

Corticosteroids and immunosuppressants are associated with a number of significant side effects. Use of Soliris only blocks the activity of complement recruited by the pathogenic IgGs directed against the ACh receptor. It does not address the blocking of the Ach receptor by pathogenic IgGs, nor the receptor cross-linking and internalization by these IgGs.

Pemphigus Vulgaris3 ~1-10 cases per 1,000,000~300-3,000 pts in the U.S.

Patients who do not respond to corticosteroids and immunosuppressants are treated with IVIg or Rituxan. Even with IVIg and Rituxan, complete remission may take several months, and some patients do not respond.

Immune Thrombocytopenia1 ~9.5 cases per 100,000~30,000 pts in the U.S.

Treatment for ITP is focused on either reducing the autoimmune destruction of the platelets, or directly stimulating platelet production with specific growth factors. Use of IVIg and plasmapheresis can lead to serious complications, and while thrombopoietin receptor agonists lead to increases in blood platelet counts, they do not address the underlying destruction of the platelets.

Sources: 1National Organization for Rare Disorders, 2Myasthenia Gravis Foundation, 3International Pemphigus & Pemphigoid Foundation

Potential Indications for a BCMA-Directed Cell Depletion Agent


NKp30 x BCMA effect on serum IgM in a Monkey is similar to 6 courses of Plasmapheresis in humansTARGETING PATHOGENIC ANTIBODIES IN AUTOIMMUNE DISEASE

D a y 0 D a y 4 8

0

2 5

5 0

7 5

1 0 0

Se

ru

m I

gM

(

%)

Guptill, Autoimmunity, 2016Animal #1, Drop of IgM level in serum


NKp30 x BCMA effect on serum IgM in a Monkey is similar to Fc/FcRnblockade in humansTARGETING PATHOGENIC ANTIBODIES IN AUTOIMMUNE DISEASE

D a y 0 D a y 4 8

0

2 5

5 0

7 5

1 0 0

Se

ru

m I

gM

(

%)

Ulrichts, 2017 (ARGX-113)Animal #1, Drop of IgM level in serum


• NKp30 identified as optimal bispecific partner for targeting and activating NK cells through unbiased screen leveraging Compass discovery platform

• Key properties of NKp30 bispecifics– Potent - Enhance ADCC, cytokine production, and NK-cell proliferation compared to monoclonal antibodies

– Large therapeutic window - Active against target cells with wide range of antigen expression, but no activity in the absence of target

– Resistant to CD16a downregulation - Activate NK cells in the absence of CD16a engagement

– Highly manufacturable - Monoclonal-like drug-like properties and pharmacokinetics

– Flexible format – Common-LC format amenable to multi-TAA or multi-NKR targeting

– Potential to target additional effector cell types

• BCMA x NKp30 program– Robust killing of target cells with high, medium, & low BCMA

– Potent depletion of plasma cells in cynomolgus monkey

– Cell line development & additional primate studies underway with potential IND’s in multiple myeloma or autoimmune disease in 1H2020

• Her2 x NKp30– Bispecifics identified against multiple epitopes of Her2 with improved ADCC potency compared to trastuzumab

– Lead clone CTX-7144 entering affinity maturation

• Multiple campaigns in progress for additional targets in hematological and solid tumors with preliminary lead ID in 2019

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NKp30 Bispecific Engager Platform Summary


I

Our Pipeline

Effective Modulation of the Immune System

26


Compass Therapeutics: 2019 and Beyond

27

BUILDING A FULLY INTEGRATED BIOPHARMACEUTICAL COMPANY

-

-

Val

ue

Cre

atio

n

2015-2016

2017

2018

2019

2020

• CTX-471 Efficacy Data

• BCMA x NKp30 Phase 1

• TAA#2 x NKp30 IND

• Next-Gen checkpoint

blocking bispecific

• Clinical stage company

• 2nd clinical candidate at IND-

enabling studies

• 3rd clinical candidate

announced

• Several prospects for

candidates 4th, 5th and 6th

• Pharma collaboration

• Clinical candidate

• 2nd lead: NKp30 x BCMA

• Candidates for IND3, IND4

• Multiple CLC mAbs

• Bispecifics with unique activity

• Several I&I programs

advancing in parallel

• Clinical lead CTX-471

• CLC antibodies

• StitchMabs™

• 30 discovery campaigns

complete

• Infrastructure

• In vitro and in vivo

platforms

• Bispecific from published

seq.

• Proprietary mAbs


Compass Therapeutics Jefferies 2019 Global Healthcare Conference

June 7th, 2019

28

june 7 , 2019 - jefferies group · 2019-06-13 · confidential| © 2019confidential| © 2019...

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