Cobomarsen as a Therapy for Mycosis Fungoides...+ microRNA-targeted therapy is focused on disease...

Cobomarsen as a Therapy

for Mycosis Fungoides

C O N F I D E N T I A L

2

Content

+ miR-155 and Cobomarsen Mechanism Overview

+ Phase I Data in Mycosis Fungoides

+ Phase I Data in ATLL

+ Cobomarsen Phase II Overview (SOLAR)

Confidential Pg. 3 3

miR-155 and Cobomarsen Mechanism Overview


microRNAs Regulate Network

Biology to Maintain Homeostasis

4

+ microRNAs have been evolutionarily selected to

regulate networks of genes

+ microRNAs are dysregulated in many diseases

+ Dysregulation of microRNAs is associated with

alteration of downstream gene networks and disease

+ microRNA-targeted therapy is focused on disease

modification by restoring homeostasis to

dysregulated processes

+ microRNA therapeutics are particularly suited for

complex, multigenic disorders

Conventional Therapies

(Small molecules, Antibodies, siRNA, etc)

Single molecule as target

microRNA-based Therapies

Network (pathway) as target

% IN

HIB

ITIO

N

100

50

0


miR-155 Regulates Disease Gene Pathways Implicated in Mycosis Fungoides

5

↑ miR-155

Proliferation

Apoptosis

T-cell activation

Conventional Therapy

(e.g., idelalisib)

Cobomarsen

Multiple survival and

immune pathways activated

One survival

pathway inactivatedMultiple survival and immune

pathways inactivated

idelalisib

Proliferation

Apoptosis

T-cell activation

Proliferation

Apoptosis

T-cell activation

PI3K/AKT

JAK/STAT

NF-kB

RAS/MAPK

PI3K/AKT

JAK/STAT

NF-kB

RAS/MAPK

PI3K/AKT

JAK/STAT

NF-kB

RAS/MAPK


miR-155 is Increased in Multiple Hematologic Malignancies

6

MIR-155 EXPRESSION


7

miR-155 Expression is Linked to Multiple Hematologic Malignancies

• EXPRESSION OF miR-155 IS SUFFICIENT to drive B-cell expansion and formation of B-cell lymphoma

THE HOST GENE FOR miR-155 (BIC) was identified as a proto-oncogene for

virally-induced B-cell lymphomas

• ELEVATED miR-155 expression correlates with poor prognosismiR-155 IS HIGHLY EXPRESSED in

multiple hematologic malignancies

• THERAPEUTIC INHIBITION OF miR-155 reduces proliferation and increases apoptosis in hematologic cancer cell lines

miR-155 IS REGULATED by NF-kB, PI3K/AKT, and JAK/STAT, and functions in

a feedback loop with these survival pathways


Cobomarsen Affects Pathophysiology of Multiple Hematological Malignancies

8

+ Cobomarsen is a miR-155 inhibitor that inactivates multiple disease-

relevant pathways

+ Cobomarsen can enable induction of pro-apoptotic and anti-proliferative

pathways in these cancer cells while not causing global immunosuppression

+ Cobomarsen may provide long term benefit with few potential resistance

mechanisms by affecting multiple signaling pathways in cancer cells


miR-155 is Increased in Mycosis Fungoides Lesions

9

+ miR-155 is upregulated in MF

+ miR-155 expression

correlates with lesion severity*

+ miR-155 upregulation was

confirmed in miRagen’s

Phase 1 Clinical Trial in MF

N=10 N =13 N =21N =13

*In collaboration with Madeleine Duvic (MD Anderson)

COBOMARSEN IS A

MIR-155 INHIBITOR

MIR-155 COPY NUMBER BY

LESION TYPEMIR-155 COPY NUMBER IN MF

LESIONS


CobomarsenReverses the Disease Gene Signature in Mycosis Fungoides

10

GENES REGULATED IN MF LESIONS

COMPARED TO NORMAL SKIN

Patch PlaqueTumorMF Cells+ Cobo

T cell activation,

survival signaling,

cytokine signaling

Cell cycle

checkpoint

regulation

+ T cell activation, survival signaling, and

cytokine signaling genes ↑ in MF lesions

o REDUCED by cobomarsen

+ Cell cycle checkpoint genes ↓

in MF lesions

o INCREASED by cobomarsen


Cobomarsen Reduces

Proliferation and

Increases Apoptosis in

Cell Lines Derived

From CTCL Patient

11

+ Cobomarsen ↓ proliferation = bexarotene

+ Cobomarsen ↑ apoptosis > bexarotene

+ Potential for additivity/synergy with bexarotene and other therapeutics for CTCL

0 2 4 6 8 10 120

200

400

600

2000

4000

6000

8000

10000

Days

% C

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om

pare

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ay 1

0 2 4 6 8 10 120

200

400

600

800

Days

% c

han

ge c

om

pare

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eate

d a

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ay 1

0 2 4 6 8 10 120

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10000

Days

% C

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Untreated

Bexarotene

Cobomarsen

0 2 4 6 8 10 120

200

400

600

2000

4000

6000

8000

10000

Days

% C

han

ge C

om

pare

d t

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eate

d a

t D

ay 1

Untreated

Bexarotene

Cobomarsen

PROLIFERATION APOPTOSIS


Cobomarsen Clinical Program in Hematological Malignancies

12

CTCL MYCOSIS FUNGOIDES

MIR-155-HIGH NON-HODGKINS

LYMPHOMA (NHL)/LEUKEMIA

Dose, Schedule Optimization

and Response Durability in CTCL

Para

llel In

dic

ation

Expan

sio

n in

Ph1

mPoC cPoC Futility

AnalysisPART B/C

SYSTEMIC

PART A

LOCAL

ATLL

DLBCL

CLL

Ph 1 CTCL Ph 2 CTCL

Ph 2 in NHL / Leukemia


Cobomarsen Shows Favorable Tolerability

13

No serious adverse events attributed to

cobomarsen in CTCL

No acute inflammatory toxicities

No significant abnormalities found in liver, kidney or blood

In Total, 68 Patients

(CTCL, ATLL, DLBCL,

and CLL from Ph1 and

CTCL SOLAR) Have

Been Exposed To

Cobomarsen For Up To

2.5 Years

+ COBOMARSEN HAS BEEN GENERALLY SAFE

and well tolerated

o Multiple patients receiving more than a year

of therapy

o Total of 1254 cumulative doses

(across 68 patients)

+ NO SIGNIFICANT LAB ABNORMALITIES found

in liver function, kidney function, thyroid function

and platelet counts

+ NO EVIDENCE OF METABOLIC or

HEMATOLOGICAL toxicities

+ NO EVIDENCE OF GLOBAL

IMMUNOSUPPRESSION

+ NOVEL OLIGONUCLEOTIDE drug class

(Data Cutoff July 23, 2019)

Confidential Pg. 14 14

Cobomarsen

Phase I Results in

CTCL

Parts A and B


15

PART A

Intra-tumoral delivery

of cobomarsen

(75 mg dose)

PART B

Systemic SC or IV delivery

to determine optimal

potential dose (300, 600

and 900 mg+ dose)

OBJECTIVES

+ PRIMARY Safety and

tolerability

+ SECONDARY PK

+ EXPLORATORY PD,

histopathology, lesion

morphology

Cobomarsen: Two-part Phase 1 CTCL Study

PRETREATMENT

BIOPSY

PRETREATMENT

BIOPSY

PLACEBO COBOMARSEN

PLACEBO

BIOPSY

COBOMARSEN

BIOPSY BIOPSY

COBOMARSEN

SC or IV

PART A PART B


16

Phase I Clinical Trial Patient Flow and Disposition

SCREEN FAILURES = 8

ENROLLMENT CLOSED/MISSED DEADLINE = 1

DID NOT MEET I/E CRITERIA = 7

EXCLUDED FROM EFFICACY ANALYSIS DUE TO SEZARY SX = 1

SCREENED = 51 ENROLLED = 41

PART A: INTRA-LESIONAL

PART B: SYSTEMIC

ENROLLED = 6

ENROLLED = 37

COMPLETED = 5

DISCONTINUED DUE TO AE = 1

RECEIVED > 6 DOSES PER AMENDED PROTOCOL = 25

ONGOING = 1

COMPLETED = 9

DISCONTINUED = 25

LOST TO FOLLOW- UP = 2

TREATED = 37

RE-ENROLLED = 2


Phase I CTCL

Baseline Demographics

17

PART A n (%) PART B n (%) TOTAL n (%)

SEX

Female 1 (17) 13 (35) 14 (34.1)

Male 5 (83) 24 (65) 27 (65.9)

AGE

N 6 37 41a

Mean (SD) 59 (6) 58 (14) 58.4 (13.1)

Median 61 59 59

Min, Max 50,64 21,85 21,85

RACE

Asian 0 (0) 1 (3) 1 (2.4)

Black 1 (17) 6 (16) 7 (17.1)

Not reported 1 (17) 0 (0) 1 (2.4)

Other, specify 0 (0) 2 (5) 2 (4.9)

White/Caucasian 4 (67) 28 (76) 31 (75.6)


a 41 unique individuals

enrolled in the study

43 subjects total with

2 Part A subjects re-enrolled in Part B


18

Number of Subjects with Grade 3/4 and SAEs (n = 41a)

SYSTEM ORGAN CLASS ADVERSE EVENT (PT) SAE GRADE 3/4

Blood and lymphatic system disorders Neutropenia* 5

Leukopenia 2

Lymphopenia 1

Metabolism and nutrition disorders Hypertriglyceridaemia 3

Hypophosphataemia 2

Hypercalacemia 1 1

Hypokalaemia 1

Hyponatraemia 1

Neoplasms benign, malignant and unspecified Tumor flare 2

Tumor pain 1

Cardiac disorders Angina pectoris 1 1

Coronary artery disease 1 1

Palpitations 1

Investigations Blood uric acid Increased 1

Lymphocyte count

decreased1

Transaminases increased 1

Infections and infestations Cellulitis 1 1

Sepsis 1 1

Skin infection 1 1

Renal and urinary disorders Acute kidney injury 1

Proteinuria 1

Respiratory, thoracic and mediastinal disorders Orthopnea 1

Skin and subcutaneous tissue disorders Erythema 1

Pruritus 1

Rash 1

TOTAL 4 17

Phase I CTCL

Grade 3, 4 and SAEs in Parts A and B


enrolled in the study 43

subjects total with 2 Part A

subjects re-enrolled in

Part B

b Neutropenia is transient,

mostly in subjects on

concomitant medications

that had Grade 1-2 neutropenia at baseline



19

Adverse Events in ≥ 10% of Subjects

ADVERSE EVENT (PT) TOTAL (41a) n (%)

Fatigue 11 (26.8)

Neutropeniab 8 (19.5)

Headache 8 (19.5)

Nausea 7 (17.1)

Injection site pain 6 (14.6)

Back Pain 5 (12.2)

Constipation 5 (12.2)

Diarrhea 5 (12.2)

Oropharangeal pain 5 (12.2)

Tumor flare 5 (12.2)

Upper respiratory tract infection 5 (12.2)

Phase I CTCL

Most Frequent AEs Reported in Parts A and B





Part B







20

Phase I CTCL

Most Frequent AEs Reported in Monotherapy and Combination Therapy Patients





Part B





Adverse Events in ≥ 10% of Subjects

Monotherapy vs. Combination Therapy

PREFERRED TERMMONO (15)

n (%)

COMBO (26)

n (%)

TOTAL (41a)

n (%)

Fatigue 4 (26.7) 7 (26.9) 11 (26.8)

Neutropeniab 1 (6.7) 7 (26.9) 8 (19.5)

Headache 4 (26.7) 4 (15.4) 8 (19.5)

Nausea 1 (6.7) 6 (23.1) 7 (17.1)

Injection site pain 2 (13.3) 4 (15.4) 6 (14.6)

Back Pain 2 (13.3) 3 (11.5) 5 (12.2)

Constipation 3 (20.0) 2 (7.7) 5 (12.2)

Diarrhea 2 (13.3) 3 (11.5) 5 (12.2)

Oropharangeal pain 2 (13.3) 3 (11.5) 5 (12.2)

Tumor flare 2 (13.3) 3 (11.5) 5 (12.2)

Upper respiratory tract infection 2 (13.3) 3 (11.5) 5 (12.2)



Cobomarsen Reverses the Disease Gene Signature And Reduces Malignant Cell Clonality in Mycosis Fungoides Patients

21

Survival

signaling


22

Phase I CTCL Thirty-three of Thirty-six Patients (92%) Treated Systemically with Cobomarsen Have Shown mSWAT Score Improvement

-100

-90

-80

-70

-60

-50

-40

-30

-20

-10

0

10

20

30

Be

st

Ch

an

ge

in

mS

WA

T S

co

re (

%)

300 mg

600 mg

900 mg

* treatment ongoing

*

*

56

0

12

6

68

NE

NE

49

5

21

4

58

2

39

315

4

35

7

18

1

48

52

NE

14

8

IV Infusion IV BolusSC

STAGE

BASELINE mSWAT

DOSES

1A 2A 1B 1B 2B 1A 2B 1B 1B 2B 2B 1B 2B 3A 1B 2A 2B 1B 2B 2B 2B 1B 1B 1B 1B 1B 1A 1A 2B 2A 1B 3B 2A 2A 1B 1B

6 103 43 20 2 2 47 17 22 18 20 33 9 178 100 78 58 18 6 11 178 43 82 54 27 180 6 5 86 85 54 71 59 18 132 66

9 3 6 6 6 6 6 85 79 6 7 17 11 14 12 9 6 13 6 11 9 56 29 34 27 77 26 41 5 10 6 10 27 32 9 33

*

(Data Cutoff January 9, 2019)


23

Phase I CTCL

63%

Patients Treated

with Cobomarsen

Administered

as a 300 mg

IV-infusion

Achieved a PR

Reached ORR450%

-100

-90

-80

-70

-60

-50

-40

-30

-20

-10

0

10

Ch

an

ge

in

mS

WA

T S

co

re (

%)

300 mg IV-inf

*

* Treatment is ongoing

ORR4 ORR4 ORR4

214

582

393148

NE

ORR4

STAGE

DOSES

1B 1B 2B 2B 1B 1B 1B 1A

17 13 11 9 34 27 77 26

300 mg IV-inf *Treatment ongoing

ORR4 ORR4 ORR4 ORR4

NE

148393

*

582214


Phase I CTCL Cobomarsen Substantially Reduces Lesion Severity Following IV Administration

24

C1D1 Pretreatment

CAILS: 12

C3D1

CAILS: 3

C6D1

CAILS: 0

C12D1

CAILS: 0


Phase I CTCL

Cobomarsen Shows

Similar Efficacy When

Administered as Monotherapy

or in Combination with stable regimens of other CTCL

systemic therapies

25

CONCOMITANT MEDICATION

Bexarotene (N=12)

Interferon-alfa (N=2)

Methotrexate (N=2)

Other* (N=6)

*Other medications include single patients on

pralatrexate, methoxsalen, brentuximab,

gemcitabine, gamma interferon or romidepsin


26

+ 15 out of 17 (88%)

patients saw an

improvement in their

mean Skindex-29

score

+ Improvements mostly

occurred in patients

that received > 6

doses of cobomarsen

Phase I MFQuality of Life Improved as Measured by Skindex-29 Total Score

Stage 1A 1B 2A 2A 2A 2B 1B 2A 1B 2A 1B 2B 1B 2A 1B 1B 2B

Baseline mSWAT 5 27 18 10 6 6 66 59 82 78 132 18 180 85 54 43 58

# doses rec’d 56 27 32 103 26 6 33 27 29 9 9 6 89 10 6 56 6


Phase I MF Clinical Trial of Cobomarsen

27

Investigators

Francine M. Foss

Yale Cancer Center

New Haven, CT

Christiane Querfeld

City of Hope

Duarte, CA

Lauren Pinter-Brown

University of California,

Irvine

Irvine, CA

Joan Guitart

Feinberg School of Medicine

Northwestern University

Chicago, IL

Auris Huen

MD Anderson Cancer Center

Houston, TX

Theresa Pacheco

University of Colorado

Aurora, CO

Basem M. William

Division of Hematology

The Ohio State University

Columbus, OH

Herbert Eradat

University of California,

Los Angeles

Los Angeles, CA

Youn Kim

Stanford Cancer Institute

Stanford University

Palo Alto, CA

Bradley Haverkos

University of Colorado

Aurora, CO

Jennifer DeSimone

Inova

Fairfax, VA

Pierluigi Porcu

Sidney Kimmel Cancer Center

Thomas Jefferson University

Philadelphia, PA

Ahmad Halwani

Huntsman Cancer Center

Salt Lake City, UT

28

Cobomarsen

Phase I Results in

ATLL

Part F


29

Epidemiology of Adult T-cell Leukemia/Lymphoma

Arch Pathol Lab Med 2014;138-282

Blood Advances, 2018 (March27); 2(6)

+ Adult T-cell leukemia/lymphoma (ATLL) is a mature

peripheral T-cell neoplasm caused by human T-cell

leukemia virus type 1 (HTLV-1)

+ HTLV-1 establishes lifelong latency in human

T-cells (50-70 years) before development of ATLL

+ Malignant transformation leading to ATLL occurs in

HTLV-1–infected individuals with a cumulative

lifetime risk of 2.1% for women and 6.6% for men

+ The median survival time for acute ATLL patients is

reported from 4.1 to 8.3 months, approximately 10

months for lymphomatous ATLL and 27 to 67

months for chronic unfavorable ATLL


ATLL has a High Expression of miR-155

30

MIR-155 EXPRESSION


31

The Role of miR-155 in ATLL

Normal

Normal

Normal

Acute PBMC

Acute PBMC

Acute LN

Acute PBMC

miR-155 is Upregulated in Patient PBMCs

or Lymph Biopsy (n = 4)+ miR-155 upregulation has

been reported in HTLV-1 cell

lines and ex vivo tumor cells

from ATLL patients

+ Increased expression of

miR-155-5p enhances the

growth of HTLV-1 infected

T-cells

Yeung et al, Cancer Res 2008


32

Cobomarsen Reduces Proliferation and Induces Apoptosis in a Dose-Dependent Manner in an HTLV-1+ CTCL Cell Line

0.1 1 10 1000

20

40

60

80

100

120

uM

% c

han

ge c

om

pare

d t

o u

ntr

eate

d

0.1 1 10 1000

250

500

750

1000

1250

uM

% c

han

ge c

om

pare

d t

o u

ntr

eate

d0 2 4 6 8 1 0 1 2

0

2 0 0

4 0 0

6 0 0

2 0 0 0

4 0 0 0

6 0 0 0

8 0 0 0

1 0 0 0 0

D a y s

% C

ha

ng

e C

om

pa

re

d t

o U

ntr

ea

ted

at

Da

y 1

M R G -1 0 6

U n tre a te dUntreated

Cobomarsen (0.1-100 µM)

APOPTOSIS

+ miR-155 expression is increased in HuT102 cells (HTLV-1+ CTCL line)

+ Cobomarsen inhibits cellular proliferation and induces apoptosis in vitro

PROLIFERATION


33

Cobomarsen Clinical Experience in ATLL

PART F:

Open-label, dose-ranging, multiple dose trial of cobomarsen in ATLL

OVERALL TRIAL DESIGN

+ INCLUSION CRITERIA

o Acute, lymphomatous, chronic, and smouldering

subtypes

o Relapsing or in PR/CR after prior therapy

o Progressed on, or refractory to, at least one prior

therapy

+ DOSING AND DURATION

o SQ or IV

o 3 loading doses the first week

o Weekly dosing thereafter

o Discontinue if subject becomes intolerant, develops

clinically significant side effects, or progresses

OBJECTIVES

+ PRIMARY: Safety and tolerability

+ SECONDARY: PK

+ EXPLORATORY: PD, histopathology, lesion morphology


34

Subject Characteristics and Disposition

9 Patients Enrolled 89% Black, 67% Male; Median Age of 49 Years

SUBJECT

ID

ATLL TYPE AT

DIAGNOSIS

ATLL

PRESENTATION

AT SCREENING

RELAPSE OR

PARTIAL

REMISSION

% ABNORMAL

LYMPHOCYTES

AT SCREENING

LYMPH

NODES AT

SCREENING

CT SCAN/PET

DOSE (mg)

DAYS

SINCE

LAST

TX

DURATION OF

COBOMARSEN

TX (DAYS)

DISPOSITION

101-008 Acute Acute Partial Remission 9% Normal 600 21 500 Ongoing

101-010 Lymphomatous Lymphomatous Partial Remission 14% Normal 600 46 465 Ongoing

101-012 Lymphomatous Lymphomatous Partial Remission 10% Normal 600 108 186 Ongoing

101-014 Lymphomatous Lymphomatous Partial Remission 15% Normal 600 28 136 Discontinued

119-001 Chronic Unfavorable Chronic unfavorable Partial Remission None Abnormal 600 450 274 Ongoing

101-011 Lymphomatous Lymphomatous Relapsing Not Done Abnormal 600 219 10 Discontinued

102-012/

102-015Acute

Lymphomatous

transformation,

mostly skin

Relapsing

9% Not Done 600 21 92 Discontinued

26% Normal 600 30 43 Discontinued

118-001 Smouldering Aggressive, LCT,

mostly skin

Relapsing 0.3% Abnormal 600 31 24 Discontinued

119-002 Chronic Unfavorable Acute Relapsing 45% Abnormal 900 469 18 Discontinued

(Data Cutoff March 15, 2019)


Safety Summary of Cobomarsen in ATLL Cohort

35

+ NO DEATHS while on cobomarsen treatment

+ NO DOSE LIMITING TOXICITIES (maximum tolerated dose not yet established) and NO

DISCONTINUATION FROM TRIAL due to related AEs

+ 4 SAEs in 3 subjects DUE TO DISEASE PROGRESSION (unrelated to drug)

+ NO RELATED GRADE 3 OR GRADE 4 AEs

+ NO SIGNIFICANT HEMATOLOGICAL EVENTS

+ MOST COMMON (in more than 2 subjects) RELATED AEs (all grade 1 and 2) were DIARRHEA and

NAUSEA

Data Cutoff March 15, 2019


36

C1D

1

C1D

5

C1D

27

C2

C4

C6

C8

C10

C12

C14

C16

0

2 0

4 0

6 0

8 0

1 0 0

% o

f C

D1

9+

B c

ell

s

M a tu re N a iv e

T ra n s itio n a l

1 1 /6 /1 7 1 2 /2 0 /1 7 2 /2 1 /1 8 4 /2 5 /1 8 7 /1 1 /1 8 1 1 /1 4 /1 8 1 /2 3 /1 9 3 /2 0 /1 9

0

2 0 0

4 0 0

6 0 0

8 0 0

1 0 0 0

1 2 0 0

0

5 0

1 0 0

1 5 0

2 0 0

2 5 0

Nu

mb

er

of

NK

or

B c

ell

s /

L Nu

mb

er o

f CD

8 c

ells

/

L

N K c e lls

C D 8 T c e lls

B c e lls

F irs t

c o b o m a rs e n

d o se

1 1 /6 /1 7 1 2 /2 0 /1 7 2 /2 1 /1 8 4 /2 5 /1 8 7 /1 1 /1 8 1 1 /1 4 /1 8 1 /2 3 /1 9 3 /2 0 /1 9

2 5

3 0

3 5

4 0

4 5

5 0

2

3

4

5

1 0

1 2

1 4

1 6

% H

ct

RB

C x

10

^6

/

L o

r Hb

g / d

LH c t

H b

R B CF irs t c o b o m a rs e n d o s e

Cobomarsen Allows For Rapid Bone Marrow Recovery Following Chemotherapy in 4 Subjects

+ Subject 101-008 received EPOCH 21 days prior to

cobomarsen treatment

+ During Cycle 1 cobomarsen treatment, immature B cells

populate the periphery as transitional B cells

+ B cells mature into naïve B cells over the next few cycles

Example – Subject 101-008



37

Subject 101-008 Acute ATLL in Partial Remission

+ Diagnosed Dec 2016 with acute ATLL

+ Relapsed after treatment with zidovudine, interferon ɑ-2b, lenalidomide and EPOCH chemotherapy

+ Cobomarsen monotherapy initiated Nov 2017o Stable abnormal ATL cells for

> 16 moo Normalization of residual enlarged

lymph node after chemotherapy (1.0 to 0.8 cm), which remained normal as of last imaging Nov 2018

o Reduction in biomarkers of cell activation and proliferation (Ki67, CD69 and HLA-DR)

+ Subject remains on treatment and has completed Cycle 18, missing only 1 dose due to sciatic pain

2/2

2/1

7

7/1

9/1

7

8/1

2/1

7

9/8

/17

10/1

2/1

7

11/6

/17

12/1

3/1

7

1/3

1/1

8

3/1

8/1

8

5/9

/18

7/2

5/1

8

10/1

0/1

8

12/2

6/1

8

3/2

0/1

9

0

3

6

9

1 2

1 5

1 8

2 1

2 4

2 7

3 0

3 3

Ce

lls

x 1

0^

3 /

L

L a s t E P O C H d o s e

F irs t c o b o m a rs e n d o s e

A Z T /IF NL e n a lid o m id e

E P O C H

c o b o m a rs e n

A b n o rm a l T c e lls

W B C

m is s e d

d o se



38

C1D

1

C1D

5

C1D

27

C2

C4

C6

C8

C10

C12

C14

C16

0 .0

0 .5

1 .0

1 .5

Fo

ld C

ha

ng

e f

ro

m B

as

eli

ne

K i-6 7

H L A -D R

C D 6 9

C1D

1

C1D

5

C1D

27

C2

C4

C6

C8

C10

C12

C14

C16

0

2 0

4 0

6 0

8 0

%C

ell

s P

os

itiv

e f

or M

ark

er

% K i-6 7 +

% H L A -D R +

% C D 6 9 +

Subject 101-008 Cobomarsen Decreases Activation and Proliferation Status of Circulating Tumor Cells in ATLL

FLOW CYTOMETRIC ASSESSMENT of ACTIVATION and PROLIFERATION

Biomarkers’ Expression in Circulating ATLL Cells

7%

Acti

va

tio

n M

ark

ers

Pro

life

rati

on

35% 25% 5% 5% 7%

CD69

C1D1

HLA-DR

C1D5 C1D27 C2D22 C6D22 C14D22

SS

C

Ki-67

SS

C

50%

1179

71%

2880

67%

214856%

1264

53%

1129

50%

1283

Percent

MFI

19%

3436

13%

21058%

1885

8%

1900

8%

2011

Percent

MFI7%

1810

C1D1 C1D5 C1D27 C2D22 C6D22 C14D22

SS

C

Percent

MFI: Median Fluorescence Intensity, ATL cells: CD3+CD4+CD8-CD25+CD127-

ATL cells: CD3+CD4+CD8-CD7-CD25+CD45RA-

% CELLS POSITIVE FOR BIOMARKERS

CHANGE FROM BASELINE IN BIOMARKERS



39

2 /2 8 /1 8 6 /2 0 /1 8 9 /1 7 /1 8 1 0 /4 /1 8 1 1 /1 /1 8 1 1 /2 9 /1 8 1 /1 1 /1 9 2 /1 4 /1 9 3 /1 4 /1 9

0

1

4

6

8

1 0

1 2

1 4

1 6

ce

lls

x 1

0^

3/u

L


W B C

F irs t

c o b o m a rs e n

d o s e

C H O E P

m is s e d

d o se

2 m is s e d

d o s e s

m is s e d

d o se

Subject 101-012 Acute ATLL in Partial Remission

+ Diagnosed Dec 2017 with ATLL,

lymphomatous sub-type

+ Received 6 cycles of CHOEP (Jan-May

2018) with complete response in nodes

but relapsing peripheral ATL cells

+ CT scan at screening was normal

+ Cobomarsen first dose Sept 2018

o Completed Cycle 6 as of cut off

date

o CT scans have remained normal

o LDH all within normal range

o Reduction in biomarkers of

activation (CD69) and

proliferation (Ki67)



40

Subject 101-010 Lymphomatous ATLL in Partial Remission

+ Diagnosed April 2017 with lymphomatous ATLL

+ Extensive and bulky lymphadenopathy reduced by 6 cycles of CHOEP (completed 5 months prior to initiation of cobomarsen)

+ Restaging o Resolution of adenopathy but increased splenic

uptake

o 20% of ATL cells in peripheral blood

+ Cobomarsen initiated Dec 2017o Stable lymph node size and peripheral blood

tumor cell counts maintained for 15 monthso CR obtained in viscera – CT scan Nov 2018 is

now normal (resolution of splenic lesion)o Reduction in biomarkers of cell activation and

proliferation (Ki67, CD69 and HLA-DR)o Subject has completed Cycle 16 as of cut off

date

+ Rhinovirus infection Nov 2018 and concurrent increase in neutrophil count showed evidence of a normal immune response

6/1

5/1

7

10/4

/17

12/1

1/1

7

1/3

/18

2/7

/18

3/2

1/1

8

5/9

/18

7/1

8/1

8

9/2

6/1

8

11/1

4/1

8

1/2

/19

2/2

0/1

9

0

1

2

3

6

9

1 2

1 5

Ce

lls

x 1

0^

3 /

L

F irs t

c o b o m a rs e n

d o s e

c o b o m a rs e n


W B C

C H O E P

In c re a s e d n e u tro p h ils in re s p o n s e to

d o c u m e n te d rh in o v iru s in fe c t io n

m is s e d d o s e s



41

C1D

1

C1D

5

C1D

27

C2

C4

C6

C8

C10

C12

C14

C16

0

1

2

3

Fo

ld C

ha

ng

e f

ro

m B

as

eli

ne

K i-6 7

H L A -D R

C D 6 9

M is s e d

C 4 D 1

D o s e c P A R P

C1D

1

C1D

5

C1D

27

C2

C4

C6

C8

C10

C12

C14

C16

0

1 0

2 0

3 0

4 0

5 0

%C

ell

s P

os

itiv

e f

or M

ark

er

% C D 6 9 +

% K i-6 7 +

% H L A -D R +M is s e d

C 4 D 1

D o s e

% c P A R P +

Subject 101-010 Cobomarsen Decreases Activation and Proliferation Status of Circulating Tumor Cells

SS

C

CD69

C1D1

HLA-DR

C1D5 C2D22 C4D22 C6D22S

SC

Ac

tiv

ati

on

M

ark

ers

Pro

life

rati

on

Ki-67

SS

C

33%

1539

27%

111517%

1076

16%

854

8%

814

Percent

MFI

5%

1346

1%

12522%

1375

1%

1281

2%

1498

Percent

MFI

C1D1 C1D5 C2D22 C4D22 C6D22

C12D2210%

921

1%

1526

C4D1 dose missed

C12D2216% 16% 12% 24% 14%Percent

MFI: Median Fluorescence Intensity, ATL cells: CD3+CD4+CD8-CD25+CD127-

ATL cells: CD3+CD4+CD8-CD7-CD25+CD45RA-

SS

C

Ap

op

tosis

cPARP

C1D1 C1D5 C2D22 C4D22 C6D22 C12D2218% 16% 17% 42% 12%Percent

C4D1 dose missed

11%

17%


% CELLS POSITIVE FOR BIOMARKERS

CHANGE FROM BASELINE IN BIOMARKERS


42

C1D

1

C1D

5

C1D

27

C2

C4

C6

C8

C10

C12

C14

C16

0 .0

0 .5

1 .0

1 .5

2 .0A c tiv a tio n M a rk e rs A T L T u m o r C e lls

Av

era

ge

Fo

ld C

ha

ng

e o

f

% C

ell

s P

os

itiv

e f

ro

m B

as

eli

ne % C D 6 9 +

% H L A -D R +

n = 4 n = 4

n = 3n = 4

n = 4

n = 3 n = 2

n = 2

n = 2 n = 2

C1D

1

C1D

5

C1D

27

C2

C4

C6

C8

C10

C12

C14

C16

0 .0

0 .5

1 .0

1 .5P ro life ra tio n In d e x A T L T u m o r C e lls

Av

era

ge

Fo

ld C

ha

ng

e o

f

% C

ell

s P

os

itiv

e f

ro

m B

as

eli

ne

% K i-6 7 +

n = 4 n = 4

n = 3

n = 4

n = 4

n = 3

n = 2n = 2

n = 2

n = 2

Cobomarsen Decreases the Activation and Proliferation of Circulating Tumor Cells

ACTIVATION MARKERS ATL TUMOR CELLS PROLIFERATION INDEX ATL TUMOR CELLS



Conclusions

43

+ Study continues to enroll subjects with acute and lymphomatous ATLL, relapsing and in partial or

complete remission

+ Cobomarsen treatment resulted in durable clinical stabilization of all subjects with acute,

lymphomatous and unfavorable chronic ATLL for up to 16 months (median = 9 months) after partial

remission induced by chemotherapy

+ Biomarkers of cell activation and proliferation decrease with cobomarsen treatment underscoring the

biological effect of the drug

+ Safety and tolerability profile appears benign with dose up to 600 mg – no deaths, DLTs, related SAEs,

related Grade 3 or Grade 4 AEs, hematological events or discontinuation from trial due to related AEs

+ Cobomarsen therapy allows for normal bone marrow recovery after chemotherapy-induced suppression

+ The preliminary results are encouraging and supports trial continuation to explore cobomarsen for the

treatment of ATLL subjects


Phase I ATLL Clinical Trial of Cobomarsen

44

Investigators

Juan Carlos Ramos

University of Miami

Sylvester Comprehensive

Cancer Center

Miami, FL

Christiane Querfeld

City of Hope

Duarte, CA

Jasmine Zain

City of Hope

Duarte, CA

Noah Kornblum

Montefiore Medical Center

Bronx, NY

Alison Moskowitz

Memorial Sloan Kettering

Cancer Center

New York, NY

Adrienne A. Phillips

Weill Cornell Medicine

New York, NY

Francine M. Foss

Yale Cancer Center

New Haven, CT

Lauren Pinter-Brown

University of California

Irvine

Orange, CA

Matthew Weinstock

Beth Israel Medical Center

Boston, MA

45

SOLAR: A Phase II Clinical

Trial of Cobomarsen in

Mycosis Fungoides

Protocol Overview


SOLAR Phase 2 Clinical Trial

46

A Randomized, Open-Label, Parallel-group,

Active Comparator, Global Trial in Patients

with Stage IB-III Mycosis Fungoides (MF)

Primary Endpoint

+ Overall Response Rate of Four Months (ORR4)

using Global Response Criteria

Secondary Endpoints

+ Progression-free Survival

+ Patient Reported Outcomes

OPEN LABEL RANDOMIZE TO:COBOMARSEN IV

INFUSION VS. VORINOSTAT

RANDOMIZE

COBOMARSEN (282MG IV INFUSION)

N=63 SUBJECTS

VORINOSTATN=63 SUBJECTS

FOLLOW UNTIL PROGRESSION

FOLLOW UNTIL PROGRESSION

OPEN LABEL EXTENSION

PRISM


47

SOLAR Design as a Patient-centric Clinical Trial

47

Detailed Patient Risk Assessment

Travel Concierge

Research HomeInfusion Services

Patient Reported Outcomes


SOLAR Study Participating Countries

48

+ Austria

+ Australia

+ Belgium

+ Canada

+ France

+ Germany

+ Italy

+ Netherlands

+ Spain

+ United Kingdom

+ United States

126 Subjects at ~60 Sites

Across 11 Countries


SOLAR Design

49

+ PHASE 2 STUDY: comparing cobomarsen to

vorinostat

o Up to 126 subjects – 1:1 randomization

o ~60 sites in US, Canada, EU & Australia

o Duration of study – up to 36 months

+ STRATIFICATION FACTORS:

o Skin tumors (0 vs 1 or more)

o Having 0-1 vs 2 of the following prognostic

factors:

• 60 years age at diagnosis

• LDH level > ULN at diagnosis

+ DURATION OF TREATMENT: until progression

or study completion

o 28-day screening period, active treatment

period, follow-up for progression and

survival

+ INTERIM ANALYSIS FOR FUTILITY: after the

first 40 subjects followed for at least 6 months

+ LONG-TERM FOLLOW UP: every 3 months

(phone call) for survival


Selection of the Comparator

50

+ REGULATORY REQUIREMENT TO HAVE ONLY ONE

COMPARATOR

+ BEXAROTENE OR METHOTREXATE were not selected

(limited patient population naïve to these therapies)

+ LIMITED CONTROLLED TRIALS in CTCL to gather

comparator response rates that can be utilized to calculate

sample size

+ HDAC INHIBITOR CONSIDERED A GOOD

COMPARATOR so vorinostat and romidepsin were

considered; vorinostat administration is less burdensome

on patients (oral medication vs. 4-hour in hospital IV

infusion)

+ VORINOSTAT EFFICACY IS SIMILAR TO OTHER

CANDIDATE COMPARATORS

Data from Mavoric and ALCANZA trials * Includes pcALCL and MF patients

MF PATIENTS ORR ORR4 PFS

Vorinostat 7% N/A 3.1 mos

Methotrexate 16% 7.7%* 3.5 mos

Bexarotene 16% 15.8%* 3.5 mos


KEY EXCLUSION CRITERIA

51

+ Previous enrollment in a cobomarsen study

+ Prior therapy with HDAC inhibitors or contraindication to

vorinostat (or HDAC inhibitors)

+ Evidence of (current) large cell transformation (LCT)

+ Prior or current Sézary syndrome or mycosis fungoides with IIB

+ Extensive nodal involvement with complete or partial effacement

of LN (i.e., N3) or visceral involvement

+ Unresolved toxicities from prior therapy

+ Other medical conditions such as bleeding diathesis, prolonged

QT syndrome or previous or concurrent malignancies

+ Stages IB, IlA, IlB, III

+ Must have received at least one prior

therapy for CTCL (per NCCN guidelines

for generalized skin involvement)

+ mSWAT score ≥ 10

SPAIN At least 2 prior systemic therapies

ITALY Prior therapies, at least 1 systemic

FRANCEStage IIB or III only; 2 prior therapies,

at least 1 systemic

KEY INCLUSION CRITERIA

Protocol V3.0


52

5 Half Lives 8 Weeks 4 Weeks Day -28

Treatment Washout Requirements (Prior to Screening)

Investigational Small

Molecule Drug

Investigational

Biologic Drug

Systemic

corticosteroid

prednisone equivalent

> 10 mg per day1

• Chronic use, more

than 20 days total

• More than 3 short

courses of 7 days

Immune therapy

• Antibody-directed

• Immunoglobulin-

based

• Other monoclonal

antibody therapies

Macrolide or tetracycline

antibiotics

Total skin electron beam

(TSEB) therapy

Phototherapy

High potency topical

corticosteroids (chronic

use, more than 20 days

total)2

Other topical MF

treatments (chronic use,

more than 20 days total)

Previous systemic MF

treatments

Screening

Begins

1 Stable regimen of systemic prednisone equivalent to ≤ 10 mg per day is permitted2 Stable doses of low to medium potency topical corticosteroids are permitted


Concomitant Steroid and Anti-pruritic Agent Guidance

53

Patient may continue on:

Stable regimens of systemic

prednisone equivalent to ≤10mg

per day

Stable dose of medium or low

potency topical corticosteroids for

the treatment of pruritus

Stable dose of systemic anti-

pruritic agents (not used for

prophylaxis)

Topical moisturizers

Patients may not:

Start new prophylactic systemic anti-

pruritic agents

Increase corticosteroid dose for CTCL-

related symptoms

Start new chronic courses of topical or

systemic agents for pruritus or CTCL-

related symptoms

NEW SYSTEMIC TREATMENT FOR CTCL WILL BE PROHIBITED DURING THE STUDY

Patient may start new:

Short courses (≤ 7 days) of low- and

medium-potency topical corticosteroids

Short courses of systemic or high-

potency topical corticosteroids for non-

CTCL indications

Short courses (≤ 7 days) of systemic

corticosteroids for CTCL indication

allowed in exceptional cases

Short courses (≤ 7 days) of oral

antihistamines for symptomatic pruritus

Short courses of other anti-pruritic

agents for symptomatic pruritus are

allowed in exceptional cases


Strategies For Management of Vorinostat Side Effects And Patient Retention Until Progression

54

+ miRagen PROVIDES patient and physician

guidelines on managing vorinostat side effects

+ MOST COMMON AEs are gastrointestinal

+ PRACTICAL STRATEGIES

o Take vorinostat before bed

o Remind patients to stay hydrated

o Popsicles

o Inform patients of possible side effects of

the drug

+ OPTIONS TO MANAGE side effects:

o Lowering dose to 300 mg qd

o Decreasing to 5 days per week

o Stopping medication (but continue with follow-up

until progression)

+ CAN PATIENTS WITH STABLE DISEASE OR PR/CR

that discontinue for tolerability cross to PRISM?

o No: patients can discontinue treatment, but they

NEED to remain on study UNTIL PROGRESSION

to be eligible for PRISM

55

PRISM Overview


Open Label PRISM Study

For patients that have progressed

on the vorinostat arm in SOLAR

56

+ TO BE ELIGIBLE FOR PRISM, SOLAR patients on vorinostat must have confirmed progression

+ ADDITIONAL THERAPIES for MF should not be initiated between SOLAR and PRISM

+ INCLUSION CRITERIA: allows patients with nodal progression (N3)

+ EXCLUSION CRITERIA: patients with blood progression (B2)

+ PRISM SCREENING ASSESSMENTS will not need to be repeated if rolling directly from SOLAR

57

For the most up to date study information,

please visit

miRagen.com/clinicians

Cobomarsen as a Therapy for Mycosis Fungoides...+ microRNA-targeted therapy is focused on disease...

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