cobomarsen, an emerging potential treatment for patients ......101-011 lymphomatous –in remission...

Pg. 1

Restoring Biological Harmony for Patients with Debilitating DiseaseRestoring Biological Harmony for Patients with Debilitating Disease

Cobomarsen, an emerging potential treatment for patients with miR-155 elevated cancersT-cell Lymphoma Forum

January 2019

Pg. 2

microRNA Therapeutics Regulate Systems Biology to Modify Disease

▪ microRNA-targeted therapy is focused on disease modification by restoring homeostasis to dysregulated processes

▪ microRNAs regulate complex biological systems

▪ microRNA-targeted therapies are intrinsically focused on disease-relevant pathways

▪ microRNA therapeutics particularly suited for complex, multigenic disorders

Pg. 3

miR-155

PU.1CEBPb SOCS SHIP-1

Cytokines

T-cell activation

PI3K/AKT/MAPK

Proliferation

Inflammation

M1M2

Jarid2

Leukemic

transformation

Myeloid

differentiation

Wee1

DNA repair

Inflammation Cancer

B-cell and DC

activation

IL-6, TNFa

Proliferation

Hematopoietic

progenitor

self-renewal

PI3K/AKT/MAPK

Proliferation

miR-155 is a Master Regulator of Inflammation and Oncology

Genomic

Instability

Increased activity

Decreased activity

Apoptosis

Apoptosis

EMT

Invasion/

metastasis

NF-kB

NF-kB

Leukemic

transformation

Pg. 4

Cobomarsen (MRG-106), a miR-155-5p Inhibitor, Regulates Genes Implicated in T Cell Regulation, Cell Cycle and Apoptosis

▪ Cobomarsen is a chemically synthesized, chimeric phosphorothioate oligonucleotide, 14 nucleotides in length

▪ Genome-wide expression analysis demonstrates that cobomarsen regulates numerous genes implicated in T cell regulation and cell cycle and apoptosis,.

▪ A subset of these genes has been identified monitor cobomarsen activity in clinical samples.

CD4+ T cells:Cobomarsen vs PBS

GenesActivation of immune response

Inflammatory response

T cell receptor signaling pathway

2Coagulation, response to wounding,

hemostasis

SMAD3, TGFBR2, PIK3R5,

LCK, VAV1, IL10

Adaptive immune response

Regulation of T cell activation

T cell costimulation, lymphocyte costimulation

4 Positive regulation of interleukin-6 production IL6R, IL10, IL1R, IL17A

5 Cytokine-mediated signaling pathway

STAT2, TICAM2, IL12RB2,

CXCR5, MAP3K5, IL1R,

CD44, IL17A

1

3

DOWN regulated gene culstersCXCR5, ICAM3, CD44, LCK,

IL17A, IL17RA, IL10, IL6R,

IL1R

CD28, IL17A, PI3KR5,

ICOS, IL6R, IL10, CXCR5,

LCK, VAV1

Genes

1Ribonucleotide binding, ATP binding, RNA

binding, nucleic acid binding

RPF2, CDK7, NARS,

ALKBH5

Apoptotic process, Programmed cell death

Apoptotic signaling pathway

Immune response

Cytokine-mediated signaling pathway3

2

UP regulated gene culsters

CASP3, TNFRSF9, BNIP3L,

PPP3CC, MAP3K7

IL5, IL4, IL13, GATA3,

CCR7, VEGFA, SMAD7

Figure 1. Gene regulation by cobomarsen in activated, primary CD4+ T cells isolated from healthy donors.

Pg. 5

Link Between miR-155 and Cancer

▪ The host gene for miR-155 (BIC) was identified along with myc as a proto-oncogene for virally-induced B-cell lymphomas

▪ miR-155 and its precursor BIC are highly expressed in hematologic malignancies and solid tumors

▪ Elevated miR-155 expression correlates with poor prognosis

▪ miR-155 is regulated by NF-kB, PI3K/AKT, and JAK/STAT, and functions in a feedback loop with these survival pathways

▪ miR-155 promotes chemoresistance in cancer cell lines

▪ Expression of miR-155 is sufficient to drive B cell expansion and formation of B cell lymphoma

▪ Therapeutic inhibition of miR-155 reduces proliferation and increases apoptosis in hematologic and non-hematologic cancer cell lines

Pg. 6

Increased miR-155 is Implicated in Multiple Oncology Indications

Hematologic

▪ Cutaneous T-cell lymphoma (CTCL)

▪ Acute myelogenous leukemia (AML)

▪ B-cell lymphoma (DLBCL)

▪ Chronic lymphocytic leukemia (CLL)

▪ Adult T-cell leukemia/lymphoma (ATLL)

▪ Peripheral T-cell lymphoma (PTCL)

▪ Burkitt’s lymphoma

▪ Waldenstrom macroglobulinemia (WM)

Non-Hematologic

▪ Non-small cell lung cancer

▪ Glioblastoma

▪ Triple negative breast cancer

▪ Melanoma

▪ Colorectal cancer

▪ Gastric cancer

▪ Pancreatic cancer

▪ Gall bladder cancer

▪ Head and neck squamous cell carcinoma

▪ Neurofibromatosis

Pg. 7

miR-155 is Up-regulated in Multiple Hematological Cancer Cell Lines

n o r m

C D1 9 +

B c e ll

n o r m

C D4 +

T c e ll

KM -

H2

L 1 2 3 6 O c i-

L y 3

J ijo y e M y -

L a

HH M J Hu T 1 0 2

0

5 0 0 0 0

1 0 0 0 0 0

1 5 0 0 0 0

2 0 0 0 0 0

A b s o lu te m iR -1 5 5 E x p re s s io n

Co

pie

s o

f m

iR-1

55

pe

r c

ell

ATLL

MF

Burkitt

lymphoma

ABC-

DLBCLHodgkin

lymphoma

Pg. 8

0 2 4 6 8 1 0 1 2

0

2 0 0

4 0 0

6 0 0

8 0 0

H u T 1 0 2 a p o to s is p a th w a y a c t iv a tio n

C a s p a s e 3 /7 a c t iv ity

D a y s

% c

ha

ng

e c

om

pa

re

d t

o u

ntr

ea

ted

at

da

y 1

B e x a ro te n e

M 1 1 6 6 7

U n tre a te dUntreated

Bexarotene (10uM)

Cobomarsen (10uM)

miR-155 is Upregulated in Malignant T-cell lines and Inhibition Affects Cell Growth and Apoptosis

▪ Effects on cell proliferation similar to bexarotene

▪ Unlike bexarotene, cobomarsen mechanism enhances apoptosis in cell lines

▪ Different mechanisms suggests potential for additivity/synergy with other therapeutics for CTCL

Pg. 9

Cobomarsen PK and Preclinical Safety

▪ Cobomarsen displays linear kinetics, with dose proportional increases in Cmax and AUC across dose groups.

▪ Cobomarsen is well tolerated in non-human primates up to 30 mg/kg administered by IV 2hr-infusion or as a SC or IV bolus injection

▪ No toxicity related to

TLR activation

Liver Function

Complement

Platelet function

Mild reversible decrease in renal function in rodents with good margin of safety

Pg. 10

Cobomarsen Clinical Program in Hematological Malignancies

Ph 2 CTCL

Dose, Schedule Optimization and Response Durability in CTCL

Par

alle

l In

dic

atio

nEx

pan

sio

n in

Ph

1Ph 2 in NHL / Leukemia

mPoC cPoC

ATLL

DLBCL

Ph 1 CTCL

CLL

FutilityAnalysis

CTCLMycosis Fungoides

miR-155-high Non-HodgkinsLymphoma (NHL)/Leukemia

Pg. 11


Cobomarsen in CTCL

Pg. 12

miR-155 Detection Decreases in Lesion Biopsies After Cobomarsen Treatment

▪ Pretreatment miR-155-5p expression levels quantitated by qPCR were elevated in the majority of CTCL patients compared to normal skin

▪ Highest levels of miR-155 were found in tumor lesions that had the highest density of neoplastic cells

▪ Intralesional and systemic cobomarsen treatment led to loss of miR-155 detection in the majority of subjects that was maintained up to 36 days post the last dose (EOS visit)

Figure 3. miR-155-5p copy number in lesion biopsies taken before and after cobomarsen treatment from CTCL subjects enrolled in Parts A and B compared to normal skin biopsies from healthy donors

Pg. 13

Thirty-three of Thirty-six Subjects (92%) Treated Systemically with Cobomarsen Have Shown mSWAT Score Improvement

• mSWAT score represents best score achieved while on study for 36 patients who had evaluable mSWAT scores as of the data cutoff (16OCT2018).

• Duration of response (days) as of 16OCT2018 for each evaluable patient achieving a 50% reduction in mSWATscore is shown in individual bar.

• NE = Not Evaluable; patients not allowed to continue on trial as per protocol or lost to follow up.

Pg. 14

Five of Eight (63%) Subjects Treated with Cobomarsen Administered as a 300 mg IV-infusion Achieved a PR. 50% of these reached ORR4

Subject 112-001: 300 mg IV-inf

ORR4

Pg. 15

Cobomarsen SOLAR Phase 2 Clinical Trial Initiated in 4Q18 A Randomized, Parallel, Open Label, Active Control, Global Trial in Patients with Stage Ib-III Mycosis Fungoides

Open Label; Randomize to:

cobomarsen IV Infusionvs.

vorinostat

Randomize

Cobomarsen (300mg IV Infusion anticipated)

n=~65 subjects

vorinostatn=~65 subjects

Follow until progression

FutilityAnalysis

Follow until progression

PRISM

(Open label extension)

Primary Endpoint• Overall Response Rate of four months (ORR4) using Global

Response Criteria

Key Secondary Endpoint• Progression-free survival

Additional Secondary Endpoint• Patient reported outcomes

• Skindex-29, pruritus, pain

Key Inclusion Criteria

▪ Stage Ib-III

▪ Must have received at least one prior therapy for CTCL

(per NCCN guidelines for generalized skin involvement)

▪ mSWAT score ≥ 10

Pg. 16

CTCL: Adverse Events

▪No serious AEs have been attributed to cobomarsen

▪Eight serious adverse events (SAEs) have been reported in 4 subjects These SAEs were either related to underlying disease (known complications of the CTCL patient population) or related to other comorbidities in these subjects, and unrelated to study treatment

▪Thirty-nine subjects (90.7%) have reported at least 1 non-serious AE, for a total of 307 unique AEs

▪The maximum severity of AEs has been Grade 1/Grade 2 (275 of 307 events [89.6%]) or Grade 3/Grade 4 (32 of 307 events [10.4%])

▪Of the 32 Grade 3/Grade 4 events,14 events in 6 subjects (all in Part B) were assessed to be related to study drug

One subject (101-003) had tumor flare followed by erythema, rash, leukopenia, lymphopenia and hyperuricemia (all within 2 weeks, reported as 6 separate AEs)

In 5 subjects, the following were reported:▪ 102-008: Flare-erythema and Tumor pain

▪ 105-004: Tumor Flare, Neutropenia, Leukopenia

▪ 3 other subjects (each in 1 subject): Intermittent ANC Decreased, hypokalemia, Intermittent Neutropenia

Pg. 17


Cobomarsen in ATLL

Pg. 18

Patient Characteristics and Disposition

Subject ID Presentation at Screening

Blood

Involvement

(% tumor cells of

WBC1)

# of Prior

Therapies

Days Since

Last Tx and

Start of

Cobomarsen

Cobomarsen

Treatment

Duration (days)

Disposition

(reason for

discontinuation)

101-008

101-012

102-012 /

102-0152

Acute – in remission

Acute – in remission

Relapsing – primarily skin disease

9%

10%

9%

4

1

10

21

108

21 / 30

401 days

87 days

91 / 42 days2

Ongoing

Ongoing

Discontinued

(progression)

101-010

101-014

101-011

Lymphomatous – in remission

Lymphomatous – in remission

Lymphomatous – relapsing

14%

15% (7/9/18)

Data not collected

1

2

7

46

28

219

366 days

80 days

9 days

Ongoing

Ongoing

Discontinued

(progression)

119-0013

118-001

Lymphomatous – stable disease

Relapsing – primarily skin disease

No abnormal cells

Data not collected

10

5

NA4

31

161 days

23 days

Ongoing

Discontinued

(progression)

1 The percentage ATL tumor cells of WBCs at screening prior to cobomarsen treatment. Any numbers reported were determined by flow cytometry performed locally at the

clinical site and tumor cells were defined phenotypically as CD3+ CD4+ CD8- CD25+ CD7- CD26-2 Patient 102-012 was re-enrolled on study as 102-0153 Patient 119-001 had extensive skin, lymph and blood involvement at diagnosis. Abnormal cells were not quantified by flow cytometry, but visual blood smear only on

C3D224 Patient continued to receive AZT/VPA as antiviral therapy while on cobomarsen. Last dose of alemtuzimab was 15 months (450 days) prior to initiation of cobomarsen

Subject baseline disease characteristics, duration of cobomarsen treatment, and disposition.

Data cut off date 13DEC2018

Pg. 19

Common Acute ATLL Response to Standard Therapy

Yamada et al., Cancer 1991, 67:2605-2609

2/8

/17

4/1

2/1

7

6/7

/17

7/1

9/1

7

7/3

1/1

7

8/1

0/1

7

8/1

7/1

7

9/1

/17

9/1

1/1

7

9/2

3/1

7

10/9

/17

10/1

6/1

7

11/6

/17

11/2

2/1

7

12/1

3/1

7

1/1

7/1

8

2/2

1/1

8

3/2

1/1

8

4/2

5/1

8

5/3

0/1

8

7/5

/18

8/8

/18

9/2

0/1

8

10/2

5/1

8

11/2

8/1

8

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

6/1

5/1

7

6/2

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7

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/17

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/17

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/17

11/2

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7

12/1

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1/3

/18

1/1

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8

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8

2/2

8/1

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8

4/4

/18

4/2

5/1

8

5/2

3/1

8

6/2

0/1

8

7/1

8/1

8

8/1

5/1

8

9/1

2/1

8

10/1

0/1

8

10/2

4/1

8

11/7

/18

11/2

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8

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/18

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2

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lls

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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

1/1

6/1

8

4/4

/18

6/1

1/1

8

7/2

/18

9/5

/18

9/1

9/1

8

9/2

7/1

8

10/1

0/1

8

10/2

5/1

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11/8

/18

11/2

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8

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1

4

6

8

1 0

1 2

1 4

1 6

ce

lls

x 1

0^

3/u

L


W B C


C H O E P

Acute ATLL Subject 101-012Acute ATLL Patient 101-008

Lymphomatous ATLL 101-010

7/9

/18

7/1

8/1

8

9/1

0/1

8

9/2

4/1

8

9/2

5/1

8

9/2

6/1

8

9/2

7/1

8

10/4

/18

10/1

1/1

8

10/1

7/1

8

10/2

5/1

8

11/1

/18

11/8

/18

11/1

5/1

8

11/2

1/1

8

11/2

9/1

8

0

1

2

3

4

5

6

7

8

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lls

x 1

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3 /

L



W B C

Lymphomatous ATLL Subject 101-014Diagnosed on DEC2017 Diagnosed on 21APR2017

Diagnosed 14DEC2016 ▪ Diagnosed on 18DEC2017

4/4 Patients with Aggressive Disease Treated with Cobomarsen Directly After ChemotherapyHave Significantly Prolonged Response Compared to Chemotherapy Alone

▪ Patients all feel well without typical ATLL signs

and symptoms

▪ Response ranges from 3 months to one year

after cobomarsen initiation as of data cut off

▪ Bone marrows restored

▪ No drug related Grade 3, 4 AEs or SAEs

▪ No new opportunistic infections reported

Last CHOP 6/16/18

Pg. 20

Cobomarsen Decreases Activation and Proliferation Status of Circulating Tumor Cells in ATLL Subjects

C1D1

Ki67

C1D5 C1D27 C2D22 C4D22

35% 25% 5% 5% 8%

C6D22

7%

SSC

FSC

CD69

19%3441

13%2112

8%1892

8%1913

9%2120

PercentMFI

8%2035

C1D1

HLA-DR

C1D5 C1D27 C2D22 C4D22

61%3667

56%2845

43%1772

40%1649

36%1852

PercentMFI

C6D22

39%1782

FSC

Activa

tio

n M

ark

ers

Pro

life

ration

C1D

1

C1D

5

C1D

27

C2D

22

C3D

22

C4D

22

C5D

22

C6D

22

C7D

22

C8D

22

C9D

22

C10D

22

C11D

22

C12D

22

0 .0

0 .5

1 .0

1 .5

2 .0

B io m a rk e r E x p re s s io n

o n 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 +

% K i-6 7 +

n=7 n=7 n=3 n=3 n=2 n=2 n=2 n=1

Representative patient with Acute ATLL (101-008)

Average (SD) change in biomarkers in 7 ATLL subjects

Pg. 21

Cobomarsen Did Not Inhibit Normal Bone Marrow Recovery of Leukemic ATLL Patient When Administered Starting 21 Days After Last EPOCH Chemotherapy Dose

B cells

Maturing

Naive B

cells

Non-

Plasmablasts

C1D1 C1D5 C1D27 C2D22

Immature B cells from bone marrow populate periphery and mature normally during cobomarsen therapy

11/6

/17

11/9

/17

11/2

2/1

7

12/6

/17

12/2

0/1

7

1/3

/18

1/1

7/1

8

1/3

1/1

8

2/1

4/1

8

2/2

8/1

8

3/1

4/1

8

3/2

8/1

8

4/1

1/1

8

4/2

5/1

8

5/9

/18

5/3

0/1

8

6/1

3/1

8

7/1

/18

8/8

/18

10/3

/18

10/1

7/1

8

10/3

1/1

8

11/1

4/1

8

11/2

8/1

8

2 5

3 0

3 5

4 0

4 5

5 0

0

3

6

9

1 2

1 5

1 8

% H

ct

RB

C x

10

^6

/

L o

r Hb

g / d

L

H c t

H b

R B C


11/6

/17

11/9

/17

11/2

2/1

7

12/6

/17

12/2

0/1

7

1/3

/18

1/1

7/1

8

1/3

1/1

8

2/1

4/1

8

2/2

8/1

8

3/1

4/1

8

3/2

8/1

8

4/1

1/1

8

4/2

5/1

8

5/9

/18

5/3

0/1

8

6/1

3/1

8

7/1

/18

8/8

/18

10/3

/18

10/1

7/1

8

10/3

1/1

8

11/1

4/1

8

11/2

8/1

8

0

2 0 0

4 0 0

6 0 0

8 0 0

1 0 0 0

1 2 0 0

1 4 0 0

1 6 0 0

0

5 0

1 0 0

1 5 0

2 0 0

2 5 0

3 0 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

Pg. 22


Cobomarsen in DLBCL

Pg. 23

One of Three Relapsing Patients with DLBCL, ABC Subtype has Demonstrated Beneficial Response

▪ mir-155 is documented to be elevated in the ABC subtype

▪ Three patients with ABC have been treated with cobomarsen

▪ All three had relapsed after multiple therapies prior to trial initiation

▪ Two of three progressed while on therapy and cobomarsen discontinued after one cycle or less

▪ One patients demonstrated response in measurable lesions after seven weeks of therapy*

▪ 60 year old female with four year history of DLBCL

▪ Relapsed after multiple regimens

▪ Responded to experimental Pi3K +BTK inhibitor – sponsor discontinued trial and patient relapsed

▪ Disease at initiation and following cobomarsen below:

Patient data courtesy of Dr. L. Pinter-Brown

LesionScreening Measurement

C1D3 C1D10 C1D17 C2D1 C2D15

Size LxW (cm2)

Right Neck 9 11 20 16 4 0

Inguinal Node Not done 9 5 5 23 5

Pg. 24

Conclusions

▪ miR-155 associated with multiple hematologic and non-hematologic malignancies

▪ miR-155 regulated genes are essential for malignant processes

▪ Cobomarsen, and antimiR to miR-155 has shown evidence of activity and clinical benefit

in early studies of three hematologic cancers

▪ CTCL

▪ ATLL

▪ DLBCL

▪ Cobomarsen has demonstrated good safety and tolerability to date

▪ Continued study of cobomarsen in these and other miR-155 upregulated malignancies is

clearly warranted.

cobomarsen, an emerging potential treatment for patients ......101-011 lymphomatous –in remission...

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