MRG106-101-001: A Phase I Clinical Trial of Cobomarsen in ... · 4 SAEs in 3 subjects due to disease progression (unrelated to drug) No related grade 3 or grade 4 AEs No significant

Restoring Biological Harmony for Subjects with Debilitating Disease

MRG106-11-101A Phase I Clinical Trial of Cobomarsen in Patients with ATLL

Preliminary Results19th International Congress HTLV 2019

Lima, Peru

DocuSign Envelope ID: AD1F5B7C-C361-4471-BEA5-1859AF679C65

microRNA Therapeutics Regulate Systems Biology to Modify Disease

microRNA-targeted therapy is focused on disease modification by restoring homeostasis to dysregulated processesmicroRNAs regulate complex biological systemsmicroRNA-targeted therapies are intrinsically focused on disease-relevant pathways microRNA therapeutics particularly suited for complex, multigenic disorders


Cobomarsen miR-155-5p Inhibitor

Cobomarsen is a chemically synthesized, phosphorothioateoligonucleotide,14 nucleotides in length, that contains a mixture of deoxyribonucleotides and 2’-O, 4'-C-methylene-β-d-ribonucleotides

Genome-wide expression analysis demonstrates that cobomarsen regulates numerous genes implicated in cell cycle and apoptosis, consistent with the pharmacologic impact on cell survival

A subset of these genes has been identified as potentially translatable biomarkers to monitor cobomarsen activity in clinical samples


ATLL/HTLV-1 Epidemiology

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 subjects is reported from 4.1 to 8.3 months, approximately 10 months for lymphomatous ATLL and 27 to 67 months for chronic unfavorable ATLL

Arch Pathol Lab Med 2014;138-282Blood Advances, 2018 (March27); 2(6)

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The Role of miR-155 in ATLL

miR-155 upregulation has been reported in HTLV-1 cell lines and ex vivo tumor cells from ATLL patients1,2

Increased expression of miR-155-5p enhances the growth of HTLV-1 infected T-cells

NormalNormalNormalAcute PBMCAcute PBMCAcute LNAcute PBMC

miR-155 is upregulated in patient PBMCs or lymph biopsy (n=4)3

1 Bellon et al. Blood. 20092 BeSeto et al. Br J Haematol. 20183 Yeung et al. Cancer Res. 2008


Cobomarsen Reduces Proliferation and Induces Apoptosis in a Dose-Dependent Manner in an ATLL Cell Line

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M R G -1 0 6U n tre a te dUntreated Cobomarsen (0.1-100 μM)

Proliferation Apoptosis

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

Cobomarsen inhibits cellular proliferation and induces apoptosis in vitro

miRagen Generated Data


Phase I Clinical Trial of MRG-106 (Cobomarsen) in ATLL, DLBCL and CLL

Interim Efficacy in ATLL and Therapy Effects of Cobomarsen on Immunologic and Tumor-Associated MarkersData Cutoff: March 15, 2019


Overall Trial Design

Open-label, dose-ranging, multiple dose study of subcutaneous or intravenous administration of cobomarsen in subjects with HTLV-1 associated ATLL, acute, lymphomatous, chronic, and smouldering subtypesSubjects receive 3 loading doses the first week of Cycle 1 followed by weekly dosing until subject becomes intolerant, develops clinically significant side effects, or progressesSafety Review Committee (SRC) comprised of study investigators and sponsor reviews the safety of enrolled subjects to assess dose-limiting toxicities, dose escalation, or dose de-escalationPrimary objective is to determine safety and tolerability of cobomarsen in patients with ATLLSecondary and exploratory outcomes include pharmacokinetics (PK), clinical efficacy and effect on biomarkers of cell proliferation and activation


Subject Characteristics and Disposition

1 PI diagnosis verified by miRagen2 Per miRagen assessment of disease status at screening3 The percentage ATLL 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- CD26-4 Subjects discontinued due to disease progression5 Data from historical control, not screening date6 Subject 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 C3D227 Subject continued to receive AZT/VPA as antiviral therapy while on cobomarsen. Last dose of Alemtuzumab was 15 months (450 days) prior to initiation of cobomarsen

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

Subject ID ATLL Type at Diagnosis1

ATLL Presentation at Screening

Relapse or Partial Remission2

% Abnormal Lymphocytes at Screening3

Lymph Nodes

at Screening CT Scan/PET

Dose (mg)

Days Since

last TX

Duration of Cobomarsen

Tx (Days)Disposition4

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%5 Normal 600 28 136 Discontinued

119-0016 Chronic Unfavorable Chronic unfavorable Partial Remission None Abnormal 600 4507 274 Ongoing

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

102-012/102-015 Acute

Lymphomatous transformation, mostly skin

Relapsing9% 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


Safety Summary of Cobomarsen in ATLL Cohort

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


Case Study in Acute ATLL Subject 101-008 in Partial Remission

Diagnosed in Dec 2016 with acute ATLLRelapsed after treatment with zidovudine, interferon alfa-2b, lenalidomide and EPOCH chemotherapyCobomarsen treatment was initiated on Nov 2017; cobomarsen monotherapy resulted in stable peripheral WBC counts for over 16 monthsCobomarsen treatment resulted in normalization of enlarged lymph node after chemotherapy (1.0 to 0.8 cm) as measured by CT scan (Oct 2017 compared to Jan 2018) that remain normal as of last imaging in Nov 2018 Subject remains on treatment and has completed Cycle 18, missing only 1 dose, due to sciatic pain (Cycle 4 Day 15)

Graphical representation of the absolute WBC and abnormal T cell counts (CD4+ CD7-CD25+ CD26-) for subject 101-008 since diagnosis in relation to treatment course.

1 2 /23 /1

64 /1

2 /17

7 /19 /1

78 /8

/17

8 /22 /1

79 /8

/17

9 /25 /1

71 0 /1

6 /17

1 1 /6/1

71 1 /2

9 /17

1 2 /28 /1

71 /3

1 /18

3 /1/1

84 /1

/18

5 /9/1

87 /5

/18

8 /22 /1

81 0 /1

0 /18

1 1 /21 /1

81 /2

3 /19

3 /20 /1

9

0

3

6

9

1 2

1 5

1 8

2 1

2 4

2 7

3 0

3 3

Cel

lsx

10^

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 dd o se


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

Representative Subject with Acute ATLL (101-008)

7%

Flow cytometric assessment of A) activation, HLA-DR and CD69, and B) proliferation, Ki-67, marker expression in circulating ATL cells for subject 101-008 over the course of cobomarsen treatment. MFI – median fluorescence intensity C) The percentage of ATL cells positive for each biomarker and D) the fold change from baseline (C1D1) is graphed over the course of cobomarsen treatment.

Act

ivat

ion

Mar

kers

Prol

ifera

tion

35% 25% 5% 5% 7%

CD69

C1D1

HLA-DR

C1D5 C1D27 C2D22 C6D22 C14D22

SSC

Ki-67

SSC

50%1179

71%2880

67%2148

56%1264

53%1129

50%1283

PercentMFI

19%3436

13%2105

8%1885

8%1900

8%2011

PercentMFI

7%1810

C1D1 C1D5 C1D27 C2D22 C6D22 C14D22

SSC

Percent

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

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

A

B

C 1D 1C 1D 5C 1D 2 7C 2D 2 2C 4D 2 2C 6D 2 2C 8D 2 2C 1 0D 2 2C 1 2D 2 2C 1 4D 2 2C 1 6D 2 2

0

2 0

4 0

6 0

8 01 0 1 -0 0 8

%C

ells

Po

siti

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rM

arke

r

% K i-6 7 +

% H L A -D R +% C D 6 9 +


0 .0

0 .5

1 .0

1 .51 0 1 -0 0 8

Fo

ldC

ha

ng

efr

om

Ba

se

lin

e

K i-6 7H L A -D RC D 6 9

C

D


1 /16 /1

8

4 /25 /1

8

7 /2/1

89 /1

7 /18

9 /27 /1

81 0 /1

8 /18

1 1 /8/1

81 1 /2

9 /18

1 2 /20 /1

8

1 /24 /1

9

2 /21 /1

9

3 /14 /1

9

0

1

4

6

8

1 0

1 2

1 4

1 6

ce

lls

x1

0^

3/u

L


W B C

F irs tc o b o m a rs e n

d o s e

C H O E P

m is s e dd o se

2 m is s e dd o s e s

m is s e dd o se

Case Study in Acute ATLL Subject 101-012 in Partial RemissionDiagnosed in December 2017 with ATLL, lymphomatous sub-type

Subject received 6 cycles of CHOEP therapy from January to May 2018 and had a complete response based on CT scan but persistent peripheral ATLL cells by flow cytometry

CT scan at screening was normal

Cobomarsen first dose on September 2018

Subject has completed Cycle 6 and continues to receive treatment; Subject has missed 4 doses (shown in graph)

CT scans have remained normal over the course of treatment (last scan performed in January 2019)

LDH values for this subject were all within normal range


Case Study in Lymphomatous ATLL Subject 101-010 in Partial RemissionDiagnosed in April 2017 with lymphomatous ATLLExtensive and bulky lymphadenopathy on initial CT scan was reduced by 6 cycles of CHOEP chemotherapy completed in June 2017Restaging PET scan showed resolution of adenopathy but with increased splenic uptake; Flow cytometry at the end of treatment showed 20% ATLL cells in peripheral bloodAfter starting cobomarsen in Dec 2017, the stable lymph node size and peripheral blood tumor cell counts have been maintained for 15 months; RecentCT scan in November 2018 is now normal (resolution of splenic lesion)Subject has completed Cycle 16 and continues treatmentSubject missed 2 doses of cobomarsen (Cycle 4 Day 1 and Cycle 5 Day 8)Rhinovirus infection in November 2018 showed a normal immune response as an increase in neutrophil count

Graphical representation of the absolute WBC and abnormal T cell counts (CD4+ CD7- CD25+ CD26-) for subject 101-010 since diagnosis in relation to treatment course.

6 /15 /1

76 /2

6 /17

9 /14 /1

71 0 /2

3 /17

1 1 /8/1

71 2 /1

1 /17

1 2 /14 /1

71 2 /2

8 /17

1 /10 /1

81 /2

4 /18

2 /7/1

82 /2

1 /18

3 /14 /1

83 /2

8 /18

4 /18 /1

85 /9

/18

6 /6/1

87 /5

/18

8 /1/1

88 /2

9 /18

9 /26 /1

81 0 /1

7 /18

1 1 /7/1

81 1 /2

8 /18

1 2 /12 /1

81 /2

/19

1 /23 /1

92 /6

/19

2 /27 /1

9

0

1

2

3

6

9

1 2

1 5

Ce

lls

x1

0^

3/

L


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 tod 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



0

1 0

2 0

3 0

4 0

5 0

1 0 1 -0 1 0

%C

ells

Po

siti

vefo

rM

arke

r % C D 6 9 +

% K i-6 7 +

% H L A -D R +M is s e dC 4 D 1D o s e

% c P A R P +

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

Flow cytometric assessment of: A) activation, HLA-DR and CD69; B) proliferation, Ki-67; C) apoptosis, cPARP, marker expression in circulating ATL cells for subject 101-010 (MFI – median fluorescent intensity); D) The percentage of ATL cells positive for each biomarker; and E) the fold change from baseline (C1D1) is graphed over the course of cobomarsen treatment.

SSC

CD69

C1D1

HLA-DR

C1D5 C2D22 C4D22 C6D22

SSC

Act

ivat

ion

Mar

kers

Prol

ifera

tion

Ki-67

SSC

33%1539

27%1115

17%1076

16%854

8%814

PercentMFI

5%1346

1%1252

2%1375

1%1281

2%1498

PercentMFI

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-

SSC

Apo

ptos

is

cPARP

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

C4D1 dose missed

11%

17%

A

B

C

D

E


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2

3

1 0 1 -0 1 0

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Ba

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M is s e dC 4 D 1D o s e c P A R P


Case Study in Chronic Unfavorable (Residual Nodal Disease at Screening) ATLL Subject 119-001 in Partial Remission

Diagnosed in June 2013 with ATLL, chronic unfavorable sub-type, with aggressive disease involving skin, blood and lymph nodes Failed and relapsed after many therapies and was finally stabilized on Alemtuzuma; Subject was switched to, and maintained on, AZT/VPA and remained stable with residual abnormal nodes for 15 monthsIn first 10 months of cobomarsen treatment there were no opportunistic infections; CT scans showed stable disease with mesenteric nodes clearly decreasing in size; LDH decreased and remains in normal rangeContinues to receive treatment and has completed Cycle 10

A) The percent change in size of 4 lymph nodes over the course of Cobomarsen treatment for subject 119-001. The size refers to area (width x length) as measured by CT scans.

B) The concentrations of LDH in blood over the course of treatment.

A

6/6/1

86 /2

9 /18

7 /14 /1

87 /3

1 /18

8 /13 /1

89 /4

/18

1 0 /8/1

81 1 /8

/18

1 1 /21 /1

81 2 /3

/18

1 2 /17 /1

81 /7

/19

2 /7/1

93 /5

/19

0

5 0

1 0 0

1 5 0

% C h a n g e in L y m p h N o d e S iz e

Pe

rce

nt

of

Ba

se

lin

eA

rea

(Wx

L)

E x te rn a l I lia c L N

A x illa ry L N

In g u in a l L N

M e s e n te ric L N Missed dose

6 /6/1

86 /2

2 /18

7 /11 /1

88 /6

/18

1 0 /8/1

81 1 /1

2 /18

1 2 /3/1

81 /7

/19

1 /29 /1

92 /1

8 /19

0

5 0

1 0 0

1 5 0

2 0 0

2 5 0

3 0 0

3 5 0

4 0 0L D H

LD

H(U

/L)

F irs td o s e

B


1 0 /30 /1

71 1 /8

/17

1 1 /22 /1

71 2 /1

3 /17

1 /3/1

81 /2

4 /18

2 /14 /1

83 /8

/18

3 /28 /1

84 /1

8 /18

5 /9/1

86 /8

/18

7 /1/1

89 /5

/18

1 0 /17 /1

81 1 /7

/18

1 1 /28 /1

81 2 /2

6 /18

1 /16 /1

92 /6

/19

2 /27 /1

93 /2

0 /19

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

Cx

10

^6/

Lo

rH

bg

/d

LH c tH 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 and Does Not Inhibit B Cell Maturation In 4 Subjects

A

B

C

A) Hemoglobin (Hb, g/dL), Hematocrit (Hct, percentage), and Red Blood Cell (RBC, cells x 10^6/μL) lab values are shown for subject 101-008 who underwent recent (21 day washout period) EPOCH chemotherapy. Flow cytometric assessments for B) CD8 T cells, NK cells, and B cells, reported as number of cells per μL for subject 101-008.

1 0 /30 /1

71 1 /8

/17

1 1 /22 /1

71 2 /1

3 /17

1 /3/1

81 /2

4 /18

2 /14 /1

83 /8

/18

3 /28 /1

84 /1

8 /18

5 /9/1

86 /8

/18

7 /1/1

89 /5

/18

1 0 /17 /1

81 1 /7

/18

1 1 /28 /1

81 2 /2

6 /18

1 /16 /1

92 /6

/19

2 /27 /1

93 /2

0 /19

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

Bce

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mb

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of

CD

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L

N K c e lls

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B c e lls


d o se

101-008

101-008

Subject 101-008 underwent EPOCH chemotherapy 21 days prior to cobomarsen treatmentOver the first cycle of cobomarsen treatment, immature B cells populate the periphery as transitional B cells and undergo maturation into mature naïve B cells over the next few cycles of cobomarsen treatmentEvidence of B cell maturation in 3 other subjects

C) B cell maturation is shown as %mature B cell (CD10-CD27-IgD+) and %transitional B cells (CD10+CD38++) of CD19+ cells over the course of treatment

M a tu re N a iv e

T ra n s itio n a l

C 1D 1

C 1D 5

C 1D 2 7

C 2D 2 2

C 4D 2 2

C 6D 2 2

C 8D 2 2C 1 0D 2 2C 1 2D 2 2C 1 4D 2 2C 1 6D 2 2

0

2 0

4 0

6 0

8 0

1 0 0 1 0 1 -0 0 8

%o

fC

D1

9+

Bc

ell

s


LDH Values in ATLL Subjects in Partial Remission and in Relapsing Subjects Subjects in Partial Remission Still on Study

11 /12 /1

71 2 /2

0 /17

1 /31 /1

83 /1

1 /18

4 /14 /1

86 /2

0 /18

8 /22 /1

81 0 /2

1 /18

1 2 /26 /1

83 /6

/19

0

5 0

1 0 0

1 5 0

2 0 0

2 5 01 0 1 -0 0 8

LD

HU

/L

F irs td o se

9 /14 /1

71 1 /2

9 /17

1 2 /28 /1

71 /3

1 /18

3 /14 /1

84 /2

5 /18

7 /5/1

89 /1

2 /18

1 1 /7/1

81 2 /2

6 /18

2 /6/1

9

0

5 0

1 0 0

1 5 0

2 0 0

2 5 01 0 1 -0 1 0

LD

HU

/L

F irs t d o s e

9 /17 /1

89 /2

0 /18

1 0 /4/1

81 0 /1

8 /18

1 1 /1/1

81 1 /1

5 /18

1 1 /29 /1

81 2 /1

3 /18

1 /11 /1

91 /2

4 /19

2 /14 /1

9

0

5 0

1 0 0

1 5 0

2 0 0

2 5 01 0 1 -0 1 2

LD

HU

/L

F irs td o se

7 /18 /1

89 /2

4 /18

9 /26 /1

81 0 /4

/18

1 0 /17 /1

81 1 /1

/18

1 1 /15 /1

81 1 /2

9 /18

1 2 /13 /1

81 2 /2

8 /18

1 /10 /1

91 /2

4 /19

2 /11 /1

9

0

5 0

1 0 0

1 5 0

2 0 0

2 5 0

3 0 0

3 5 0

4 0 01 0 1 -0 1 4

LD

HU

/L

F irs td o se

E O S

5 /18 /1

85 /2

1 /18

5 /23 /1

85 /2

4 /18

5 /25 /1

85 /3

1 /18

6 /7/1

86 /1

2 /18

6 /26 /1

86 /2

8 /18

0

1 0 0 0

2 0 0 0

3 0 0 0

4 0 0 0

5 0 0 01 0 1 -0 1 1

LD

HU

/L

L a s tc o b o m a rs e n

d o s e

s ta r t c h e m o

F ir s tc o b o m a rs e n

d o s e

1 2 /6/1

71 2 /2

7 /17

1 /2/1

81 /1

8 /18

1 /29 /1

82 /1

2 /18

3 /14 /1

84 /5

/18

7 /18 /1

88 /3

/18

8 /13 /1

88 /2

7 /18

9 /12 /1

81 0 /1

0 /18

0

5 0

1 0 0

1 5 0

2 0 0

2 5 0

3 0 0

3 5 0

4 0 0

4 5 01 0 2 -0 1 2 /1 0 2 -0 1 5

LD

HU

/L

F ir s td o s e

1 0 2 - 0 1 2

E O SF ir s td o s e

1 0 2 - 0 1 5

E O S

1 0 2 - 0 1 5

1 0 2 - 0 1 2

o f f d r u g

9 /24 /1

81 0 /1

/18

1 0 /3/1

81 0 /5

/18

1 0 /10 /1

81 0 /1

7 /18

1 0 /24 /1

81 1 /1

6 /18

0

5 0

1 0 0

1 5 0

2 0 0

2 5 0

3 0 0

3 5 01 1 8 -0 0 1

LD

HU

/L

F irs td o se

E O S

6 /6/1

86 /2

2 /18

7 /11 /1

88 /6

/18

1 0 /8/1

81 1 /1

2 /18

1 2 /3/1

81 /7

/19

1 /29 /1

92 /1

8 /19

0

5 0

1 0 0

1 5 0

2 0 0

2 5 0

3 0 0

3 5 0

4 0 01 1 9 -0 0 1

LD

H(U

/L)

F irs td o se

1 /15 /1

91 /2

5 /19

1 /28 /1

91 /3

0 /19

2 /1/1

92 /7

/19

2 /14 /1

93 /1

1 /19

0

1 0 0

2 0 0

3 0 0

4 0 0

5 0 0

6 0 0

7 0 0

8 0 01 1 9 -0 0 2

LD

HU

/L

F irs td o se

L a std o se

E O S

Subjects Off Study

Relapsing Subjects with Primarily Skin DiseaseRelapsing SubjectsSubject in Partial Remission


C 1D 1C 1D 5C 1D 1 2C 1D 2 7C 2D 2 2C 3D 2 2C 4D 2 2C 5D 2 2C 6D 2 2C 7D 2 2C 8D 2 2C 9D 2 2C 1 0D 2 2C 1 1D 2 2C 1 2D 2 2C 1 3D 2 2C 1 4D 2 2C 1 5D 2 2C 1 6D 2 2

0 .0

0 .5

1 .0

1 .5

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

Av

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ge

Fo

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ha

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f%

Ce

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Po

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fro

mB

as

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ne % C D 6 9 +

% H L A -D R +

Cobomarsen Decreases the Activation and Proliferation Status of Circulating Tumor Cells for ATLL Subjects in Partial Remission Who Remain on Study

Average Fold Change in Biomarkers for 4 ATLL Subjects in Partial Remission

Average fold change (±SEM) from the pretreatment time point (C1D1) in the percentage of ATL tumor cells expressing A) HLA-DR and CD69 activation and B) Ki-67 proliferation markers from all evaluable ATLL subjects over multiple cycles of cobomarsentreatment. The number of subjects assessed is indicated as n on the x axis. Fold change for subject 119-001 could not be assessed due to a missing baseline (C1D1) sample.

n=4 n=4 n=3 n=4 n=4 n=3 n=2 n=2n=2

C 1D 1C 1D 5C 1D 1 2C 1D 2 7C 2D 2 2C 3D 2 2C 4D 2 2C 5D 2 2C 6D 2 2C 7D 2 2C 8D 2 2C 9D 2 2C 1 0D 2 2C 1 1D 2 2C 1 2D 2 2C 1 3D 2 2C 1 4D 2 2C 1 5D 2 2C 1 6D 2 2

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

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ne % K i-6 7 +

A B

Subjects in Remission101-008101-010101-012101-014 – off study119-001

n=2 n=4 n=4 n=3 n=4 n=4 n=3 n=2 n=2n=2 n=2


Conclusions

Cobomarsen treatment resulted in durable clinical stabilization of all subjects with acute, lymphomatous and unfavorable chronic ATLL after partial remission for up to 16 months (median= 9 months); Four of 5 subjects continue dosing on study

Biomarkers of cell activation and proliferation decrease with cobomarsen treatment underscoring the biological effect of the drug in supporting the clinical stabilization in subjects in partial remission

Safety and tolerability profile appears benign, with no deaths, DLTs, related SAEs, related Grade 3 or Grade 4 AEs, hematological events, or discontinuation from trial due to related AEs

The preliminary results are encouraging and supports trial continuation to explore cobomarsen for the treatment of ATLL subjects


Francine Foss, MD – Smilow Cancer Hospital at Yale-New HavenJuan Carlos Ramos, MD – University of Miami Sylvester Comprehensive Cancer CenterChristiane Querfeld, MD – City of HopeJasmine Zain, MD – City of HopeAlison Moskowitz, MD – Memorial Sloan Kettering Cancer CenterAdrienne A. Phillips, MD – Weill Cornell Medicine

Phase I Investigators (USA)

Study Sponsored bymiRagen Therapeutics, Inc


Documents

MRG106-101-001: A Phase I Clinical Trial of Cobomarsen in ... · 4 SAEs in 3 subjects due to disease progression (unrelated to drug) No related grade 3 or grade 4 AEs No significant