cobomarsen, an emerging potential treatment for patients ... · implicated in t cell regulation,...
TRANSCRIPT
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
Restoring Biological Harmony for Patients with Debilitating DiseaseRestoring Biological Harmony for Patients with Debilitating Disease
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
Restoring Biological Harmony for Patients with Debilitating DiseaseRestoring Biological Harmony for Patients with Debilitating Disease
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
6/1
7
9/1
/17
10/4
/17
11/1
/17
11/2
9/1
7
12/1
3/1
7
12/2
1/1
7
1/3
/18
1/1
7/1
8
1/3
1/1
8
2/1
4/1
8
2/2
8/1
8
3/2
1/1
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
1/1
8
12/5
/18
0
2
4
6
8
1 0
1 2
1 4
1 6
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
A b n o rm a l T c e lls
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
8
11/8
/18
11/2
1/1
8
0
1
4
6
8
1 0
1 2
1 4
1 6
ce
lls
x 1
0^
3/u
L
A b n o rm a l T c e lls
W B C
F irs t c o b o m a rs e n d o s e
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
Ce
lls
x 1
0^
3 /
L
F irs t c o b o m a rs e n d o s e
A b n o rm a l T c e lls
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
F irs t c o b o m a rs e n d o s e
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
Restoring Biological Harmony for Patients with Debilitating DiseaseRestoring Biological Harmony for Patients with Debilitating Disease
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.