Emerging rationale for targeting miRNAs in CTCL
T Cell Lymphoma Forum, February 1-3, 2018
La Jolla, CA, U.S.A.
Christiane Querfeld, Francine M. Foss, Youn Kim, Lauren Pinter-Brown, BasemM. William, Pierluigi Porcu, Theresa Pacheco, Bradley Haverkos, Jennifer
DeSimone, Joan Guitart, Ahmad Halwani, Herbert Eradat, Anita G. Seto, Linda A. Pestano, Aimee L. Jackson, Paul J. Williams Jr., Gilad S. Gordon, Paul Rubin,
William S. Marshall
▪ Epigenetic alterations have been implicated in the pathogenesis of lymphomas
and leukemias including CTCL
▪ miRNA profiling and RT-PCR discriminate CTCL and non-malignant
inflammation with a high accuracy
▪ miR-155 is overexpressed; miR-203 & miR-205 are decreased in CTCL skin
▪ JAK/STAT and PI3K pathways are activated in CTCL and regulated by miR-
155 that lead to uncontrolled clonal cell expansion
MicroRNA-155 Regulates Key Pathogenic Pathways in CTCL
Ralfkiaer et al. Blood 2011; Netchiporouk et al. Cell Cycle 2014; Van Kester et al. 2011; Maj et al. Br J Derm 2012;
Kopp et al. APMIS 2013; Kopp et al. Cell Cycle 2013; Moyal et al. Exp Derm 2013; Moyal et al. Br J Derm 20172
Preclinical Data:
miR-155 is Upregulated in MF Lesions and Inhibition Affects Cell Growth & Apoptosis
Archived tissue provided by
Madeleine Duvic (MD Anderson)
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
miR-155 Inhibitor (MRG-106) 3
n=10 n=13 n=21n=13
First-In-Human Phase 1 Study of MRG-106 in Patients with Mycosis Fungoides
4
▪ MRG-106 is an optimized oligonucleotide inhibitor of miR-155 formulated in saline
▪ Study objectives:
▪ Primary objective: Safety and tolerability
▪ Secondary objectives: PK profile, efficacy, recommended Phase 2 dose and route of
administration
▪ Study design:
▪ Subjects permitted to continue background CTCL therapy if stable dose > 4 weeks
prior to MRG-106 administration
▪ Part A: Activity of MRG-106 through intralesional injection
▪ Part B: Dose-escalation by systemic administration (subcutaneous or I.V.)
▪ Original protocol limited dosing to 6 doses over 4 weeks
▪ Subsequent amendments allowed subjects to continue therapy
▪ Dose schedule: Three doses in the first week followed by weekly doses
▪ Dose schedule reductions were allowed after the first 4 weeks in responding subjects
Baseline Patient Characteristics:
5Database Jan. 22, 2018
Improvement of CAILS with Intralesional Injection of MRG-106 (Part A)
75 mg/dose of MRG-106 was well-tolerated with generally minor injection site reactions
Early termination
CAILS assessment day
MRG-106 injected lesions
= last injection day
6
Gene Expression Changes with Intralesional Injection of MRG-106 Correlate to
Drug Levels in MF Lesion Biopsies (Part A)
102-001 102-003 101-001 102-003 102-001 101-001 110-001
Saline MRG-106
Saline MRG-106
BLOQ BLOQ
MR
G-1
06
(mg
/g tis
su
e)
122 transcripts
Up-regulated vs. untreatedDown-regulated vs. untreated
7
MRG-106 Treatment Decreases Key CTCL Disease Pathways Including STAT and NFkB Pathways (Part A)
Activated
Inactivated
Saline
Lesions
MRG-106
Lesions
8
IL4
IL6 IL2 SOCS1IL12 (complex)
TP53 ESR1 STAT6 STAT4 NFKB1 NFKBIA NR3C1
NFkB (complex)
IL4
IL6 IL2 SOCS1IL12
TP53 ESR1 STAT6 STAT4 NFKB1 NFKBIA NR3C1
NFkB(complex)
(complex)
26 of 29 (90%) Subjects Treated Systemically with MRG-106 Showed mSWATScore Improvement
Database Jan. 25, 2018
106-002
106-003
101-005
104-001
112-005
112-006
102-010
101-009
105-003
102-008
102-009
112-001
101-004
102-007
107-003
102-005
112-004
Subject ID
-100
-90
-80
-70
-60
-50
-40
-30
-20
-10
0
10
20
30
Pe
rce
nt
Ch
an
ge
fro
m B
as
elin
e
600 mg300 mg900 mgCohort
106-002
106-003
101-005
104-001
112-005
112-006
102-010
101-009
105-003
102-008
102-009
112-001
101-004
102-007
107-003
102-005
112-004
Subject ID
-100
-90
-80
-70
-60
-50
-40
-30
-20
-10
0
10
20
30
Pe
rce
nt
Ch
an
ge
fro
m B
as
elin
e
9 10 8 25 10 7 21 8 57 44 29 25 9 43 26 55 21Doses
10 of 17 (59%) Pts Treated for > 1 Month Show ≥ 50% mSWAT Score Improvement
10
106-002
106-003
112-005
108-001
101-003
111-001
106-001
101-009
111-002
105-002
112-003
101-005
108-002
104-001
102-010
102-004
101-002
105-003
102-008
102-009
112-001
101-004
102-007
107-003
112-004
102-005
Patient Number
-100
-80
-60
-40
-20
0
20P
erc
en
t C
ha
ng
e f
rom
Ba
se
lin
e
600 mg300 mg900 mgCohort
106-002
106-003
112-005
108-001
101-003
111-001
106-001
101-009
111-002
105-002
112-003
101-005
108-002
104-001
102-010
102-004
101-002
105-003
102-008
102-009
112-001
101-004
102-007
107-003
112-004
102-005
Patient Number
-100
-80
-60
-40
-20
0
20
Pe
rce
nt
Ch
an
ge
fro
m B
as
elin
e
600 mg300 mg900 mgCohort
106-002
106-003
112-005
108-001
101-003
111-001
106-001
101-009
111-002
105-002
112-003
101-005
108-002
104-001
102-010
102-004
101-002
105-003
102-008
102-009
112-001
101-004
102-007
107-003
112-004
102-005
Patient Number
-100
-80
-60
-40
-20
0
20
Pe
rce
nt
Ch
an
ge
fro
m B
as
elin
e
600 mg300 mg900 mgCohort
106-002
106-003
112-005
108-001
101-003
111-001
106-001
101-009
111-002
105-002
112-003
101-005
108-002
104-001
102-010
102-004
101-002
105-003
102-008
102-009
112-001
101-004
102-007
107-003
112-004
102-005
Patient Number
-100
-80
-60
-40
-20
0
20
Pe
rce
nt
Ch
an
ge
fro
m B
as
elin
e
600 mg300 mg900 mgCohort
Once 50% mSWAT PR is achieved, response was durable
Database Jan. 25, 2018
0 30 60 90 120 150 180 210 240 270 300 330 360 390 420 450 480 510
Study Day
112-006
101-009
112-005
101-004
106-002
106-003
101-005
104-001
102-010
102-009
107-003
112-004
102-008
112-001
102-007
105-003
102-005
Su
bje
ct
ID
Ongoing
Last Dose
Drug Holiday
PD = Progressive Disease
LR = Loss of Response
PR = Partial Response
SD = Stable Disease
NONE
methotrexate
bexarotene
bexarotene
interferon alfa
NONE
NONE
bexarotene
NONE
NONE
vorinostat, prednisone
NONE
NONE
NONE
bexarotene
NONE
bexarotene
Concomitant med N Median time (min, max)
on therapy prior to study day 1
bexarotene 7 16 months (2, 26)
interferon-alfa 2 26 months (17, 34)
methotrexate 1 22 months
vorinostat 1 4 months
other 2 21 months (3, 45)
Best mSWAT Improvement with MRG-106 Independent of Administration as Monotherapy or Combination with Another CTCL therapy
Database Jan. 25, 2018
300 and 600 mg 2-hour IV Infusion Dose Regimens Have the Best Efficacy and Tolerability Profiles
12
▪ Durable partial responses have been achieved at all dose levels
▪ 300-900 mg appear to represent the top of the dose response curve
▪ 300 mg IV bolus
▪ Fewer subjects remained on drug for more than one cycle compared to
other cohorts
▪ May be due to lower total exposure or tolerability due to higher plasma
Cmax.
▪ Subcutaneous administration of large volumes at ≥ 600 mg dose levels correlates with higher incidence of injection site reactions
▪ 300 and 600 mg IV-infusions had similar efficacy and tolerability, offering the most consistent response rate based on skin mSWAT scores
▪ 6 of 8 (75%) patients (initially assigned to 300 or 600 mg dose level)
achieved skin PR
Case Example (102-007): 300 mg IV Infusion Cohort
▪ Age: 51; Sex: Male
▪ Date of diagnosis: 2013
▪ CTCL stage at screening: IB
▪ Baseline mSWAT: 180
▪ Concomitant systemic therapy: Methotrexate (started June 2015)
▪ Has skin (mSWAT) PR lasting > 4 months
13
Day 1
mSWAT: 180
Day 93
mSWAT: 68
(62% reduction)
Database Dec. 4, 2017
Adverse Events
▪ No SAEs attributed to MRG-106
▪ Two Dose-Limiting Toxicities:
▪ Grade 3 worsening pruritus, possible tumor flare, occurred twice in one patient at 900 mg SC and 300 mg
IV infusion
▪ Grade 3 tumor flare (300 mg IV bolus)
▪ MRG-106 has a favorable safety profile
AEs by preferred term, N (%) Any grade*Any grade
attributed to MRG-106Grade 3-4
Grade 3-4
attributed to MRG-106
Fatigue 8 (22) 5 (14)
Neutropenia 7 (19) 6 (16) 4 (11) 2 (5)
Injection site pain 6 (16) 6 (16)
Nausea 6 (16) 2 (5)
Pruritus 6 (16) 2 (5) 2 (5) 2 (5)
Headache 6 (16) 2 (5)
* Coded AEs occurring in ≥ 15% of subjects (N=37)
Database Jan. 25, 201814
Circulating CD8 T cells inversely correlate with mSWAT score improvement
All Patients (n=26)
Database 1/8/18
P=0.0020
R2=0.4031
• Circulating CD8 T cell levels (lower proportions of effector TEMRA)
inversely correlates with mSWAT score reductions
• Patients with PRs had significantly higher percentages of naïve CD8 T
cells and decreased TEMRA CD8 T cells in their peripheral blood
• CD28- TEMRA CD8 T cells accumulate during aging or long-standing
disease and may have an immunosuppressive role in anti-tumor
immune responses (Effros et al. Immunol. Rev. 2005).
PR
SD/P
D
PR
SD/P
DPR
SD/P
D
PR
SD/P
D
0
20
40
60
80
CD8 T Cell Populations in Patients with Partial Responses (PR) vs Stable or Progressive Disease (SD/PD)
%C
D8 T
cell
subset * *
Naive CentralMemory
TEMRAEffectorMemory
TEMEffectorMemory
Summary
▪ MRG-106 is generally well-tolerated to date
▪ No SAEs deemed related to study drug
▪ Two Dose-Limiting Toxicities:
▪ Grade 3 worsening pruritus, possible tumor flare, occurred twice in one patient (900 mg
SC cohort, 300 mg IV-inf)
▪ Grade 3 tumor flare in 300 mg iv bolus patient
▪ 10/17 (59%) patients treated for > 1 month had ≥ 50% mSWAT score reduction
▪ Best improvement in mSWAT score appeared to be seen after one or more
months of dosing
▪ Study in CTCL is on-going
▪ Study has expanded to include patients with CLL, DLBCL, and ATLL, diseases
in which miR-155 expression is increased
16
MRG106-11-101 CTCL Investigators
Jennifer DeSimone (Inova)
Herbert Eradat (UCLA)
Francine Foss (Yale)
Joan Guitart (Northwestern)
Ahmad Halwani (Huntsman)
Auris Huen (MD Anderson)
Youn Kim (Stanford)
Theresa Pacheco (University of Colorado)
Lauren Pinter-Brown (UC Irvine)
Pierluigi Porcu (Thomas Jefferson)
Christiane Querfeld (City of Hope)
Basem William (The Ohio State University)
17