emerging rationale for targeting mirnas in ctcl · 2019-03-01 · emerging rationale for targeting...

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


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


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


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


Once 50% mSWAT PR is achieved, response was durable


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


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)


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

emerging rationale for targeting mirnas in ctcl · 2019-03-01 · emerging rationale for targeting...

Documents