Phase 1 Trial Evaluating MRG-106, a Synthetic Inhibitor of microRNA-

155, in Patients with CTCL

EORTC CLTF 2017 meeting onCutaneous Lymphomas: Insights & Therapeutic Progress

Christiane Querfeld, Francine Foss, Lauren Pinter-Brown, Pierluigi Porcu, Basem M. William, Theresa

Pacheco, Bradley Haverkos, Youn Kim, Joan Guitart, Ahmad Halwani, Jennifer DeSimone, Anita G. Seto,

Linda A. Pestano, Judy Ruckman, Michele Landry, Gilad S. Gordon, Paul Rubin, William S. Marshall

▪ Epigenetic alterations have been implicated in the pathogenesis of 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, PI3K, and RAS 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 2017

Preclinical Data:

miR-155 is Upregulated in MF Lesions and Inhibition Affects Cell Growth and Apoptosis

In collaboration with Madeleine Duvic

(MD Anderson)

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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 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.)

▪ Dose schedule for systemic administration:

▪ Three doses in the first week followed by weekly doses

▪ Five subjects were eligible for only 4 weeks of treatment due to original protocol version

Patient Characteristics:

ParameterPart A

Intralesional, N=6

Part B

Systemic, N=23

Total

N=29

Sex

Female 1 ( 16.7%) 7 ( 30.4%) 8 ( 27.6%)

Male 5 ( 83.3%) 16 ( 69.6%) 21 ( 72.4%)

Age

Median (range) 61 (50 - 64) 63 (21 - 85) 63 (21 - 85)

Race

Asian 0 ( 0.0%) 1 ( 4.3%) 1 ( 3.4%)

African American 1 ( 16.7%) 1 ( 4.3%) 2 ( 6.9%)

Not reported 1 ( 16.7%) 0 ( 0.0%) 1 ( 3.4%)

Other 0 ( 0.0%) 1 ( 4.3%) 1 ( 3.4%)

Caucasian 4 ( 66.7%) 20 ( 87.0%) 24 ( 82.8%)

Disease Stage at Diagnosis

Stage IA 0 ( 0.0%) 4 ( 17.4%) 4 ( 13.8%)

Stage IB 1 ( 16.7%) 7 ( 30.4%) 8 ( 27.6%)

Stage IIA 2 ( 33.3%) 2 ( 8.7%) 4 ( 13.8%)

Stage IIB 3 ( 50.0%) 6 ( 26.1%) 9 ( 31.0%)

Stage IIIA 0 ( 0.0%) 2 ( 8.7%) 2 ( 6.9%)

Stage IIIB 0 ( 0.0%) 1 ( 4.3%) 1 ( 3.4%)

Unknown 0 ( 0.0%) 1 ( 4.3%) 1 ( 3.4%)

Baseline mSWAT

N 3 23 26

Median (range) 22.5 (3 - 96) 42.7 (2 -180) 34.9 (2 -180)

Prior Systemic CTCL Therapies

Median (range) 3 (1 - 4) 2 (0 - 9) 2 (0 - 9)

Concomitant Systemic CTCL Therapies

Median (range) 1 (0 - 2) 1 (0 - 3) 1 (0 - 3)

Mean miR-155 copy

number from lesional

skin biopsy (range)

Part A

Intralesional, N=6744 (109,3154)

Part B

Systemic, N=5554 (NQ,912)

Total

N=11690 (NQ,3154)

Normal skin miR-155 = Not Quantifiable (N/Q)

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Improvement of CAILS with Intralesional Injection of MRG-106 (Part A)

▪ MRG-106 was well-tolerated with generally minor injection site reactions

Early termination

CAILS assessment day

MRG-106 injected lesions

= last injection day

6

22 of 23 Patients treated systemically with MRG-106 have mSWAT score improvement independent of treatment duration

▪ 19 subjects were eligible for > 1 month of treatment

▪ 13 subjects chose to continue with additional months of treatment

6 doses = initial cycle4 doses in subsequent cycles

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69% Patients treated for > 1 Month show ≥ 50% mSWAT Score Improvement

Database Oct 11, 2017 8

0 30 60 90 120 150 180 210 240 270 300 330 360

Study Day

104-001

102-010

101-005

101-004

106-002

112-004

102-009

102-008

102-007

112-001

107-003

105-003

102-005

Su

bje

ct

Ongoing

Last Dose

Drug HolidayPD = Progressive DiseasePR = Partial ResponseSD = Stable Disease

Subject ID

bexarotene

NONE

NONE

bexarotene

methotrexate

narrow band UVB, intron A, interferon

NONE

bexarotene

bexarotene

NONE

NONE

prednisone, vorinostat

NONE

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

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Day 1mSWAT: 180

Day 93mSWAT: 68(62% reduction)

Case Example (112-001): 300 mg IV Infusion Cohort

▪ Age: 63; Sex: Male

▪ Date of diagnosis: 2015

▪ CTCL stage at screening: IIB

▪ Concomitant systemic therapy: Bexarotene (started 2015)

▪ Has skin (mSWAT) PR lasting > 4 months

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Day 1 Day 29 Day 127 Day 182

CAILS: 12 CAILS: 9 CAILS: 3 CAILS: 0

MRG-106 Has a Favorable Safety Profile

▪ No SAEs attributed to MRG-106

▪ No Grade 4 Adverse Events attributed to MRG-106

▪ One Grade 3 worsening pruritus attributed to MRG-106 (Dose-Limiting Toxicity)

AEs by preferred term, N (%) Any grade Grade 3-4

Injection site pain (I.L. & S.Q.) 6 (21) 0

Fatigue 6 (21) 0

Nausea 4 (14) 0

Pruritus 4 (14) 1

Erythema 4 (14) 0

Most common coded Adverse Events:

Database Oct 11, 201711

Part A

(Intra-

tumoral)

Part B

(Subcutaneous)

Part B

(IV, 2 hr infusion)

Part B

(IV Bolus)

System Organ Class

Preferred Term

75mg

(6)

300mg

(3)

600mg

(3)

900mg

(3)

300mg

(3)

600mg

(3)

900mg

(3)

300mg

(5)

Total

(29)

Metabolism and nutrition

disorders1 ( 16.7%) 1 ( 33.3%) 3 ( 10.3%)

Hypercalcemia 1 ( 16.7%) 1 ( 3.4%)

Hyponatremia 1 ( 33.3%) 1 ( 3.4%)

Hypophosphatemia 1 ( 33.3%) 1 ( 3.4%)

Blood and lymphatic

system disorders1 ( 16.7%) 1 ( 33.3%) 1 ( 33.3%) 3 ( 10.3%)

Leukopenia 1 ( 33.3%) 1 ( 3.4%)

Neutropenia 1 ( 33.3%) 1 ( 33.3%) 2 ( 6.9%)

Lymphopenia 1 ( 16.7%) 1 ( 3.4%)

Laboratory findings 1 ( 16.7%) 1 ( 20.0%) 2 ( 6.9%)

Blood creatine

phosphokinase increased1 ( 16.7%) 1 ( 3.4%)

Uric acid increased 1 ( 20.0%) 1 ( 3.4%)

Infections 1 ( 16.7%) 1 ( 3.4%)

Cellulitis 1 ( 16.7%) 1 ( 3.4%)

Skin and subcutaneous

tissue disorders1 ( 33.3%) 1 ( 3.4%)

Pruritus 1 ( 33.3%) 1 ( 3.4%)

Vascular disorders 1 ( 33.3%) 1 ( 3.4%)

Hypertension 1 ( 33.3%) 1 ( 3.4%)

MRG-106 Has a Favorable Safety ProfileAll Grade 3 or 4 Adverse Events

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Database Oct 11, 2017

Conclusions

▪ MRG-106 is generally well-tolerated to date

▪ No SAEs or Grade 4 AEs deemed related to study drug

▪ One Grade 3 AE deemed potentially related to study drug: pruritus

▪ 9 of 13 (70%) patients treated for > 1 month have ≥ 50% mSWAT score reduction

▪ mSWAT improvement is durable in all patients, who continued on treatment

▪ Magnitude of mSWAT improvements appeared to correlate with time on MRG-106 treatment

▪ Efficacy appears similar across dose range tested (300-900 mg/dose)

▪ Study in CTCL is on-going

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MRG106-11-101 CTCL Investigators

▪ Jennifer DeSimone (Inova)

▪ Herbert Eradat (UCLA)

▪ Francine Foss (Yale)

▪ Joan Guitart (Northwestern)

▪ Ahmad Halwani (Huntsman)

▪ 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)

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