Phase 1 Study of the Safety and Efficacy of MRG-106, a ... · MRG-106 administration Part A:...
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Phase 1 Study of the Safety and Efficacy of MRG-106, a Synthetic Inhibitor of microRNA-155, in CTCL Patients ASH Annual Meeting, December 11, 2017 Atlanta, Georgia, U.S.A. Christiane Querfeld, Francine M. Foss, Lauren Pinter-Brown, Pierluigi Porcu, Basem M. William, Theresa Pacheco, Bradley Haverkos, Youn Kim, Joan Guitart, Ahmad Halwani, Jennifer DeSimone, Anita Seto, Linda Pestano, Aimee Jackson, Paul Williams Jr., Brent Dickinson, Judy Ruckman, Gilad Gordon, Paul Rubin, William Marshall
Transcript of Phase 1 Study of the Safety and Efficacy of MRG-106, a ... · MRG-106 administration Part A:...
Phase 1 Study of the Safety and Efficacy of MRG-106,
a Synthetic Inhibitor of microRNA-155, in CTCL Patients
ASH Annual Meeting, December 11, 2017
Atlanta, Georgia, U.S.A.
Christiane Querfeld, Francine M. Foss, Lauren Pinter-Brown, Pierluigi Porcu, Basem M.
William, Theresa Pacheco, Bradley Haverkos, Youn Kim, Joan Guitart, Ahmad Halwani,
Jennifer DeSimone, Anita Seto, Linda Pestano, Aimee Jackson, Paul Williams Jr., Brent
Dickinson, Judy Ruckman, Gilad Gordon, Paul Rubin, William 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
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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
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▪ 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: 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:
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DemographicPart A
Intralesional (N=6)
Part B
Systemic
(N=27)
Total
(N=33)
Sex
Female 1 (17%) 8 (30%) 9 (27%)
Male 5 (83%) 19 (70%) 24 (73%)
Age Range (Years)
18 - 45 0 (0%) 3 (11%) 3 (9%)
46 - 65 6 (100%) 15 (56%) 21 (64%)
> 65 0 (0%) 9 (33%) 9 (27%)
Race
Asian 0 (0%) 1 (4%) 1 (3%)
Black 1 (17%) 2 (7%) 3 (9%)
Not reported 1 (17%) 0 (0%) 1 (3%)
Other, specify 0 (0%) 2 (7%) 2 (6%)
White/Caucasian 4 (67%) 22 (81%) 26 (79%)
Ethnicity
Hispanic 1 (17%) 2 (7%) 3 (9%)
Non-Hispanic 5 (83%) 25 (93%) 30 (91%)
Disease Stage at Diagnosis
Stage IA 0 (0%) 5 (19%) 5 (15%)
Stage IB 1 (17%) 7 (26%) 8 (24%)
Stage IIA 2 (33%) 3 (11%) 5 (15%)
Stage IIB 3 (50%) 7 (26%) 10 (30%)
Stage IIIA 0 (0%) 2 (7%) 2 (6%)
Stage IIIB 0 (0%) 3 (11%) 3 (9%)
Prior Therapies
IV 3 (30%) 9 (28%) 12 (29%)
ORAL 6 (60%) 20 (63%) 26 (62%)
OTHER 1 (10%) 3 (9%) 4 (10%)
Baseline mSWAT
N 3 26 29
Median (Min-Max) 23 (3-96) 45 (2-186) 43 (2-186)
Database Dec. 4, 2017
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
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Gene Expression Changes with Intratumoral 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
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MRG-106 Treatment Decreases Key CTCL Disease Pathways Including STAT and NFkB Pathways (Part A)
Activated
Inactivated
Saline
Lesions
MRG-106
Lesions
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23/26 (88%) Patients Treated Systemically with MRG-106 Have mSWATScore Improvement Independent of Treatment Duration (Part B)
▪ 21 subjects were
eligible for > 1 month
of treatment
▪ 15 subjects chose to
continue with
additional months of
treatment
Database Dec. 4, 2017
6 doses = initial cycle
4 doses in subsequent cycles
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9 6 8 6 3 6 6 5 6 6 6 8 6 18 17 6 6 50 36 29 23 10 36 26 16 47Doses
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9/14 (64%) Pts Treated for > 1 Month Show ≥ 50% mSWAT Score Improvement
Database Dec. 4, 2017
Once 50% mSWAT PR is achieved, response is durable
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0 30 60 90 120 150 180 210 240 270 300 330 360 390 420
Study Day
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Pa
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Nu
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Ongoing
Last Dose
Drug HolidayLR = Loss of ResponsePD = Progressive DiseasePR = Partial ResponseSD = Stable Disease
NONE
methotrexate
bexarotene
NONE
NONE
NONE
NONE
NONE
bexarotene
NONE
bexarotene
NONE
interferon alfa
bexarotene
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600 mg300 mg900 mgCohort
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 1
mSWAT: 180
Day 93
mSWAT: 68
(62% reduction)
Database Dec. 4, 2017
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
CAILS: 12 CAILS: 9 CAILS: 3Database Dec. 4, 2017
MRG-106 Has a Favorable Safety Profile
▪ No SAEs attributed to MRG-106
▪ No Grade 4 Adverse Events attributed to MRG-106
▪ Two Dose-Limiting Toxicities:
▪ Grade 3 worsening pruritus, possible tumor flare, occurred twice in one patient
▪ Grade 3 tumor flare
AEs by preferred term, N (%) Any grade* Grade 3-4
Fatigue 6 (17)
Injection site pain 6 (17)
Neutropenia 5 (14) 2 (6)
Nausea 4 (11)
Pruritus 4 (11) 1 (2)
Erythema 4 (11)
* Coded AEs occurring in ≥ 10% of subjects
Database Dec. 4, 201713
All coded Grade 3 or 4 Adverse Events
Database Dec. 4, 2017
MRG-106 Has a Favorable Safety Profile
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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
(6)
600mg
(3)
900mg
(3)
300mg
(8)
Total
(35)
Blood and lymphatic
system disorders
1 ( 33.3%) 1 ( 33.3%) 2 ( 5.7%)
Neutropenia 1 ( 33.3%) 1 ( 33.3%) 2 ( 5.7%)
Leukopenia 1 ( 33.3%) 1 ( 2.9%)
Investigations 2 ( 33.3%) 2 ( 5.7%)
Blood creatine
phosphokinase increased
1 ( 16.7%) 1 ( 2.9%)
Lymphocyte count
decreased
1 ( 16.7%) 1 ( 2.9%)
Metabolism and nutrition
disorders
1 ( 16.7%) 1 ( 33.3%) 2 ( 5.7%)
Hypercalcaemia 1 ( 16.7%) 1 ( 2.9%)
Hyponatraemia 1 ( 33.3%) 1 ( 2.9%)
Infections and infestations 1 ( 16.7%) 1 ( 2.9%)
Cellulitis 1 ( 16.7%) 1 ( 2.9%)
Skin and subcutaneous
tissue disorders
1 ( 33.3%) 1 ( 2.9%)
Pruritus 1 ( 33.3%) 1 ( 2.9%)
Vascular disorders 1 ( 33.3%) 1 ( 2.9%)
Hypertension 1 ( 33.3%) 1 ( 2.9%)
Conclusions
▪ MRG-106 is generally well-tolerated to date
▪ No SAEs or Grade 4 AEs deemed related to study drug
▪ Two Dose-Limiting Toxicities:
▪ Grade 3 worsening pruritus, possible tumor flare, occurred twice in one patient
▪ Grade 3 tumor flare
▪ 9 of 14 (64%) patients treated for > 1 month have ≥ 50% mSWAT score
reduction
▪ mSWAT improvement is durable in all patients, who continued on treatment
▪ mSWAT improvements correlate with time on MRG-106 treatment
▪ Efficacy appears similar across dose range tested (300-900 mg/dose)
▪ Study in CTCL is on-going
▪ Study is expanded to enroll patients with DLBCL, CLL, and ATLL
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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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