Emerging rationale for targeting miRNAs in CTCL Christiane Querfeld, - - PowerPoint PPT Presentation

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, Basem

• M. 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 2017

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Preclinical Data: miR-155 is Upregulated in MF Lesions and Inhibition Affects Cell Growth & Apoptosis

Archived tissue provided by Madeleine Duvic (MD Anderson) Untreated Bexarotene miR-155 Inhibitor (MRG-106)

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n=10 n=13 n=21 n=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 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:

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Database 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

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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

MRG-106 (mg/g tissue)

122 transcripts Up-regulated vs. untreated Down-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

8 IL4 IL6 IL2 SOCS1 IL12 (complex) TP53 ESR1 STAT6 STAT4 NFKB1 NFKBIA NR3C1 NFkB (complex) IL4 IL6 IL2 SOCS1 IL12 TP53 ESR1 STAT6 STAT4 NFKB1 NFKBIA NR3C1 NFkB(complex) (complex)

26 of 29 (90%) Subjects Treated Systemically with MRG-106 Showed mSWAT Score 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

10 20 30 Percent Change from Baseline 600 mg 300 mg 900 mg Cohort 9 10 8 25 10 7 21 8 57 44 29 25 9 43 26 55 21 Doses

10 of 17 (59%) Pts Treated for > 1 Month Show ≥ 50% mSWAT Score Improvement

10 900 mg rt 600 mg g g rt 300 mg g rt Cohort

Once 50% mSWAT PR is achieved, response was durable

Database Jan. 25, 2018

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 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)

• n 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

• ther

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

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▪ 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

• ther 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

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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-106 Grade 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, 2018

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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).

P R S D / P D P R S D / P D P R S D / P D P R S D / P D 20 40 60 80

CD8 T Cell Populations in Patients with Partial Responses (PR) vs Stable or Progressive Disease (SD/PD)

%CD8 T cell subset

* *

Naive Central Memory TEMRA Effector Memory TEM Effector Memory

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

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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)

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