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

T Cell Lymphoma Forum, February 1-3, 2018 La Jolla, CA, U.S.A. Emerging rationale for targeting miRNAs in CTCL 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

MicroRNA-155 Regulates Key Pathogenic Pathways in CTCL ▪ 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 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 2

Preclinical Data: miR-155 is Upregulated in MF Lesions and Inhibition Affects Cell Growth & Apoptosis n=10 n=13 n=21 n=13 Untreated Archived tissue provided by Bexarotene Madeleine Duvic (MD Anderson) 3 miR-155 Inhibitor (MRG-106)

First-In-Human Phase 1 Study of MRG-106 in Patients with Mycosis Fungoides ▪ 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 4

Baseline Patient Characteristics: 5 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 MRG-106 injected lesions Early termination = last injection day CAILS assessment day 6

Gene Expression Changes with Intralesional Injection of MRG-106 Correlate to Drug Levels in MF Lesion Biopsies (Part A) 122 transcripts Up-regulated vs. untreated Down-regulated vs. untreated 102-001 102-003 101-001 102-003 102-001 101-001 110-001 Saline MRG-106 (mg/g tissue) MRG-106 BLOQ BLOQ Saline MRG-106 7

MRG-106 Treatment Decreases Key CTCL Disease Pathways Including STAT and NF k B Pathways (Part A) MRG-106 Saline Lesions Lesions IL4 IL4 IL6 IL12 (complex) IL2 SOCS1 IL12 (complex) SOCS1 IL6 IL2 STAT4 NFKBIA NR3C1 ESR1 STAT6 NFKB1 NFKB1 TP53 ESR1 STAT6 STAT4 NFKBIA NR3C1 TP53 NFkB(complex) NFkB (complex) Activated Inactivated 8

26 of 29 (90%) Subjects Treated Systemically with MRG-106 Showed mSWAT Score Improvement Database Jan. 25, 2018

10 of 17 (59%) Pts Treated for > 1 Month Show ≥ 50% mSWAT Score Improvement Once 50% mSWAT PR is achieved, response was durable Doses 9 10 8 25 10 7 21 8 57 44 29 25 9 43 26 55 21 30 bexarotene 102-005 20 NONE 105-003 10 methotrexate 102-007 Percent Change from Baseline 0 bexarotene 112-001 -10 interferon alfa -20 102-008 -30 bexarotene 112-004 -40 NONE 107-003 -50 NONE 102-009 -60 NONE -70 102-010 -80 NONE 104-001 -90 vorinostat, prednisone 101-005 -100 NONE 106-003 106-002 106-003 101-005 104-001 112-005 112-006 102-010 101-009 105-003 102-008 102-009 112-001 101-004 102-007 107-003 102-005 112-004 bexarotene 106-002 Subject ID NONE 101-004 SD = Stable Disease Cohort 900 mg 300 mg 600 mg PR = Partial Response rt rt Cohort g g 300 mg g 600 mg rt 900 mg NONE 112-005 LR = Loss of Response PD = Progressive Disease NONE 101-009 Drug Holiday Last Dose bexarotene 112-006 Ongoing 0 30 60 90 120 150 180 210 240 270 300 330 360 390 420 450 480 510 Study Day 10 Database Jan. 25, 2018

Best mSWAT Improvement with MRG-106 Independent of Administration as Monotherapy or Combination with Another CTCL therapy 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) Database Jan. 25, 2018

300 and 600 mg 2-hour IV Infusion Dose Regimens Have the Best Efficacy and Tolerability Profiles ▪ 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 C max . ▪ 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 12

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 Day 1 Day 93 mSWAT: 180 mSWAT: 68 (62% reduction) 13 Database Dec. 4, 2017

Adverse Events Any grade Grade 3-4 AEs by preferred term, N (%) Any grade* Grade 3-4 attributed to MRG-106 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) ▪ 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 14 Database Jan. 25, 2018

Circulating CD8 T cells inversely correlate with mSWAT score improvement • 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). CD8 T Cell Populations in Patients with Partial Responses (PR) vs Stable or Progressive Disease (SD/PD) P=0.0020 80 R 2 =0.4031 * * %CD8 T cell subset 60 40 20 0 D D R R D R D R P P P P P P P P / / / D / D D D S S S S Naive Central TEMRA TEM Memory Effector Effector All Patients (n=26) Memory Memory Database 1/8/18

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