potential treatment for patients with miR-155 elevated cancers - - PowerPoint PPT Presentation

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Restoring Biological Harmony for Patients with Debilitating Disease Restoring Biological Harmony for Patients with Debilitating Disease

Cobomarsen, an emerging potential treatment for patients with miR-155 elevated cancers

T-cell Lymphoma Forum January 2019

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microRNA Therapeutics Regulate Systems Biology to Modify Disease

▪ microRNA-targeted therapy is focused

• n disease modification by restoring

homeostasis to dysregulated processes ▪ microRNAs regulate complex biological systems ▪ microRNA-targeted therapies are intrinsically focused on disease-relevant pathways ▪ microRNA therapeutics particularly suited for complex, multigenic disorders

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 miR-155 PU.1 CEBPb SOCS SHIP-1

Cytokines T-cell activation PI3K/AKT/MAPK Proliferation Inflammation M1M2

Jarid2

Leukemic transformation Myeloid differentiation

Wee1

DNA repair

Inflammation Cancer

B-cell and DC activation IL-6, TNFa Proliferation Hematopoietic progenitor self-renewal PI3K/AKT/MAPK Proliferation

miR-155 is a Master Regulator of Inflammation and Oncology

Genomic Instability

Increased activity Decreased activity

Apoptosis Apoptosis EMT Invasion/ metastasis NF-kB NF-kB Leukemic transformation

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Cobomarsen (MRG-106), a miR-155-5p Inhibitor, Regulates Genes Implicated in T Cell Regulation, Cell Cycle and Apoptosis

▪ Cobomarsen is a chemically synthesized, chimeric phosphorothioate oligonucleotide, 14 nucleotides in length ▪ Genome-wide expression analysis demonstrates that cobomarsen regulates numerous genes implicated in T cell regulation and cell cycle and apoptosis,. ▪ A subset of these genes has been identified monitor cobomarsen activity in clinical samples.

CD4+ T cells: Cobomarsen vs PBS

Genes

Activation of immune response Inflammatory response T cell receptor signaling pathway 2 Coagulation, response to wounding, hemostasis SMAD3, TGFBR2, PIK3R5, LCK, VAV1, IL10 Adaptive immune response Regulation of T cell activation T cell costimulation, lymphocyte costimulation 4 Positive regulation of interleukin-6 production IL6R, IL10, IL1R, IL17A 5 Cytokine-mediated signaling pathway STAT2, TICAM2, IL12RB2, CXCR5, MAP3K5, IL1R, CD44, IL17A 1 3

DOWN regulated gene culsters

CXCR5, ICAM3, CD44, LCK, IL17A, IL17RA, IL10, IL6R, IL1R CD28, IL17A, PI3KR5, ICOS, IL6R, IL10, CXCR5, LCK, VAV1

Genes

1 Ribonucleotide binding, ATP binding, RNA binding, nucleic acid binding RPF2, CDK7, NARS, ALKBH5 Apoptotic process, Programmed cell death Apoptotic signaling pathway Immune response Cytokine-mediated signaling pathway 3 2

UP regulated gene culsters

CASP3, TNFRSF9, BNIP3L, PPP3CC, MAP3K7 IL5, IL4, IL13, GATA3, CCR7, VEGFA, SMAD7

Figure 1. Gene regulation by cobomarsen in activated, primary CD4+ T cells isolated from healthy donors.

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Link Between miR-155 and Cancer

▪ The host gene for miR-155 (BIC) was identified along with myc as a proto-oncogene for virally- induced B-cell lymphomas ▪ miR-155 and its precursor BIC are highly expressed in hematologic malignancies and solid tumors ▪ Elevated miR-155 expression correlates with poor prognosis ▪ miR-155 is regulated by NF-kB, PI3K/AKT, and JAK/STAT, and functions in a feedback loop with these survival pathways ▪ miR-155 promotes chemoresistance in cancer cell lines ▪ Expression of miR-155 is sufficient to drive B cell expansion and formation of B cell lymphoma ▪ Therapeutic inhibition of miR-155 reduces proliferation and increases apoptosis in hematologic and non-hematologic cancer cell lines

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Increased miR-155 is Implicated in Multiple Oncology Indications Hematologic

▪ Cutaneous T-cell lymphoma (CTCL) ▪ Acute myelogenous leukemia (AML) ▪ B-cell lymphoma (DLBCL) ▪ Chronic lymphocytic leukemia (CLL) ▪ Adult T-cell leukemia/lymphoma (ATLL) ▪ Peripheral T-cell lymphoma (PTCL) ▪ Burkitt’s lymphoma ▪ Waldenstrom macroglobulinemia (WM)

Non-Hematologic

▪ Non-small cell lung cancer ▪ Glioblastoma ▪ Triple negative breast cancer ▪ Melanoma ▪ Colorectal cancer ▪ Gastric cancer ▪ Pancreatic cancer ▪ Gall bladder cancer ▪ Head and neck squamous cell carcinoma ▪ Neurofibromatosis

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miR-155 is Up-regulated in Multiple Hematological Cancer Cell Lines

n o r m C D1 9 + B c e ll n o r m C D4 + T c e ll KM - H2 L 1 2 3 6 O c i- L y 3 J ijo y e M y - L a HH M J Hu T 1 0 2

5 0 0 0 0 1 0 0 0 0 0 1 5 0 0 0 0 2 0 0 0 0 0

A b s o lu te m iR -1 5 5 E x p re s s io n

C o p ie s o f m iR -1 5 5 p e r c e ll

ATLL MF Burkitt lymphoma ABC- DLBCL Hodgkin lymphoma

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Untreated Bexarotene (10uM) Cobomarsen (10uM)

miR-155 is Upregulated in Malignant T-cell lines and Inhibition Affects Cell Growth and Apoptosis

▪ Effects on cell proliferation similar to bexarotene ▪ Unlike bexarotene, cobomarsen mechanism enhances apoptosis in cell lines ▪ Different mechanisms suggests potential for additivity/synergy with other therapeutics for CTCL

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Cobomarsen PK and Preclinical Safety

▪ Cobomarsen displays linear kinetics, with dose proportional increases in Cmax and AUC across dose groups. ▪ Cobomarsen is well tolerated in non-human primates up to 30 mg/kg administered by IV 2hr-infusion or as a SC or IV bolus injection ▪ No toxicity related to TLR activation Liver Function Complement Platelet function Mild reversible decrease in renal function in rodents with good margin of safety

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Cobomarsen Clinical Program in Hematological Malignancies

Ph 2 CTCL Dose, Schedule Optimization and Response Durability in CTCL Parallel Indication Expansion in Ph1 Ph 2 in NHL / Leukemia mPoC cPoC ATLL DLBCL Ph 1 CTCL CLL Futility Analysis

CTCL Mycosis Fungoides miR-155-high Non-Hodgkins Lymphoma (NHL)/Leukemia

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Restoring Biological Harmony for Patients with Debilitating Disease Restoring Biological Harmony for Patients with Debilitating Disease

Cobomarsen in CTCL

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miR-155 Detection Decreases in Lesion Biopsies After Cobomarsen Treatment

▪ Pretreatment miR-155-5p expression levels quantitated by qPCR were elevated in the majority of CTCL patients compared to normal skin ▪ Highest levels of miR-155 were found in tumor lesions that had the highest density

• f neoplastic cells

▪ Intralesional and systemic cobomarsen treatment led to loss of miR-155 detection in the majority of subjects that was maintained up to 36 days post the last dose (EOS visit)

Figure 3. miR-155-5p copy number in lesion biopsies taken before and after cobomarsen treatment from CTCL subjects enrolled in Parts A and B compared to normal skin biopsies from healthy donors

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Thirty-three of Thirty-six Subjects (92%) Treated Systemically with Cobomarsen Have Shown mSWAT Score Improvement

• mSWAT score represents best score

achieved while on study for 36 patients who had evaluable mSWAT scores as of the data cutoff (16OCT2018).

• Duration of response (days) as of

16OCT2018 for each evaluable patient achieving a 50% reduction in mSWAT score is shown in individual bar.

• NE = Not Evaluable; patients not allowed

to continue on trial as per protocol or lost to follow up.

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Five of Eight (63%) Subjects Treated with Cobomarsen Administered as a 300 mg IV-infusion Achieved a PR. 50% of these reached ORR4

Subject 112-001: 300 mg IV-inf

ORR4

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Cobomarsen SOLAR Phase 2 Clinical Trial Initiated in 4Q18

A Randomized, Parallel, Open Label, Active Control, Global Trial in Patients with Stage Ib-III Mycosis Fungoides

Open Label; Randomize to: cobomarsen IV Infusion vs. vorinostat Randomize Cobomarsen (300mg IV Infusion anticipated) n=~65 subjects vorinostat n=~65 subjects Follow until progression

Futility Analysis

Follow until progression PRISM (Open label extension)

Primary Endpoint

• Overall Response Rate of four months (ORR4) using Global

Response Criteria

Key Secondary Endpoint

• Progression-free survival

Additional Secondary Endpoint

• Patient reported outcomes
• Skindex-29, pruritus, pain

Key Inclusion Criteria

▪ Stage Ib-III ▪ Must have received at least one prior therapy for CTCL (per NCCN guidelines for generalized skin involvement) ▪ mSWAT score ≥ 10

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CTCL: Adverse Events

▪No serious AEs have been attributed to cobomarsen ▪Eight serious adverse events (SAEs) have been reported in 4 subjects

These SAEs were either related to underlying disease (known complications of the CTCL patient population) or related to other comorbidities in these subjects, and unrelated to study treatment

▪Thirty-nine subjects (90.7%) have reported at least 1 non-serious AE, for a total

• f 307 unique AEs

▪The maximum severity of AEs has been Grade 1/Grade 2 (275 of 307 events [89.6%]) or Grade 3/Grade 4 (32 of 307 events [10.4%]) ▪Of the 32 Grade 3/Grade 4 events,14 events in 6 subjects (all in Part B) were assessed to be related to study drug

One subject (101-003) had tumor flare followed by erythema, rash, leukopenia, lymphopenia and hyperuricemia (all within 2 weeks, reported as 6 separate AEs) In 5 subjects, the following were reported:

▪ 102-008: Flare-erythema and Tumor pain ▪ 105-004: Tumor Flare, Neutropenia, Leukopenia ▪ 3 other subjects (each in 1 subject): Intermittent ANC Decreased, hypokalemia, Intermittent Neutropenia

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Restoring Biological Harmony for Patients with Debilitating Disease Restoring Biological Harmony for Patients with Debilitating Disease

Cobomarsen in ATLL

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Patient Characteristics and Disposition

Subject ID Presentation at Screening Blood Involvement (% tumor cells of WBC1) # of Prior Therapies Days Since Last Tx and Start of Cobomarsen Cobomarsen Treatment Duration (days) Disposition (reason for discontinuation) 101-008 101-012 102-012 / 102-0152 Acute – in remission Acute – in remission Relapsing – primarily skin disease 9% 10% 9% 4 1 10 21 108 21 / 30 401 days 87 days 91 / 42 days2 Ongoing Ongoing Discontinued (progression) 101-010 101-014 101-011 Lymphomatous – in remission Lymphomatous – in remission Lymphomatous – relapsing 14% 15% (7/9/18) Data not collected 1 2 7 46 28 219 366 days 80 days 9 days Ongoing Ongoing Discontinued (progression) 119-0013 118-001 Lymphomatous – stable disease Relapsing – primarily skin disease No abnormal cells Data not collected 10 5 NA4 31 161 days 23 days Ongoing Discontinued (progression)

1 The percentage ATL tumor cells of WBCs at screening prior to cobomarsen treatment. Any numbers reported were determined by flow cytometry performed locally at the

clinical site and tumor cells were defined phenotypically as CD3+ CD4+ CD8- CD25+ CD7- CD26-

2 Patient 102-012 was re-enrolled on study as 102-015 3 Patient 119-001 had extensive skin, lymph and blood involvement at diagnosis. Abnormal cells were not quantified by flow cytometry, but visual blood smear only on

C3D22

4 Patient continued to receive AZT/VPA as antiviral therapy while on cobomarsen. Last dose of alemtuzimab was 15 months (450 days) prior to initiation of cobomarsen

Subject baseline disease characteristics, duration of cobomarsen treatment, and disposition. Data cut off date 13DEC2018

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Common Acute ATLL Response to Standard Therapy

Yamada et al., Cancer 1991, 67:2605-2609

2 /8 /1 7 4 /1 2 /1 7 6 /7 /1 7 7 /1 9 /1 7 7 /3 1 /1 7 8 /1 0 /1 7 8 /1 7 /1 7 9 /1 /1 7 9 /1 1 /1 7 9 /2 3 /1 7 1 0 /9 /1 7 1 0 /1 6 /1 7 1 1 /6 /1 7 1 1 /2 2 /1 7 1 2 /1 3 /1 7 1 /1 7 /1 8 2 /2 1 /1 8 3 /2 1 /1 8 4 /2 5 /1 8 5 /3 0 /1 8 7 /5 /1 8 8 /8 /1 8 9 /2 0 /1 8 1 0 /2 5 /1 8 1 1 /2 8 /1 8 3 6 9 1 2 1 5 1 8 2 1 2 4 2 7 3 0 3 3 C e lls x 1 0 ^ 3 / L L a s t E P O C H d o s e F irs t c o b o m a rs e n d o se A Z T /IF N L en alid om ide E P O C H c o b o m a rs e n

C e lls x 1 0 ^ 3 / L

1 /1 6 /1 8 4 /4 /1 8 6 /1 1 /1 8 7 /2 /1 8 9 /5 /1 8 9 /1 9 /1 8 9 /2 7 /1 8 1 0 /1 0 /1 8 1 0 /2 5 /1 8 1 1 /8 /1 8 1 1 /2 1 /1 8 1 4 6 8 1 0 1 2 1 4 1 6 c e lls x 1 0 ^ 3 /u L

A b n o rm a l T ce lls W B C

F irs t c o b o m a rs e n d o s e

C H O E P

Acute ATLL Subject 101-012 Acute ATLL Patient 101-008 Lymphomatous ATLL 101-010

7 /9 /1 8 7 /1 8 /1 8 9 /1 0 /1 8 9 /2 4 /1 8 9 /2 5 /1 8 9 /2 6 /1 8 9 /2 7 /1 8 1 0 /4 /1 8 1 0 /1 1 /1 8 1 0 /1 7 /1 8 1 0 /2 5 /1 8 1 1 /1 /1 8 1 1 /8 /1 8 1 1 /1 5 /1 8 1 1 /2 1 /1 8 1 1 /2 9 /1 8 1 2 3 4 5 6 7 8

C e lls x 1 0 ^ 3 / L

F irs t c o b o m a rs e n d o s e A b n o rm a l T c e lls W B C

Lymphomatous ATLL Subject 101-014

Diagnosed on DEC2017

Diagnosed on 21APR2017 Diagnosed 14DEC2016 ▪ Diagnosed on 18DEC2017

4/4 Patients with Aggressive Disease Treated with Cobomarsen Directly After Chemotherapy Have Significantly Prolonged Response Compared to Chemotherapy Alone

▪ Patients all feel well without typical ATLL signs and symptoms ▪ Response ranges from 3 months to one year after cobomarsen initiation as of data cut off ▪ Bone marrows restored ▪ No drug related Grade 3, 4 AEs or SAEs ▪ No new opportunistic infections reported

Last CHOP 6/16/18

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Cobomarsen Decreases Activation and Proliferation Status of Circulating Tumor Cells in ATLL Subjects

C1D1 Ki67 C1D5 C1D27 C2D22 C4D22

35% 25% 5% 5% 8%

C6D22

7%

SSC FSC CD69

19% 3441 13% 2112 8% 1892 8% 1913 9% 2120 Percent MFI 8% 2035

C1D1

HLA-DR

C1D5 C1D27 C2D22 C4D22

61% 3667 56% 2845 43% 1772 40% 1649 36% 1852 Percent MFI

C6D22

39% 1782

FSC

Activation Markers Proliferation

C 1 D 1 C 1 D 5 C 1 D 2 7 C 2 D 2 2 C 3 D 2 2 C 4 D 2 2 C 5 D 2 2 C 6 D 2 2 C 7 D 2 2 C 8 D 2 2 C 9 D 2 2 C 1 0 D 2 2 C 1 1 D 2 2 C 1 2 D 2 2

0 .0 0 .5 1 .0 1 .5 2 .0

B io m a rk e r E x p re s s io n

• n A T L T u m o r C e lls

A v e ra g e F o ld C h a n g e o f % C e lls P o s itiv e fro m B a s e lin e

% C D 6 9 + % H L A -D R + % K i-6 7 + n=7 n=7 n=3 n=3 n=2 n=2 n=2 n=1

Representative patient with Acute ATLL (101-008)

Average (SD) change in biomarkers in 7 ATLL subjects

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Cobomarsen Did Not Inhibit Normal Bone Marrow Recovery of Leukemic ATLL Patient When Administered Starting 21 Days After Last EPOCH Chemotherapy Dose

B cells Maturing Naive B cells Non- Plasmablasts

C1D1 C1D5 C1D27 C2D22

Immature B cells from bone marrow populate periphery and mature normally during cobomarsen therapy

1 1 /6 /1 7 1 1 /9 /1 7 1 1 /2 2 /1 7 1 2 /6 /1 7 1 2 /2 0 /1 7 1 /3 /1 8 1 /1 7 /1 8 1 /3 1 /1 8 2 /1 4 /1 8 2 /2 8 /1 8 3 /1 4 /1 8 3 /2 8 /1 8 4 /1 1 /1 8 4 /2 5 /1 8 5 /9 /1 8 5 /3 0 /1 8 6 /1 3 /1 8 7 /1 /1 8 8 /8 /1 8 1 0 /3 /1 8 1 0 /1 7 /1 8 1 0 /3 1 /1 8 1 1 /1 4 /1 8 1 1 /2 8 /1 8

2 5 3 0 3 5 4 0 4 5 5 0 3 6 9 1 2 1 5 1 8

% H ct R B C x 1 0 ^6 /  L o r H b g / d L H ct H b R B C F irs t c o b o m a rs e n d o s e

1 1 /6 /1 7 1 1 /9 /1 7 1 1 /2 2 /1 7 1 2 /6 /1 7 1 2 /2 0 /1 7 1 /3 /1 8 1 /1 7 /1 8 1 /3 1 /1 8 2 /1 4 /1 8 2 /2 8 /1 8 3 /1 4 /1 8 3 /2 8 /1 8 4 /1 1 /1 8 4 /2 5 /1 8 5 /9 /1 8 5 /3 0 /1 8 6 /1 3 /1 8 7 /1 /1 8 8 /8 /1 8 1 0 /3 /1 8 1 0 /1 7 /1 8 1 0 /3 1 /1 8 1 1 /1 4 /1 8 1 1 /2 8 /1 8 2 0 0 4 0 0 6 0 0 8 0 0 1 0 0 0 1 2 0 0 1 4 0 0 1 6 0 0 5 0 1 0 0 1 5 0 2 0 0 2 5 0 3 0 0

N u m b e r o f N K o r B c e lls /  L N u m b e r o f C D 8 c e lls /  L N K c e lls C D 8 T c e lls B c e lls

F irs t c o b o m a rs e n d o se

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Restoring Biological Harmony for Patients with Debilitating Disease Restoring Biological Harmony for Patients with Debilitating Disease

Cobomarsen in DLBCL

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One of Three Relapsing Patients with DLBCL, ABC Subtype has Demonstrated Beneficial Response

▪ mir-155 is documented to be elevated in the ABC subtype ▪ Three patients with ABC have been treated with cobomarsen

▪ All three had relapsed after multiple therapies prior to trial initiation ▪ Two of three progressed while on therapy and cobomarsen discontinued after one cycle or less

▪ One patients demonstrated response in measurable lesions after seven weeks of therapy*

▪ 60 year old female with four year history of DLBCL ▪ Relapsed after multiple regimens ▪ Responded to experimental Pi3K +BTK inhibitor – sponsor discontinued trial and patient relapsed ▪ Disease at initiation and following cobomarsen below:

Patient data courtesy of

• Dr. L. Pinter-Brown

Lesion Screening Measurement C1D3 C1D10 C1D17 C2D1 C2D15 Size LxW (cm2) Right Neck 9 11 20 16 4 Inguinal Node Not done 9 5 5 23 5

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Conclusions

▪ miR-155 associated with multiple hematologic and non-hematologic malignancies ▪ miR-155 regulated genes are essential for malignant processes ▪ Cobomarsen, and antimiR to miR-155 has shown evidence of activity and clinical benefit in early studies of three hematologic cancers

▪ CTCL ▪ ATLL ▪ DLBCL

▪ Cobomarsen has demonstrated good safety and tolerability to date ▪ Continued study of cobomarsen in these and other miR-155 upregulated malignancies is clearly warranted.