Nov pipelines 2016-ver17

NOV Pipelines

Non-confidential information

Sept 2016 Ver.17

Oct. 2016 v.17

Contact Information

2

Mina LeeDirector, Business DevelopmentE-mail)[email protected]) 82-31-920-2772

Young-Whan Park, Ph DSr. Vice President, Business DevelopmentE-mail)[email protected]) 82-31-920-2780

Home page: http:://nov.ncc.re.kr

Oct. 2016 v.17

Non-GLP GLP FIH IND Ph 1 Ph 2

NOV pipelines

3

NSCLC 1st 2nd

Breast

Gastric

POIV

PO

Project ID Description MOA Indication

NOV1201(Licensed Out)

Pan-Her inhibitorInhibition of ERBB

signaling

Solid tumors(NSCLC

Breast, Gastric)

NOV1105Anti-HGF Antibody

Neutralizing HGFSolid tumors(GBM, NSCLC,

Ovarian)

NOV1204Vascular

Disrupting AgentInhibition of Tubulin

polymerization

Solid tumors(CRC

Ovarian ca.)

NOV1301 ALK5 inhibitorInhibition of EMT/

Metastasis

Metastatic tumors,MDS

NOV1401 PARP 1 inhibitorInhibition of

PARP 1

Solid tumors(Ovarian ca, Breast ca)

NOV1402Pan PARP inhibitor

Inhibition ofPARP 1~5

Solid tumors(Colon ca)

NOV1501DLL4/VEGFbispecific Antibody

Inhibition of DLL4/Notch & VEGF/VEGFR2

interaction

Solid tumors(Gastric, Lung,

Colon ca)

NOV1502WNT/beta catenin & Ras signaling

Ras inhibition and EGFR down regulation

Mutant type K-Ras tumors

Oct. 2016 v.17

Project ID

NOV1105 Anti HGF Antibody on phase 1 for Solid tumors

NOV1204 Vascular Disrupting Agent targeting tumor specific vasculature on phase 1 for Solid tumors

NOV1301 Anti-ALK 5 (TGF beta Receptor 1) inhibitor on phase 1 for Metastatic tumors

NOV1401 PARP 1 selective inhibitor on preclinical stage for Solid tumor with specific biomarkers

NOV1402 Poly (ADP-ribose) polymerase-1,2,3,4 and tankyrase inhibitor

Index

4

Oct. 2016 v.17

NOV1105: Anti-HGF Antibody

• NOV1105 is an anti-hepatocyte growth factor (HGF) antibody, down-regulating its signaling pathway (HGF/c-Met pathway).

It is fully human IgG4 with the binding affinity with 3.6 pM with good safety and PK profiles. In in vivo studies, it inhibited

tumor growth and increased survival in GMB and soft tissue sarcoma model alone or in combination with other drugs. It is

under development for the treatment of solid tumors at Phase 1 studies (KFDA).

• HGF (Hepatocyte Growth Factor) and its receptor, cMet, are reported to be excessively found in various human cancer

tissues including brain, lungs, liver, prostate, colon, breasts and skin, and such excessive discovery highly correlates with

prognosis of the patient and possible spread.

• NOV1105 stops signaling cMet/HGF and shows excellent effects on the GBM (Glioblastoma) and STS (Soft Tissue Sarcoma)

animal models.

5

Target Hepatocyte Growth Factor (HGF)

MOA Inhibition of Hypoxia-induced HGF – cMET signaling by anti-HGF antibody

Dev. Stage Phase 1 (FIH), Phase 2 study planned for 2018

Profile Fully human anti-HGF antibody(IgG4), No CDC, ADCC effect.Affinity 3.6pM, Half Life 21 days in Monkey, 11 days in mouse4 weeks repeated Tox: NOAEL 200mpk, well tolerate

Efficacy Potent inhibition in in vitro /in vivo model of Glioblastoma and Leiomyosarcoma

Dosing IV, infusion, once every 2 weeks

Indication Solid tumors (Leiomyosarcoma, Glioblastoma, NSCLC)

Competition Ficlatuzumab (Phase II)

Oct. 2016 v.17

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NOV1105(YYB101): Anti-HGF Antibody

Mode of Action

Oct. 2016 v.17

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In vivo efficacy , Single agent


Tumour growth in U787MG cell (Human glioblastoma model)

Survival of mice treated with YYB101

Group Dose (mg/kg) Animal (N) TGI (%) at D40 Survival (N)

hIgG4 5 5 0 5/5

YYB101

5 5 91.6 5/5

1.5 5 84.5 5/5

0.5 5 32.6 5/5

Tumor growth inhibition (TGI) (%) = (1-T/C) x 100T = the mean tumor volume (mm3) of the test groups, C= the mean tumor volume (mm3) of the vehicle groups

Summary of tumor growth inhibition (%) in U87MG cell (Human glioblastoma model)

Group (mpk) Median Survival Days(D) ILS(%) P value vs. Control

hIgG(5) 30

YYB101(0.5) 32 6.7 <0.05

YYB101(1.5) 35 16.7 <0.05

YYB101(5) 48 60.0 <0.001

Increased Life Span (ISL) (%) = (T-C)/C x 100

T = the mean survival day of the test groups

C= the mean survival day of the vehicle groups

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In vivo efficacy, Combi with Avastin


Tumour growth in U787MG cell (Human glioblastoma sc model, combi)

Summary of tumor growth inhibition (%) in U87MG cell (Human glioblastoma, Combi)

Group Dose (mg/kg) Animal (N) TGI (%) at D61 Survival (N)

hIgG4 4 5 0 5/5

hIgG4 +Bevacizumab 1+3 5 73.9 5/5

YYB101 + hIgG4 1+3 5 62.1 5/5

YYB101+Bevacizumab 1+3 5 93.1 5/5

Tumor growth inhibition (TGI) (%) = (1-T/C) x 100T = the mean tumor volume (mm3) of the test groups, C= the mean tumor volume (mm3) of the vehiclegroups

Mouse survival in U87MG (Orthotopic human glioblastoma model, Combi)

Group (mpk) Median Survival Days(D) ILS(%) P value vs. Control

hIgG(5)+ vehicle 26

YYB(5)+ vehicle 54 110 <0.001

hIgG(5)+ TMZ(5) 35 34 <0.001

YYB(5)+ TMZ(5) 84 227 <0.001

Increased Life Span (ISL) (%) = (T-C)/C x 100

T = the mean survival day of the test groups, C= the mean survival day of the vehicle groups

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In vivo efficacy


Tumor growth curve in SK-LMS-1 cell (Human leiomyosarcoma model)

GroupDose (mg/k

g)

Animal (

N)Dosing Route

TGI (%), 1st r

ound

Survival

(N)

hIgG2 15* 7 IP, Q2W - 7/7

YYB101 15* 7 IP, Q2W 71.4 7/7

XL880 10->5 7 PO, daily 88.4 6/7

Tumor growth inhibition (TGI) (%) = (1-T/C) x 100T = the mean tumor volume (mm3) of the test groups, C= the mean tumor volume (mm3) of the vehicle groups, * 300 µg/head injection, head=20g*XL-880 (Foretinib) 은 cMET 과 vascular endothelial growth factor receptor 2 (VEGFR-2)를 표적으로하는 tyrosin 인산화저해제이다.

Human HGF concentration at day 25 in SK-LMS-1 cell (Human leimyosarcoma model)

Oct. 2016 v.17

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PharmacoKinetics


Individual YYB101 serum concentration time profiles after a single IV dose in male cynomolgus monkey (linear scale).

YYB101 PK parameter estimates (±SE) after a single IV dose in human HGF knock in transgenic SCID mouse

***/** A significant difference at p<0.001/p<0.01 level compared to the 0h each group

Group Mean(and SD) serum human HGF concentration-Time Data After a Single IV Bolus Dose in human HGF Knock In SCID mouse

Oct. 2016 v.17

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Safety


Study Design Conclusion

A 4-week toxicity study in monkeyswith an 8-week recovery period

• Species : Cynomolgus monkey

• Dose: 0, 10, 50, 200 mg/kg

• Dosing Route: IV infusion (2hours),

weekly dosing

No-Observed-Adverse-Effect-Level (NOAEL) 200 mg/kg/day

Respiratory and central nervous systems safety pharmacology evaluation of yyb101 in conscious monkeys

• Species: Cynomolgus monkey

• Dose: 0, 200 mg/kg


weekly dosing

200 mg/kg had no test article-related effect on the central nervous system and respiratory parameters.

A 4-week toxicity studyin human HGF knock-in transgenic SCID mouse

• Species : HGF K/I mouse

• Dose: 0, 10, 50, 200 mg/kg


weekly dosing

No-Observed-Adverse-Effect-Level (NOAEL) 200 mg/kg/day

Oct. 2016 v.17

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Clinical Development


P1

Condition Advanced Solid Tumors

Administration IV infusion

Dosing Schedule Once Every two weeks

Study Objectives MTD, DLT, PK

Biomarkers Serum HGF, Tissue cMET

StatusDose escalation progress (n=18)

Dose expansion progress (n=15 per indication)

Phase 2a study planned (2018)

Oct. 2016 v.17

2012

13

2014 2015 2016 2017 20182013Project ID

NOV1105

Phase 1a (IV)

Title A Phase I Study to Assess the Safety, Tolerability and Pharmacokinetics of YYB101, Hepatocyte Growth Factor (HGF)-Neutralizing Humanized Monoclonal Antibody (Mab), in Advanced Solid Tumors Patients who

are Refractory to Standard Therapy

Dosing Design Every 2 weeks, IV infusion

BioMarker Serum HGF Concentration, Tissue cMET expression

Safety DLTs and MTD

Pharmacokinetics Cmax, Tmax, t1/2, CL, AUC, Accumulation Raito, Vd…

Efficacy Best overall response, Progression-free survival, Disease control rate

IV

IND Approval2015.4

Phase 12015.6 ~



Phase 2 a

Pre clinical

Oct. 2016 v.17

NOV1204, Vascular Disrupting Agent (VDA) (1)

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• NOV1204(CKD-516) is a tubulin inhibitor under development for the treatment of advanced solid tumors at phase 1 (IV and

oral formulation). NOV1204 is a benzophenone derivative and water soluble valine prodrug which binds to tubulin and

prevents its polymerization in tumor blood vessel endothelial and tumor cells (vascular disrupting agent: VDA). It blocks the

formation of the mitotic spindle and leads to cell cycle arrest at the G2/M phase. As a result, this agent disrupts the tumor

vasculature and tumor blood flow, deprives tumor cells of nutrients and induces tumor cell apoptosis.

• In addition, this agent has a direct cytotoxic effect on tumor cells by inhibiting tubulin polymerization. In vivo studies

showed tumor inhibition or even tumor regression, in alone or in combination with good safety and PK profiles.

Target Tubulin polymerization

MOA Vascular disrupting agent

Dev. Stage • Phase 1 completed (IV)

• Phase 1 dose escalation completed (PO), dose expansion on going (PO)

• Phase 1b/2a combination study planned for 2nd half of 2016 (PO)

Profile • An orally active potent small molecule inhibitor • Excellent aqueous solubility• Excellent PK w/ good oral bioavailability

Efficacy • Good anticancer effects in various solid tumors including advanced drug-resistant tumors• Suitable for combination therapy

Dosing • IV (once or twice per week) or PO (5d on / 2d off)

Indication Solid tumors

Competition CA4P, ASA404, AVE8062, BNC-105P

Oct. 2016 v.17

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Normal tissue Tumor tissue

Normal vasculature Tumor vasculature

Cell type Mature Endothelial Cell Proliferating Endothelial Cell

Cytoskeleton Actin (microfilament) Tubulin (microtubule)

Morphology

Organized hierarchy

Homogeneous architecture

Mature vessels

Lack of hierarchy

Highly disorganized irregular shape

Immature vessels

Br J Cancer. 2001; 84: 1354–

1362, Blood Perfusion and

Microenvironment of Human

Tumors, 2002.

NOV1204(CKD-516): Vascular Disrupting Agent

Mod of Action

Tumor vasculature selective disruption

Oct. 2016 v.17

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VS.


Mod of Action

Oct. 2016 v.17

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In vivo efficacy

Lung (A549) Ovarian (OVCAR3)

Mono Combi Combi

2~7mpk QD~2QW 4mpk QD +Docetaxel 15mpk QD, 5QW +Topotecan

TGI :

70~79%

12 week survival :

NOV mono : 20%

Docetaxel mono : 0%

Decetaxel + NOV : 60%

12 week survival:

Topo 0.5 mpk mono : 10%

Topo+ NOV : 70%

Enhancement of TGI % and Survival - mono and combined

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In vivo efficacy

Colon (Colo205) Pancreatic (Panc-1) Melanoma (lox)

Combi Combi Combi

4mpk QD +Irinotecan or

+Avastin

2/4mpk QD +Gemza 4mpk QD + Avastin

TGI :

IRT or AVS Mono : 21~60%

IRT or AVS + NOV : 88~99%

TGI :

Gemza mono : 61.7%

Gemza+ NOV : 79~83%

TGI :

Avastin mono : 49.13%

Avastin+ NOV : 84.76%

Enhancement of TGI % when combined

Oct. 2016 v.17

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ADME/PK

PK

parameters

Monkey

(0.6 mg/kg, p.o.)

Monkey

(1.0 mg/kg, p.o.)

Monkey

(1.5 mg/kg, p.o.)

Monkey

(3 mg/kg, p.o.)

Monkey

(0.5 mg/kg, i.v.)

AUCinf

(ng·hr/mL)154.5 331.7 643.0 1614.4 788.8

T1/2 (h) 2.7 2.1 2.2 3.2 2.5

Cmax

(ng/mL)75.0 141.1 241.3 587.4 672.0

BA (%) 16.3 21.0 27.2 34.1

Male

PK

parameters

Monkey

(0.6 mg/kg, p.o.)

Monkey

(1.0 mg/kg, p.o.)

Monkey

(1.5 mg/kg, p.o.)

Monkey

(3 mg/kg, p.o.)

Monkey

(0.5 mg/kg, i.v.)

AUCinf

(ng·hr/mL)236.8 363.1 467.2 1619.3 725.3

T1/2 (h) 2.4 2.2 2.0 3.4 2.4

Cmax

(ng/mL)117.4 154.4 276.4 931.7 675.5

BA (%) 27.2 25.0 21.5 37.2

Female

Evaluation in Male and Female monkeys

Oct. 2016 v.17

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Safety

System & Test Species Results

Cardiac toxicity

hERG (Patch clamp) > 10uM

Rabbit purkinje fiber (ADP) (i.v.) Negative

Troponin I (i.p.) Negative

Neurotoxicity Rotarod (i.p.) Negative

Genetic toxicityAMES,

Chromosomal aberrationMicronucleus (i.v.)

Negative

AnaphylaxisAnaphylactic shock (i.v.) Passi

ve anaphylactic shock (i.v.)No effect

System & Test Species Status

• Safety pharmacology (Rat, i.v. and Dog telemetry i.v.)

• Single-dose toxicity (Rat, i.v.)

• 4-week repeated-dose toxicity (Rat)

• 2-week repeated-dose toxicity (Dog)

• 4-week repeated-dose toxicity (Dog i.v. and Cynomolgus monkey p.o.)

•Studies under GLP have been c

ompleted.

•Detail results will be arranged if

requested.

In vitro, in vivo toxicity studies completed

Oct. 2016 v.17

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Safety

Monkey 4w repeated toxicity study

4w GLP toxicity in Monkey

Dose 0.5, 1, 2 mg/kg

Schedule PO, QD

Summary

• No significant safety issue found

• No article related death found

• AEs:

• Mild vomiting within 4h post administration at all doses

• Decreased weight in thymus, spleen at high dose

• Blood chemistry:

• Decreased RBC (13~25%), Hemoglobin concentration (12~24%) & Inorganic phosphorus (10~41%) at high dose

• Pathology:

• Thymic atrophy in males at 1, 2 mg/kg/day and females at 2 mg/kg/day

• This correlated with decreased weigh of thymus

Conclusion• NOAEL: 1 mg/kg

• MTD: 2 mg/kg

Oct. 2016 v.17

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P1a P1b

Condition Unspecified adult solid tumor Unspecified adult solid tumor

Administration IV infusion IV infusion

Dosing ScheduleOnce a week (2x/cycle)

3w/cycle (dose @D1,8 / off @D9~21)

Twice a week (4x/cycle)

3w/cycle (dose @D1,4,8,11 / off @D12~21)

Study Objectives MTD, DLT, PK MTD, DLT, PK

Biomarkers DCE-MRIDCE-MRI, DWI, CEP, Cytokine,

Tubulin status

Results

Well tolerated

MTD : 12 mg/m2

DLT : Transient hypertension

ORR : SD (6/23, 26%)

Well tolerated

MTD : 11 mg/m2

DLT : Transient hypertension

ORR : SD (8/18, 44%)

IV infusion

Oct. 2016 v.17

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Oral administration

P1a P1b /2a

Condition Unspecified adult solid tumors Progressive, recurrent colorectal cancer

Administration PO NOV1204 (PO) + Irinotecan (IV)

DosingSchedule

5 time per week (5d on & 2d off), 3W/cycleNOV1204: 5 time per week (5d on & 2d off),

Irinotecan : once a week, 3W/cycle

StudyObjectives

MTD, DLT, PKPh 1b: MTD, DLT, RP2D

Ph2a: ORR, OS, PFS, DOR, DCR, Safety

Biomarkers

Polymerized tubulin

VEGF, G-CSF, GM-CSF, SDF-1

PET-CT

-

Status(goal)

Dose escalation completed (n=16)

Dose expansion progress (n=10)-

Oct. 2016 v.17

2016 2017

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2011 2012 2013 2014 201520102009Project ID

NOV1204IND Approval

2014.8

FIH IND Approval 2009.12IV Phase 1 a

2010.1~2011.4Phase 1 b

2012.6~2014.10

POPhase 1 a2014.10 ~

Phase 1a (IV) Phase 1b (IV) Phase 1a (PO) Phase 1b/2a (PO)

Title Phase I Clinical Trial to Assess the Safety and Pharmacokinetic Profile of CKD-516 in Patients With Advanced Solid Cancers Failed to Standard Therapy

Phase I Clinical Trial to Assess the Safety and Pharmacokinetic

Profile of CKD-516 Inj. Administered on A Twice-

Weekly Schedule in Patients With Advanced Solid Cancers Failed to Standard Therapy

A Phase I Study to Assess the Safety, Tolerability and

Pharmacokinetics of NOV120401 (CKD-516 Tablet) in Patients

With Advanced Refractory Solid Tumors

이전에 치료받은 진행성/재발성결직장암 환자에서 CKD-516정과Irinotecan주 병용요법의 안전성및 유효성을 평가하기 위한 제

1/2a 임상시험

Dosing Design

Once a week(2 administration/cycle)

3w/cycle (D1, 8 administration

+ D9~21 withdrawal period)

Twice a week(4 administration/cycle)

3w/cycle(D1,4,8,11 administration

+D12~21 withdrawal period)

Daily(5/week)

Not disclosed

BioMarker DCE-MRI DCE-MRI, DWI, CEP, Cytokine, Tubulin status

PET-CT, Cytokine,Tubulin status

Not disclosed

Safety/PK/Efficacy

Completed Completed Going On Not disclosed


Mod of Action

Preclinical-POPhase 1b/2a2016.9 ~

Oct. 2016 v.17

NOV1301 (TEW-7197):ALK5 inhibitor

• NOV130101(TEW-7197) is an ALK5 (TGFβ type I receptor ) antagonist under development for the treatment of solid tumors and

CML. It reduces the signaling of TGFβ increased during cancer by inhibiting its receptor ALK5, directing to normalizing the

tumor microenvironment by modulating the extracellular matrix, angiogenesis and enhancing immune surveillance. In in vivo

studies it reduced metastasis and inhibited tumor growth in breast, melanoma, HCC, GBM, CML model, leading to survival

increase. Having good safety and PK profiles, it is orally administered once a day. It is under the phase 1 FIH under the US

FDA IND approval ( April 2014~).

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Target TGFβ type I receptor inhibitor

MOA Inhibits EMT and metastasis & activates immune surveillance

Dev. Stage Phase 1 (US)

Profile • An orally active potent small molecule inhibitor • Potent & selective • Good ADME & PK profile

Efficacy • Good efficacy in various in vivo animal models• Suitable for combination therapy

Dosing • PO

Indication Solid tumors (Breast, Melanoma, HCC, GBM) or Hematologic tumor (MM, MDS, CML)

Competition LY2157299 (Phase II)

Oct. 2016 v.17

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NOV1301(TEW-7197): ALK5 inhibitor

Mod of Action

Oct. 2016 v.17

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Mod of Action

Oct. 2016 v.17

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NOV1301 vs. LY2157299

40

NOV1301(TEW-7197): ALK5 inhibitor (2)

In vitro activity

Oct. 2016 v.17

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In vivo efficacy

Breast Cancer – efficacy in metastasis and survival

Oct. 2016 v.17

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In vivo efficacy

Melanoma – efficacy in metastasis

Oct. 2016 v.17

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In vivo efficacy

Tumor inhibition in HCC and GBM

32


In vivo efficacy

Survival increase in Hematological cancer model

Oct. 2016 v.17

2011

33

2013 2014 2015 2016 20172012Project ID

NOV1301

Phase 1a (PO)

Title First-in-Human Dose-Escalation Study of TEW-7197 Monotherapy in Subjects with Advanced Stage Solid Tumors

Dosing Design 5 days followed by 2 days without treatment in 28-day Cycles, PO

BioMarker Exploratory potential biomarkers (pSmad, TGF-β1, periostin)

Safety DLTs and MTD

Pharmacokinetics Cmax, Tmax, t1/2, CL, AUC, Accumulation Raito, Vd…

Efficacy Best overall response, Progression-free survival, Disease control rate

PO

US IND Approval2014.4

Phase 1 FPI2014.8 ~



Pre clinical study

Oct. 2016 v.17

NOV1401(IDX-1197): PARP 1 inhibitor

34

• NOV1401 is an poly(ADP-ribose) polymerase -1 (PARP-1) inhibitor. PARP is a protein involved in a number of cellular

processes involving mainly DNA repair and programmed cell death. PARP plays a key role in DNA repair by detecting and

initiating repair if a DNA strand breaks.

• NOV1401 selectively binds to and inhibits PARP, inhibiting PARP-mediated repair of single strand DNA breaks. PARP

inhibition enhances the cytotoxicity of DNA-damaging agents and reverses the tumor cell chemoresistance and

radioresistance.

Target Poly (ADP-ribose) polymerase-1 (PARP-1) inhibitor

MOA Inhibition of PARP-mediated repair of single strand DNA

Dev. Stage Non-GLP development

Profile • An orally active potent small molecule inhibitor • Excellent aqueous solubility• Potent & selective • Good ADME & PK profile

Efficacy • Good efficacy in various in vivo animal models• Suitable for combination therapy

Dosing PO

Indication Solid tumors (HGS-OV, Breast, Prostate, Gastric Cancer)

Competition Olaparib (Marketed), Rucaparib (Phase III), Niraparib (Phase III)

Oct. 2016 v.17

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Concept of PARP inhibitor

PARP-1 inhibitor treated to the patients with BRCA mutation makes cytotoxic drugs overcome chemo-resistance.

Oct. 2016 v.17

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In vitro activity

Assay Cell linesResults

IDX-1197 Olaparib Rucaparib BMN-673

Cell viability

(IC50, nM)

TNBC

1 BRCA1 WT >10,000 >10,000 - ≒800

2 mBRCA1 1 ≒20 - <5

3 mBRCA1 28 ≒800 >1,000 <10

BC1 BRCA1 Me 5 ≒700 >1,000 <10

2 BRCA1 Me 404 ≒2,700 - -

OVC

1 mBRCA1 3 ≒250 ≒400 <5

2 BRCA1 WT >10,000 ≒4,000 ≒7,000 <50

3 HRD 1 ≒250 ≒100 <10

4 HRD 2 >2,000 >10,000 <5

5 HRD 0.6 ≒75 ≒75 <5

6 HRD 2 ≒550 >1,000 <5

Pancreatic 1 mBRCA2 152 ≒400 - <5

Prostate 1 ETV1 fusion 15 ≒1,000 >5,000 <5

2 CRPC 1 ≒160 - <5

Gastric1 HRD 63 ≒1,000 >3,000 <5

2 HRD 0.6 ≒80 ≒50 <5

NSCLC 1 HRD 1 ≒500 >4,000 <5

IDX-1197 showed superior potency to olaparib in cancer cell lines with HRD

Oct. 2016 v.17

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In vitro activity

Cell line

Source HRD

1 Ovarian cancer BRCA1 null

2 Ovarian cancer EMSY amplification

3 Ovarian cancer FANCF methylation, ARID1A mutation

4 Ovarian cancer CDK12 low expression

5 Ovarian cancer BRCA1 mutation, ARID1A mutation

6 Ovarian cancerBRCA1/ATM low expressionCCNE1 amplification

7 Ovarian cancer BRCA1 mutation

8 Ovarian cancer CHEK2 low expression

9 Breast cancer BRCA1 methylation

10 Breast cancer BRCA1 null , BRCA2 mutation

11 Breast cancer BRCA1 low expression

12 Gastric cancer ATM low expression

13 Gastric cancer ATM low expression

14 Gastric cancer -

15 Gastric cancer -

16 Pancreatic cancer BRCA2 mutation

17 NSCLC ATM low expression

18 Prostate cancer -

Cancer cell lines with homologous recombination deficiency (HRD) were especially sensitive to IDX-1197, while cancer cell lines without HRD were non-sensitive to our compound.

Oct. 2016 v.17

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In vivo efficacy

Group TGI(%) T/C(%)

Olaparib 100 mg/kg 36.0 71.3

IDX-1197 HCl 50 mg/kg 62.2 50.4

IDX-1197 HCl 100 mg/kg 82.5 34.1

IDX-1197 HCl 200 mg/kg 110.7 11.6

(CAPAN1 cell : mBRCA2, p53/KRAS mutant)

Mean Body Weight

Mean Tumor Volume

0.0

5.0

10.0

15.0

20.0

25.0

0 5 10 15 20 25 30

Bo

dy w

eig

ht

(g)

Day

Vehicle

Olaparib 100mg/kg

IDX-1197 50mg/kg

IDX-1197 100mg/kg

IDX-1197 200mg/kg

AACR-NCI-EORTC 2015 (Merck, TESARO)

Group TGI(%) T/C(%)

Olaparib 75 mg/kg* 54 -

Niraparib 45 mg/kg* 26 -

0

500

1000

1500

0 5 10 15 20 25 30

Tu

mo

r vo

lum

e (

mm

3)

Day

Vehicle

Olaparib 100mg/kg

IDX-1197 HCl 50mg/kg



Anti-tumor activity of IDX-1197 HCl in the CAPAN1 xenograft model

Oct. 2016 v.17

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In vivo efficacy

Anti-tumor activity of IDX-1197 HCl in the CRPC model

Sub-cutaneous Tumors

Control Olaparib IDX 11970

500

1000

1500

2000

Tu

mo

r W

eig

ht

(mg

)

P<0.01 P<0.01

4 weeks after administration, IDX 1197

showed in vivo activity in CRPC xenografts

< C4-2B Prostate Sub-Cutaneous Tumors >(4-week results)

Subcutaneous Xenograft Model

C4-2B(castration resistant prostate cancer, CRPC)

200mg/kg 100mg/kg

Control Olaparib IDX 11970.00

0.01

0.02

0.03

0.04

Ra

dio

luce

nt

Are

a(A

rbitr

ary

Un

it) P<0.01 P<0.01

< C4-2B Prostate Intra-tibia Tumors >(Osteolysis Measurement)

200mg/kg 100mg/kg

Osteolytic bone metastasis from prostate

cancer was reduced in each group treated with

olaparib or IDX-1197

Bone-Orthotopic Xenograft Model

C4-2B(castration resistant prostate cancer, CRPC)

2013

40


Future Plans

We have studied PAR levels from blood samples as a potential biomarker candidate.

After KFDA grants IND Approval for phase I study of IDX-1197 in solid tumor, we will initiate phase I study of our compound in the first quarter of 2017.

2015 2016 2017 2018 20192014Project ID

NOV1401 PO IND Approval2017.1Q~

Preclinical study

FIH phase 1~

Oct. 2016 v.17

NOV1402(JPI-547): pan-PARP inhibitor

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• NOV1402 acts by targeting poly ADP-ribose polymerases (PARPs) and Tankyrase (TNKS). PARP is a DNA nick-sensor that

signals the presence of DNA damage and facilitates DNA repair. Inhibition of PARP increases the activity of DNA damaging

agents and causes cancer cell death. By inhibiting tankyrase, the drug candidate inhibits the Wnt and beta-catenin

signaling by stabilizing axin and promoting beta-catenin degradation, this leads to prevention of tumor growth.

• In vitro/vivo results showed NOV1402 is superior to Olaparib or other tankyrase inhibitors in its efficacy and toxicity. Also, it

was proved to inhibit two biomarker-driven tumor growth indicating possible patient selection criteria in clinical trial

available. Upon confirmation of its clinical feasibility, parallel development of companion diagnostics is going to be

planned more specifically.

Target Poly (ADP-ribose) polymerase-12,3,4 and tankyrase

MOA Inhibition of PARP-mediated repair of single strand DNA and Tankyrase

Dev. Stage Non-GLP development

Profile • An orally active potent small molecule inhibitor • Excellent aqueous solubility• Potent & selective

Efficacy • Good efficacy in various in vivo animal models

Dosing PO

Indication Solid tumors

Competition Olaparib (Marketed)

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Concept of pan-PARP inhibitor

Many anti-cancer effects of PARPi and TNKSi were overlapped. We expect the synergies of PARP/TNKS dual inhibitor.

Molecular Cell, 2015, 58(6), 947-958

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Target Product Profile

Health & Medicine

Nov pipelines 2016-ver17