Nov Oncology pipelines 2015-1_ver14

NOV Pipelines

Non-confidential information.

Oct. 2015. Ver.14

Oct. 2015 v.14

Contact Information

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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

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Non-GLP

GLPFIH IND

Ph 1 Ph 2

NOV pipelines

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Project ID Description MOA Indication

NOV1201(Licensed Out)

Pan-Herinhibitor

Inhibition of ERBB signaling

Solid tumors(NSCLC

Breast, Gastric)

NOV1105Anti-HGF Antibody

Neutralizing HGFSolid

tumors(GBM, NSCLC)

NOV1204Vascular

Disrupting Agent

Inhibition ofTubulin

polymerization

Solid tumors(CRC

Ovarian ca.)

NOV1301 ALK5 inhibitorInhibition of EMT/

MetastasisMetastatic

tumors

NOV1401PARP 1 inhibitor

Inhibition ofPART 1

Solid tumors(Ovarian ca, Breast ca)

NSCLC 1st

NSCLC 2nd

Breast

Gastric

PO

IV

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Index

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Project ID Page

NOV1105 Anti HGF Antibody on phase 1 for Solid tumors 5

NOV1204 Vascular Disrupting Agent targeting tumor specific vasculature on phase 1 for Solid tumors 10

NOV1301 Anti-ALK 5 (TGF beta Receptor 1) inhibitor on phase 1 for Metastatic tumors 15

NOV1401 PARP 1 selective inhibitor on preclinical stage for Solid tumor with specific biomarkers 24

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NOV1105(A2512): Anti-HGF Antibody(1)

• 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 7 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 acceptor, cMet, are reported to be excessively found in various human cancer

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

prognosis of the patient and possible spread.

• NOV110501 stops signaling cMet/HGF and shows excellent effects on the GBM (Glioblastoma) and STS (Soft Tissue

Sarcoma) animal models.

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Target Hepatocyte Growth Factor (HGF)

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

Dev. Stage Phase 1 (FIH)

Profile Fully human anti-HGF antibody

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

Dosing IV

Indication Solid tumors (Leiomyosarcoma, Glioblastoma, NSCLC)

Competition Ficlatuzumab (Phase II)

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Clinical Development

2011 2012 2013 2014 201520102009Project 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 1 a2015.6 ~

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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 (IV and 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 & PO

Indication Solid tumors

Competition BNC105, CA4P, CA1P, (ASA404, AVE8062, ABT-751: recently no development reported)

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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.

Mechanism of Action (1)

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VS.

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2011 2012 2013 2014 201520102009Project ID

NOV1204IND Approval

2014.8

FIH IND Approval 2009.12

IVPhase 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)

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

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)

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

PET-CT, Cytokine,Tubulin status

Safety Completed Completed Going On

Pharmacokinetics

Efficacy

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NOV1301 (TEW-7197):ALK5 inhibitor (1)

• 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)

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NOV1301 vs. LY2157299

40

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Non-Clinical Development

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B16-F1(Melanoma) Syngeneic model

Scoring mammary protein(b-casein) in the lung to measure metastasis (Dose: QD, 3w, dose start @D4)


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2011 2012 2013 2014 201520102009Project 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

NOV1301 (TEW-7197):ALK5 inhibitor (9)Clinical Development

US IND Approval2014.4

Phase 1 FPI2014.8 ~

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NOV1401: PARP 1 inhibitor (1)

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• 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)

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Mechanism of Action

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


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In vitro

Items target/cell linesDATA

NOV140101 Olaparib Rucaparib

Enzyme activity (IC50, nM)

PARP1 2 2 -

PARP2 1 1 -

TNKS-1 >10000 1,664 658

Cellular PAR activity (EC50, nM)

Hela 1 1 3

Cell viability (IC50, nM)

TNBCBRCA1 WT MB-231 >10,000 >10,000 -

mBRCA1HCC-1937 28 835 >1000

OVca

UWB1.289 3 256 358

BRCA1 WT UWB1.289_BRCA1 >10,000 4,000 7,000

HRD Caov3 1 267 109

Pancreatic ca mBRCA2 Capan-1 152 331~453 -

Prostate ca ETV1 fusion LNCaP 15 1000 6000

Gastric ca HRD SNU-638 63 1021 3953


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In pancreatic model In prostate model

Capan-1 (BRCA2 null) : S.C Xenograft C4-2B (ETV1 fusion) : S.C Xenograft C4-2B (ETV1 fusion) : Bone Orthotopic

Sub-cutaneous Tumors

Control Olaparib IDX 11970

500

1000

1500

2000

Tu

mo

r W

eig

ht

(mg

)

P<0.01 P<0.01

Control

Olaparib(200mg/kg)

IDX1197 (100mg/kg)

Olaparib 200mg/kg IDH1197 100mg/kgControl

C4-2B INTRA-Tiibia tumors (X-ray images)

Control Olaparib IDX 11970.00

0.01

0.02

0.03

0.04

Ra

dio

luce

nt

Are

a(A

rbitra

ry U

nit) P<0.01 P<0.01

Osteolysis Measurement

In vivo

* NOV1401 (IDX-1197) 27

Health & Medicine

Nov Oncology pipelines 2015-1_ver14