Aberrant NOTCH Signalling in Breast Cancer: an …...2017/10/03 · Medical Need: New therapeutic option, no effective treatment available Animal model: HCC1187, multi-drug resistant,

Cellestia Biotech / Company Presentation / October 2017 / Non-Confidential slide 1

Aberrant NOTCH Signalling in Breast Cancer: an attractive target for pan-NOTCH inhibition

Dirk Weber, CMO Cellestia Biotech AG, Basel

Basel Breast ConsortiumBasel, 03 October 2017


Agenda / Topics

• Introduction and Background

• NOTCH Signalling Pathway

• NOTCH Signalling in Breast Cancer

• Pan-NOTCH inhibitor CB-103 in Breast Cancer


Cellestia Biotech AG: History & Profile

www.cellestia.com/

Cellestia Biotech Locations:• HQ & Development

Hochbergerstrasse 60CCH-4057 Basel Switzerland

• Research LabInnovation SquareEPFL Building CCH-1015 Lausanne Switzerland

• Spin-off from Swiss Institute for Experimental Cancer Research at EPFL, Lausanne, Switzerland

• Major Milestones Founded May 9th 2014 by Prof. Radtke & R. Lehal; co-

founding management team 11/2015 M. Bauer & Team

CB-103 pan-NOTCH inhibitor selected as development candidate in 2015

1st Patent granted (USA, Singapore, NZ, SA, China)

First-in-human clinical study of CB-103 approved in Spain on 11Aug17 & by Swissmedic today (03Oct17)

• Next Steps First cancer patients to be treated in Nov 2017

https://www.cellestia.com/


• New Hope: CB-103 • New Mode of Action• Good safety profile• Specific Diagnostic• Clinical Stage• First Patient 2017

Confirmed anti-cancer activity in a range of in vitro and in vivo studies, including leukemia patient blood and patient derived breast cancer model

Join us in fighting cancer – precise and personalized

Cellestia Vision & Mission


What is NOTCH ?

Cell-to-Cell communication mechanism of physically directly adjacent cells

Signal Sending Cell: „Ligand“ 5 NOTCH activating ligands

Signal Receiving Cell: „Receptor“ 4 NOTCH receptors

Signal Translation: „NICD´s“ trigger transcription in cell nucleus

Cancer

Growth, Survival, Metastasis, Invasion, Blood Vessel Formation

constitutive activation

DLL1, DLL3, DLL4JAG1, JAG2

Adapted from : Andersson & Lendahl Nature Reviews Drug Discovery, MAY 2014; VOLUME 13

NOTCH 1-2-3-4

Selective Effect: „downstream“ proteins produced due to NOTCH activation: Driving cancer if out of control

xCB-103


Notch has been implicated in diverse cancer hallmarks

Breast CaT-ALLCLLACC

Breast CaT-ALLCLL

SCCa(diverse sites)

AllCancers

Innate andAdaptive Immunity

Breast Ca(Tumor Dormancy)

MacrophagePolarization (M1)

Epithelial-Mesenchymal

Transition

Preservation ofTICs

(Breast, Lung,Pancreas)

P53 target geneP53 suppressor

Courtesy from Prof Jon Aster, MD PhDHarvard Medical School, Boston


Breast Cancer (BC):• High level co-expression

of JAG1 and NOTCH1

• Associated with poor survival (median OS): High NOTCH1: 40 mths Low NOTCH1: 83 mths

Reedjik et al.Cancer Research 2005

Significantly shorter survival for patients with high NOTCH activationNOTCH is a clinically validated target – anti NOTCH drugs show clinical efficacy

Breast Cancer (TNBC, ER+) key indications for CB-103

High NOTCH1

Low NOTCH1

Patients´ life expectance depends on NOTCH status

Clinical Relevance of NOTCH Signalling


CB-103 in Breast Cancer:Rationale for use in various BC subtypes

• NOTCH pathway activation in cancer cells interacts and cross talks with other pathways

• NOTCH inhibition by CB-103 may work synergistically in combination with other treatment strategies:

Anti-estrogens HER2 inhibitors Angiogenesis inhibitors Various chemotherapy

regimen

H Al-Hussaini, D Subramanyam, M Reedijk and S Sridhar: Notch Signaling Pathway as a Therapeutic Target in Breast Cancer. MolCancer Ther; 10(1) January 2011


Strategies to target NOTCH


Why is CB-103 unique ?

CB-103 is an new anti-cancer drug for NOTCH driven cancers

Adapted from : Andersson & Lendahl; Nature Reviews Drug Discovery, MAY 2014; VOLUME 13

constitutive activation

Proliferation

Resistance to Cell Death

Angiogenesis

Invasion

Metastasis

Cancer Stem Cells

CB-103

CB-103 is a first-in-class pan-NOTCH inhibitor with a unique MoA(Protein-Protein Interaction Inhibitor)


SELECTED KEY INDICATIONS

Adenoid Cystic Carcinoma (ACC) T-ALL Breast Cancer

(TNBC, ER+, HER2+) HL & NHLIndications based

on phase IIA expansion

• Orphan indication• NOTCH 1/2 aberration

well characterized• NOTCH-driven tumor in

20-30% of patients with very poor prognosis

• NOTCH Inhibitor in clinical studies

• Collaboration with ACC Research Foundation ongoing with clinical collaboration at MDACC

• High unmet medical need

• PDx models ongoing

• Fast-to-approval indication (2021)

• Pediatric & Orphan indication

• NOTCH causative• Constitutive activation,

well characterized (N1)

• Unmet medical need

• Established access to patients via study groups (BFM, ITCC)

• Collaboration with University Children Hospital Zürich

• PDx in vivo studies ongoing

• Single agent and combinations considered

• Fast-to-approval indication (2022)

• TNBC is orphan indication

• NOTCH well characterized (translocations, mut)

• Resistance mechanism of ER+ & HER2+ BC NOTCH-driven

• Unmet medical need

• Huge market potential

• TNBC in vivo models established and study ongoing to test single agent and combinations

• All subtypes considered for combinations in rel/ref disease

• Orphan indications• NOTCH over active

in many subtypes• CNS Lymphoma with

NOTCH1 activity

• Partially high unmet medical need

• Collaborations with various study groups possible

• Strong rationale to may consider basket clinical study to gain MoA-driven indication (NOTCH positive lymphomas)

• Large and Orphan indications

• Several indications pre-selected in phase IIA (solid tumours, leukaemias)

• NOTCH well characterized in all indications

• Solid tumours (CCC, Sarcomas, GBM)

• Leukaemias (CLL, AML)

• Several in vivo studies started (CRC, Lymphomas, CLL)

Factors and reasons justifying selection of key indications:1. Adenoid Cystic Carcinoma (ACC)2. T-ALL3. Breast Cancer4. Hodgkin Lymphoma & non-Hodgkin Lymphomas5. Indications based on phase I/IIA study


CB-103 is Active in Cancer Types with No Efficient Therapeutic Options

Activity of CB-103 in a mouse model of Triple Negative Breast Cancer

Placebo Treatment

CB-103 Treatment

Clear disease control, well tolerated daily treatment

Patient diagnosed with GSI resistant tumor

Mouse model with human derived cancer Only CB-103 works


Activity of CB-103 in a mouse model of Triple Negative Breast Cancer

Downregulation of NOTCH Target Gene HES1 and others in NOTCH activated HCC1187 by CB-103, but not GSIs

Patient diagnosed with GSI resistant tumor

In vitro cultivation and mouse model with

human derived cancer Only CB-103 works




CB-103 is active on GSI & Chemo resistant Triple Negative Breast Cancer

• Clear Disease Control with no adverse events observed in TNBC model• More potent than established standard of care paclitaxel, GSI no effect• Confirmed down-regulation of NOTCH biomarkers, no effect with GSIs• Medical Need: New therapeutic option, no effective treatment available

Animal model: HCC1187, multi-drug resistant, GSI resistant, constitutive activation of NOTCH by chromosomal translocation

Cancer Discovery 2014, Stoeck et al.

MRK-003 = GSI of Merck


Personalized medicine: Select NOTCH+ patients from various cancer indications

Cancer indications with NOTCH aberrations/activations

Diagnostic Screening of Tumor Samples for NOTCH aberrations

Treatment of NOTCH+ patients withCB-103

1. Indication Selection 2. Patient Selection 3. Treatment Selection

Increase chances of therapeutic success implementing adequate patients selection

Hematological Malignancies (% NOTCH+):- Various subtypes of Non-Hodgkin

Lymphomas (6-55%)- T-cell Acute Lymphocytic Leukemia (55%)- Chronic Lmyphatic Leukemia (12-50%)- Multiple Myeloma (30-60%)

Solid Tumor Indications (% NOTCH+):

- Breast Cancer (TNBC) (3-46%)- Breast Cancer (ER+) (14-38%)- Breast Cancer (HER2+) (60%)- Adenoid Cystic Carcinoma (11-29%)- Colorectal Cancer (10%)- Cholangiocellular Cancer (40%)- Gastric Cancer (50%)- Lung Adenocarcinoma (10-30%)- Melanoma (50%)- Glioblastoma Multiforme (30-40%)

Patient selection for NOTCH-targeted therapy

- Patients with NOTCH+ tumors will be selected for CB-103 treatment

- Technologies established:- NEXT GENERATION SEQUENCING- NANOSTRING mRNA GENE

EXPRESSION ANALYSIS- IMMUNOHISTOCHEMISTRY

NOTCH-targeted therapy with pan-NOTCH inhibitor CB-103

- CB-103 as monotherapy- CB-103 in combination with

chemotherapy or other targeted therapies

CB-103 Clinical Development StrategyIndication & Patients Selection


CB-103 Clinical Development StrategyPhase l – lla Study Design

Dose Cohort 1

Dose Cohort 2

Dose Cohort 3

Dose Cohort X

Dose Cohort 4

MTD/RP2D

Advanced/metastatic solid tumors and haematological malignancies

- No patient enrichment for NOTCH+- Bayesian Logistic Regression

Model

N = appr. 25

Expansion Arms with selected indications:- Selection of NOTCH+ patients only- Bayesian Hierarchical binomial-design- Stratification by indication, approx. 20 pts per

arm with interim analysis after 10 evaluable pts

N = appr. 140

Patients with NOTCH-positive/-activated tumours:1. Solid tumours 1 (NSCLC (lung adeno-ca), ovarian

ca, cervical ca, prostate ca, melanoma, GBM)2. Solid tumours 2 (sarcomas, desmoid tumors,

adenoid cystic carcinoma)3. TNBC Cancer with NOTCH-specific

chromosomal translocations4. Breast cancer (other TNBC, ER+/-, HER2+/-)5. GI Cancers (CRC, gastric cancer, CCC)6. Non-Hodgkin and CNS lymphomas7. Multiple Myeloma

MTD / RP2DPart A – dose escalationSafety: Dose and Schedule

Part B – dose confirmationEfficacy in selected Indications

CB-103 oral dosing (flexible 1x or 2x daily – intermittent) in 28-day cycles

Potential addition of CLL patients

Dose Cohort Y Leukaemia

Approval in Spain on Aug. 11th, 2017, study start in 4Q 2017


CB-103 Clinical Development StrategyClinical Study Centers

Part A (escalation):7-8 clinical sites in Spain, Netherlands and Switzerland• PI Dr Elena Garralda (Vall D’Hebron Oncology, Barcelona)• Dr Javier Cortes (Ramon y Cajal University Hospital, Madrid)• Dr Jose Perez (Quiron University Hospital, Barcelona)• Dr Rogier Mous (3 sites from LLPC study group, Netherlands

- Utrecht, Amsterdam, Maastricht -)• Dr Anastasios Stathis (Oncology Institute of Southern Switzerland, Bellinzona, CH)• Optional:

Dr Dagmar Hess (Sankt Gallen Kantonsspital, Switzerland)

For Part B (expansion): Up to 25 sites in Spain, Netherlands, Germany, Switzerland, US, maybe UK or France• Vall D`Hebron Oncology, Barcelona (Dr Elena Garralda, Dr Tabernero)• Ramon y Cajal University Hospital, Madrid (PI Dr Cortes)• Quiron University Hospital, Barcelona (PI Dr Perez)• San Camillo Hospital, Madrid (PI Dr Cortes)• 5-8 sites from LLPC study group, Netherlands (PI Dr Mous, University Medical Center Utrecht)• 4-5 study centers in Switzerland; 4-5 study centers in Germany, UK and France• IND submission and inclusion of US sites (MD Anderson, Vanderbilt, MSKCC)


Targeting NOTCH:Competitor´s Success, Failure and Learning

Cellestia pursues a fully integrated drug & diagnostic development program

• All competitors ignored biomarker guided patient selection or tracked biomarkerstatus with incomplete or indadequate assessment of NOTCH pathway activation, failing to reflect the complexity of NOTCH signalling

• Cellestia is utilizing a 30 gene expression profiling (Nanostring) complemented by next generation sequencing, tracking for chromosomal translocations and IHC.

Cellestia Biomarker Strategy

DNA mRNA Protein

NGS Nanostring IHC

VHIO implemented

VHIO implemented

N1-ICD, CDK available

Proprietary program started


CB-103 – Breast CancerNOTCH EXPRESSION PROFILE

NOTCH Pathway is well characterized:• Mutations• Chromosomal translocations• NOTCH receptor / ligand overexpression

INDICATION NOTCH-EXPRESSION (MODE OF ACTIVATION)

Breast Cancer (TNBC)

• 9 % chromosomal translocations (Notch1/2)• 13 % GOF mutations• 46 % JAG1 overexpression• 27-44 % NUMB deficient

Breast Cancer (ER/PR+, HER2-) • 38 % NOTCH4 upregulated• 14 % NUMB deficient/reduced

Breast Cancer (ER+/-, PR+/-, HER2+ • 39 % NUMB deficient/reduced• Promotion of dormant tumour cells

• Patient selection based on NGS, Nanostring expression analysis and IHC


• Clinical prognostic relevance of NOTCH in Breast Cancer• NOTCH genetic aberrations frequent in BC (mutations, translocations)• Pan-NOTCH inhibitor CB-103 shows clinical activity in vitro and in vivo• Phase 1-2A set-up and to be started in Q4 2017

− Full study approval in Spain (11Aug17)

− CA approval in Netherlands and final review EC CH/NL ongoing

− Approval expected in Oct17 and site initiation in Oct17 (FPI Nov 2017)

• Countries & Sites selected− Spain (3), Netherlands (3) and Switzerland (1+1) in part A (phase I dose escalation)

− Additional countries planned for part B (UK, FR, US) (phase IIA expansion)

− USA Pre-IND meeting (Q1-2018) & IND submission planned (Q2-2018)

Pan-NOTCH Inhibition in Breast Cancer with CB-103

Cellestia - from research to clinical-stage company


Cellestia Biotech Research:Innovation Square, EPFL Building C1015 Lausanne, Switzerland

For more information contact:Dirk Weber, CMOCellestia Biotech AGHochbergerstrasse 60C4057 Basel, SwitzerlandMobile: +41 79 9441580Email: [email protected]

mailto:[email protected]

http://www.cellestiabiotech.com/


Back-up Slides


Cellestia has been very successful in attracting internationally recognized experts in preclinical and clinical research and development

Clinical / Medical Advisory Board

PROF. JOSEP TABERNEROHead Med Oncology Department & Director Vall d’Hebron Institute of Oncology (VHIO)

PROF. JAVIER CORTESMedical Oncology; Vall D`Hebron, Barcelona; Ramon y Cajal Hospital, Madrid

PROF. RICHARD HERRMANNMedical Oncology, Basel

PROF. JEAN-PIERRE BOURQUINPediatric Oncology, Children Hospital Zürich, Switzerland

PROF. ANTON HAGENBEEKMedical Hemato-oncology, Chairperson LLPC, Netherlands

PROF. MARTIN DREYLINGMedical Hematooncology, LMU Munich

PROF. CHRISTIAN BUSKEMedical Hematooncology, Experimental Cancer Research, University Ulm

PROF. ANDREAS ENGERTMedical Hematooncology, Chairman of the GHSG, University of Cologne, GermanyPROF. ANASTASIOS STATHISOncology Institute of Southern Switzerland, Bellinzona, CH


Adenoid Cystic Carcinoma (ACC):• Solid tumour indication (salivary gland tumour), Orphan indication, fast-to-approval opportunity (by 2021)• Difficult-to-treat, 40-50 % recurrent, chemo-refractory, high unmet medical need• NOTCH1 GOF mutations found in tumours in 11-29 % of ACC patients• Collaboration established with MD Anderson Cancer Center (MDACC) and ACC Research Foundation• 100´000$ Grant for research on CB-103 in ACC achieved by MDACC

• Survival of patients depends on NOTCH status in tumours: NOTCH1 wildtype: 121.9 months NOTCH1 mutated: 29.6 months

Example: Clinical Relevance and Validation of NOTCH as Therapeutic Target

R. Ferrarotto et al. 2016


Adenoid Cystic Carcinoma (ACC): CB-103 shows comparable preclinical efficacy to Brontictuzumab, which is effective in clinical trials

R. Ferrarotto et al., 2016

In vivo efficacy of Brontictuzumab in ACCX9 PDX model

Efficacy in mouse

Clinical ResponsePartial Response in patient with advanced ACC and liver metastases treated with Brontictuzumab:

• CB-103 shows clear efficacy in a range of NOTCH positive cancer models, i.e. ACC, TNBC, T-ALL

• Clear proof of principle established• Expect clinical efficacy comparable to

competitor´s clinical PoC• Collaboration with MD Anderson Cancer Center

/ R. Ferrarotto / ACC Research Foundation

In vivo efficacy of CB-103 in ACCX9 PDX model

Clinical Relevance and Validation of NOTCH as Therapeutic Target : ACC


Differentiation Based On Safety And PK Profile

Contrary to GSIs CB-103 only causes mild Goblet Cell Metaplasia

Pellegrinet et al., 2011

Control GSI treatment (DBZ)

i.p injection20 µM/Kg for 4 daysGSIs induce

severe goblet cell metaplasia

CB-103 does not cause severe goblet cell metaplasia

25 mg/kg for 4 days3x daily p.o.

Differential response of CB-103 to different tissue vs GSI

Documents

Aberrant NOTCH Signalling in Breast Cancer: an …...2017/10/03 · Medical Need: New therapeutic option, no effective treatment available Animal model: HCC1187, multi-drug resistant,