Mesothelin-ADC - Molecular Diagnostics for Cancer Drug ...

Mesothelin-ADC : A Case- 

Study in Early Development 

of a Companion Diagnostic 

David Henderson 

Clinical Sciences 

Bayer Pharma AG, Berlin

Agenda 

Drug Targeting: Antibody Drug Conjugates 

Rationale and Pre-clinical Results 

Development Path for a Companion Diagnostic 

Regulatory Aspects 

Clinical Development Strategy 

Page 2 • Mesothelin ADC BAY 94-9343, MipTec 2011 Basel, Sven Golfier

Drug Targeting with an ADC 

n (2.6 - 4.0) 

• Mesothelin-ADC: a human IgG 1 

conjugated to the maytansinoid antimicrotubule 

drug DM4 through a cleavable 

linker 

• Mode of Action: Targeting tumor antigen 

mesothelin and delivery of a toxophore 

acting on proliferating cells. 

• Pharmacological profile: Tumor growth 

inhibition of mesothelin-expressing tumors. 

• ADC promises directed cytotoxicity with 

minimized off target effects 

3 • Mesothelin ADC • Boston, June 2012 • David Henderson

Scientific rationale: 

Mesothelin-ADC / BAY 94-9343 

Healthy tissue 

Human tumor tissue 

Peritoneum Mesothelioma *) Ovarian Ca *) 

Pancreas Ca *) 

• Target is located on cell-surface: 

*) score 2 

• Mesothelin is an internalizing cell-surface membrane mesothelial differentiation antigen of 

unknown function (k.o. mice have no observed phenotype) 

• Mesothelin is a tumor target: 

• Mesothelin is selectively over-expressed in many human tumors (e.g. pancreas 80-100%, 

ovary 80%, mesothelioma 100%, lung 40%NSCLC) 

• Potential for selectivity and high potency of antibody drug conjugate 

• Expression of mesothelin for patient stratification and soluble plasma biomarker for 

pharmacodynamic response 


Literature data on mesothelin expression confirmed 

Score: 0 1 2 3 

Pancreas 

all ductal adenocarcinoma 

24% 

0% 

Case 14 0 / 0% Case 55 10 / 10% 

Ovarian Cancer (serous) 

37% 

100% pos. (14/14) Ordonez et al. 2003 5B2 

82% pos. (27/33) Hassan et al. 2005 K1 

55% pos. 92/167 Johnson et al. 2008 5B2 

Ovarian Carcinoma 

Case 56 80 / 40% Case 38 300 / 100% 

20% 

Score [0-3] 

20% 

Pancreatic Cancer (ductal) 

100% pos. (60/60) Argani et al 2001 5B2 

Score 0 

86% 

Score 

pos. 

1 

(12/14) Ordonez et al. 2003 5B2 

100% Score pos. 2 14/14 Frierson et al. 2003 5B2 

62% Score pos. 3 28/62 Jhala et al. 2006 5B2 

25% 

39% 

5 • Mesothelin ADC • Boston, June 2012 • David Henderson 

35% 

n=21

Mesothelin expression is unchanged during progression 

Score: 0 1 2 3 

Case 14 0 / 0% Case 55 10 / 10% 

Case 56 80 / 40% Case 38 300 / 100% 

Mesothelin IHC on matched samples: primary ovarian cancer vs. relapse, 

111002_29 

Primary 

Score 1 

Relapse 

Score 1 

8% 

8% 6% same 

58% 

20% 

same 

raise 

raise (0 becomes 1 or 2) 

mild increase 

mild increase mild (1 decrease becomes 2) 

loss 

mild decrease (2 becomes 1) 

loss (2 or 1 becomes 0) 

58% n=50 

Mesothelin expression remains stable 

during ovarian cancer progression 

Archived tumor samples can be used 

to select ovarian cancer patients for 

mesothelin-ADC therapy. 

All staining performed on FFPE tissue with MB-G10 antibody, scoring by Dept. of Pathology, Charité 


Mesothelin-ADC: Anti-Tumor Efficacy in 

patient derived xenograft models 

Patient derived Ovarian Cancer model (OVCAR6719) 

Patient derived Pancreatic Cancer model (PAXF736) 

Tumor volume (absolute cm³, mean) 

1,6 

1,6 

1,4 

1,2 

1,0 

0,8 

0,6 

0,4 

0,2 

Control vehicle 

Cisplatin 6 mg/kg 

DM4 0,2 mg/kg 

BAY 94-9343 2,5 mg/kg 

BAY 94-9343 10 mg/kg 

M-ADC 

Cis-Pt 

Tumor volume (absolute cm³, mean) 

2,5 

2 

1,5 

1 

0,5 

Control vehicle 

Gemcitabine 240 mg/kg 

DM4 0,2 mg/kg 

BAY 94-9343 2,5 mg/kg 

BAY 94-9343 10mg/kg 

M-ADC 

Gemc 

0,0 0 

25 35 45 55 65 75 

Days after transplantation 

0 

0 4 7 10 11 14 18 2021 25 28 3032 35 3940 42 46 49 50 53 56 60 

Days after Randomization 

BAY 94-9343 treatment shows superiority to SOC in efficacy 

in patient derived xenograft models of pancreatic and ovarian cancer 


Mesothelin positive cells 

tumor area (mm²) 

Mesothelin-specific targeting and 

bystander effect 

Experimental 

design 

Mesothelin Mesothelin 

- 

+ 0 % 

20 % 

40 % 

Mesothelin 

expression 

tumor area [mm 2 ] 

200 

150 

100 

50 

Anti-tumor 

efficacy 

100% po 

100% po 

80% pos 

60% pos 

40% pos 

20% pos 

0% posi 

60 % 

80 % 

100 % 

0 

0 10 20 30 40 50 60 70 80 

time after Days tumor after tumor cell cell inoculation [days] 

100% mesothelin control 

0% mesothelin 

20% mesothelin 

40%mesothelin 




Bay 94--9343 

10 mg/kg 

Increased mesothelin expression translates into increased efficacy of BAY 94-9343 


A CDx will be needed for Mesothelin-ADC 

• Therapeutic activity in cell lines and xenograft models is dependent on 

mesothelin expression 

• There will be a cut-off level in mesothelin expression below which there is no clinical 

benefit from treatment 

• Exclude patients with low or no expression of the target to avoid futile threatment 

• Patient stratification requires a Companion Diagnostic to ensure optimal 

delivery of the therapeutic 

• The clinical development program must be designed to allow parallel 

development of the therapeutic and a companion diagnostic: 

• Achieve simultaneous marketing authorization of drug and diagnostic kit 

• Diagnostic device must be marketed globally 


A CDx will be needed for Mesothelin-ADC (2) 

• The solution - 

• Partnership between pharmaceutical and diagnostic companies: bring 

complementary expertise in clinical development and regulatory issues 

into a joint development program 

TUCSON, 17 Jan 2012 

Ventana to Collaborate with Bayer on Companion Diagnostic Test for new Biological Cancer Therapy 

Stratifying patients for the appropriate, targeted therapy may prove to be a significant step towards 

personalized medicine in cancer treatment 

Ventana Medical Systems, Inc. (Ventana), a member of the Roche Group, today announced that 

it has entered into a strategic collaboration agreement with Bayer Bayer Pharma AG (Bayer) to 

develop a molecular companion diagnostic test intended to identify patients most likely to benefit 

from a novel Bayer antibody-drug conjugate (ADC). … … . 


Companion Diagnostics in Practice 

Implementation requires validated tests – US 

• Definition of Companion Diagnostic Device 

• “diagnostic device that provides information 

that is essential for the safe and effective 

use of a corresponding product” 

• Drug is reviewed by CDER/CBER and 

diagnostic is reviewed by CDRH/OIVD 

• Diagnostic needs a Pre Market Approval, 

contemporaneous PMA - NDA/BLA approvals 

• IDE required for investigational devices, if used 

to make treatment decisions (patient selection, 

treatment assignment etc. eg: Phase III) 

• Entire system is considered for approval 

(e.g., primary antibody, detection system, 

instrument). Scoring system/cut-off 

determination are integral to approval. 


Companion Diagnostics in Practice 

Implementation requires validated tests – EU 

• Drug and Diagnostic applications are registered 

separately in the EU 

• Drugs are reviewed by the CHMP and approved by 

the EU Commission. 

• Diagnostics come under the purview of National 

Competent Authorities and are either self-declared 

or are approved by Notified Bodies 

• IVDs not reviewed by the EMA, but reflection 

paper in preparation 

• regulated by European Directive 98/97/EC 

“In vitro diagnostic medical devices” 

(currently under revision - new version in 2012) 

• CE marking applies directly to all countries 

recognizing the classification; Instrument, 

Primary antibody, detection system are CE 

marked separately 


Parallel development of a therapeutic agent 

and a companion diagnostic 

Drug Development Pathway 

Lead 

Discovery 

Compound 

Optimization 

Preclinical 

Development 

Clinical Development 

Phase 1 Phase 2 Phase 3 

Regulatory Filing 

Approval 

Launch 

Device Development Pathway 

Simultaneous 

Approval & 

Launch 

Biomarker 

identification 

Analytical 

Validation 

Feasibility 

Analysis 

Clinical 

Qualification 

Validation of 

Biomarker 

Test 

Regulatory Filing 

Approval 

Launch 


Companion Diagnostics – 

Some Practical Considerations 

• Consult with FDA, EMA early in development process 

• CDRH pre-IDE and CDER pre-IND processes aid study design and execution 

• Parallel consultation with HTAs helpful for discussion on reimbursment 

• Does the study trigger IDE Requirements? 

• Is invasive sampling (biopsy) being done for the study? 

• Do results from study influence patient management? 

• IRB oversight (approval/exemption) is needed for diagnostic testing sites 

• If archived specimens are used, Informed Consent must allow for storage and 

future use of samples: renewal of consent may be required 

• Bridging studies needed in case change is made to any part of the system 

(antibody, detection kit, instrument, scoring) 

• Ideally, test reagents and protocols finalized before starting first clinical trial 

• Analytical validation of the test procedure should include the target tissue type 

and include finalized scoring algorithm/cut-off 


Development Strategy for Mesothelin-ADC 

• First in Man study with classical 3+3 design in the dose escalation phase, 

followed by expansion cohorts at the recommended phase II dose 

• IUO test using reagents and protocols intended for companion diagnostic device is in 

development 

• Archival tumor samples from all patients: mesothelin expression will be tested 

retrospectively 

• Phase I study delivers first indications of therapeutic efficacy and relation to drug 

target expression 

• Phase II study will be used to define cut-off mesothelin expression level 

• Mesothelin expression level as stratification marker will be validated in pivotal 

Phase III trial 

• Simultaneous submission and market authorization of drug and CDx 


Summary 

Outlook 

Mesothelin is overexpressed in various carcinomas 

Mesothelin-ADC binds with high affinity and specificity and 

is efficiently internalized 

In vitro high potency and selectivity for proliferating, 

mesothelin positive cells 

In vivo high efficacy in mesothelin positive xenografts and 

pronounced bystander effect 

Phase 1 clinical trial with Mesothelin-ADC is underway 

Development of a Companion Diagnostic initiated 


Thanks to the team! 

Mesothelin-ADC Global Project Team 

Frank Reetz 

Christoph Schatz 

Ruprecht Zierz 

Sven Golfier 

Christa Hegele-Hartung 

Manuela Braun 

Martin Kornacker 

Prabhu Rajagopalan 

Frank Burkert 

Chandra Ramanathan 

Jasmina Markov 

Armin Schuetz 

Klaus Kaiser 

Marius Giurescu 

Gabriele Kapfer 

Miki Shindo 

Helena Chang 

Christine Kempter 

Inke Bahr 

David Henderson 

Ventana Project Team 

Abigail McElhinny 

Aaron Pershing 

Chester McCoy 

Penny Towne 

Bill Richardson 

Connie Cortez 

Jackie Neri 

Dionne Roberge 

Eric Lindquist 

Shalini Singh 

Jim Ranger-Moore 

Jim Ostrem 

Paula Rodgers 


Thank you for your attention!

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