Pharma&Biotech

Strategies to streamline biopharmaceutical developm ent and reduce attrition. Developability and links with QbD and PLM7th European Bioinnovation Leaders Summit, London, 11th February 2014

Pharma&Biotech

Jesús Zurdo, Future Technologies, Lonza Pharma&Biotech

2Feb-14

Disclaimer

Certain matters discussed in this presentation may constitute forward-looking statements. These statements are based on current expectations and estimates of Lonza Group Ltd, although Lonza Group Ltd can give no assurance that these expectations and estimates will be achieved.

The actual results may differ materially in the future from the forward-looking statements included in this presentation due to various factors. Furthermore, Lonza Group Ltd has no obligation to update the statements contained in this presentation.

Statements included in this presentation do not necessarily reflect Lonza Group Ltd’s views on the subject presented

Note: All slides are incomplete without verbal comments.

Developing drugs is extremely risky

Attrition Evolution

Pammolli et al. (2011) Nature Rev Drug Dis 10, 428-438

Mounting Pressure from PayersOf all registered anti-cancer drugs evaluated by NICE

43% were approved in 2012 vs 65% in 2000-2012.

*http://www.nice.org.uk/newsroom/nicestatistics/niceandcancerdrugsthefacts.jspNICE: UK National Centre for Health & Clinical Excellence

(0% approved in 2013, Jan-Dec – 6 agents)*

Beyond Cost of GoodsMaking Successful & Affordable Medicines

Pharma &PLM

Design• Concept• Target validation• Drug design /

discoveryDevelopment• Prototype optimisation• Manufacturing devel• Clinical validation• Efficacy / safety

Manufacturing• Supply chain• Costs• Quality• Regulatory

Commercialisation• Marketing• Sales• Distribution• Reimbursement

Utilisation• Disease condition• Regime / dosing• Patient segmentation

Retirement• Follow-on• New formulations• Etc.

QUALITY

6Feb-14

Moving from 2-3 σσσσ to 6-7σσσσ (3.4 dpm)Quality in Biopharma: Challenges

Processes Old & Rigid:Not easy to modify / optimize once approved

Long & Cumbersome:Resistance to change Slow in adopting innovation

Unpredictable:"The product is the process”

Not fit for purpose:Commercial process for

prototype testing & validation

Silos – FragmentedDisconnection discovery-development:

Product / process interdependence[External CROs / CMOs]

Hierarchical & linear development:Lack of a ‘holistic’ approach to development

7Feb-14

FIRST IN HUMAN

What can it be Done?

1 Early De-risking (TRUE QbD)

3 Delivery (Design Drug, not just API)

2 Fast Transition to Clinic

DISCOVERY

EffectivenessBiological ActivityRoA & DeliveryPharmacology

SafetyImmunogenicity

Immunotoxicology

ManufacturabilityProductivity

StabilityFormulability

Pharmacology / Targeting

SimplerProcess

Development

Developability: Risk Assessment / Product Design

The Importance ofFormulation & Delivery

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Subcutaneous delivery:Aggregation & Viscosity Challenges

Novel formulations:- Roche – IBM / Halozyme- Controlled release formulations

Formulation an IP / marketing strategy- Follow on / biobetters- Tracing the footsteps of insulin

10Feb-14

Hospital InfusionHome Infusion

■ Infliximab■ Nursing services / care■ Supplies■ Laboratory samples■ Duration of infusion

Total avg. cost $3,744

■ Infliximab■ Nursing services / care■ Supplies■ Laboratory samples■ Length of hospitalization■ Physician visitTotal avg. cost $7,776

The Payers Perspective

Patient self-administration as the “Holy Grail”

Source: Condino et al. (2005) J Pediatr Gastroenterol Nutr, 40: 67

Treatment of Children with Crohn DiseaseHome infliximab infusion program[Avg Costs treatment of patient (50Kg)]

$ 4,032 Savings

Strategies to improve delivery• s.c. / i.m. formulations (formulability)• controlled release / extended half-life

Developability: Early Risk ManagementAn effective way of reducing attrition

QbD – Designing Quality in the Product, starting from early risk assessment & mitigation

Manufacturability

• Productivity• Quality

oChemical stability (e.g. oxidation, degradation)

oPhysical stability (aggregation)

oPost Translational Modifications

• Formulability

Safety

• ImmunogenicityoT-cell epitopesoCellular responses

• ImmunoToxicologyoCytokine release

syndrome• Specificity

oOff-target interactions

Pharmacology & Mode of Action

• PK/PD -BioavailabilityoDelivery / RoAoHalf lifeoFormulability

• Mode of Actiono ImmunomodulationoDosing & patient

segmentationoEfficacy

Developability

The 3 Pillars of Developability

13Feb-14

Developability. A Three-Stage Process to Implementing QbD

1. Risk Assessment■ Computational approaches■ In vitro surrogate analysis■ Criticality & decision making

2. Implementing a risk-mitigation strategy.■ Select alternative candidate■ Re-design candidate■ Modify process

3. Validation of course of action■ Complete appropriate validation studies■ Monitor biological activity and reduction of risk

occurrence / impact

Lead Selection & Design:Developability: Aggregation & Stability

15Feb-14

DevelopabilityRisk Assessment & Mitigation Strategy

Late Stage Intervention

Early Stage Intervention

Potential Problem Highlighted

In Silico Analysis

Select Alternative Sequence

Re-engineering

Select Alternative Sequence

Re-engineering

Process Optimisation

Process Optimisation

Risk Identification

Aggregation

Potential

Deamidation, PTM, clipping

Risks

16Feb-14

Risk Assessment (Seq and Struct)

■ Identification of risk areas

■ Generation of library of potential substitutions

Reengineering mAbs to ImproveDevelopability.A Case Study

Lead Selection & Design:Immunogenicity & Immunotoxicology

Epibase™ In Silico immunoprofiling

Method■ Predictive tool driven by structural

bioinformatics in conjunction with experimental data

■ Peptide/HLA binding – necessary condition for T-cell activation

■ Uses structural characteristicsof the HLA receptor

■ Statistical layer based on experimentally determined binding affinities of peptides

Usage■ Ranking of lead candidates■ Lead characterisation

20Feb-14

Adalimumab:T-cell Epitopes and HAHA Response

Epitopes Region HLA allotypes

HAHA+ patients

1 FwR2-HCDR2 DRB1*0701 1

2 FwR2-HCDR2 DQA1*0201|DQB1*0303 1

DQA1*0401|DQB1*0402

DQA1*0501|DQB1*0301 3

DRB1*0101 4

DRB1*0401 7

DRB1*0405 1

DRB1*0407

DRB1*0901 1

3 FwR3-HCDR3 DRB5*0101 5

4 FwR3-HCDR3 DRB1*0407

5 FwR3-HCDR3 DRB1*0801

6 LCDR1 DQA1*0501|DQB1*0201 3

7 FwR3-LCDR3 DRB5*0101 5

■ Epibase IS™ assessment

■ The 7 strong epitopes explain 17/19 HAHA+ patients

■ Epitopes are directed against the RA associated allotypes

Test Product

B-cell Receptor repertoire

HLA allotypes (MHC class I/II)

T-Cell Receptor repertoire (CD4/CD8)

Pre-existing memory

Human PBMC

In Vitro assay to assess the immunogenicity of Biotherapeuti cs & Vaccines

In Vitro Immunogenicity Assessment

T cell epitopes

B cell epitopes

ContaminantsAggregatesFormulation

22Feb-14

Type Rank Epitope count

DRB1 Strong

DRB1 Medium

DRB3/4/5 Strong

DRB3/4/5 Medium

murine 4250 31 117 14 69

chimeric 2040 16 42 3 30

humanized 1040 7 25 3 14

Epibase™ DC:CD4 Assay – Case Study

■ DC:CD4 assay optimized for Ab responses

■ All donors respond to positive control (KLH)

■ ~85% of donors responded to murine mAb

■ ~35% of donors responded to chimeric mAb

■ 0% donors responded to humanized mAbmAb CD4+ T cell responses

KLH

Murine

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% r

espo

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nors 85%

35%

■ In vitro data supports the predicted T cell epitope content of each mAb in silico

■ Chimeric and humanized mAb T cell responses correlate well with reported ADA levels in the clinic

In silico T-cell Epitope Prediction

23Feb-14

Viventia Case Study: De-immunization of VB6-845 ®

Objective■ Minimize the potential immunogenicity risk of the fusion protein

VB6-845® by de-immunizing the Fab portion

In silico De-immunization■ Screening for T-cell epitopes using Epibase™■ Antibody structure modeling■ Substitutions to eliminate T-cell epitopes based on structure integrity

In Vitro Verification & Testing of De-immunized Protein■ Screening for T-helper cell responses using PBMCs from

healthy donors■ Individual and population responses

24Feb-14

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WT Fab De-immunized Fab

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In vitro testing: # positive donors (53 tested)

Single Donor Population

Viventia Case Study: In vitro Testing – Single Donor and Population Level

■ De-immunized Fab shows a substantial and significant reduction in its ability to raise T-cell responses

25Feb-14

Maximizing SuccessEx-vivo Biological Activity Assessment (Human Blood)

■ Most approved Mabs (over 30) have immunomodulatoryfunctions

■ Validation of Mode of Action & Efficacy■ Early evidence of efficacy in human systems (pre-clinical)■ Closer to intended pharmacological intervention than animal

models

■ Patient segmentation■ Evaluation of response from patients with different genetic

makeups & disease background■ Segregation of patients between responders and non-

responders for clinical trials

■ De-risking clinical development■ Dosing regime & safe human starting dose■ Identification of relevant biomarkers (surrogate efficacy / toxicity)

26Feb-14

Maximizing SuccessEx-vivo Immunotoxicity & CRS Assessment

■ Challenge: Human immunopharmacology in many cases cannot be replicated in animal models

■ Ex-vivo systems can be utilised to replicate at least some of the aspects of immunotoxicology of therapeutic candidates

■ Immunotoxicity / inflammation / modulation of immune response

■ Cytokine Release Syndrome (CRS) modelling

■ Clinical trial protocols changed after Anti-CD28 superagonistic antibody TGN1412

■ Modelling a (cytokine) storm in a test tube

■ Possibility of testing different genetic make-ups / disease background

■ HLA allotypes

■ Ethnicity

■ Disease background

© Paul Ehrlich Institute

27Feb-14

Summary

■ Research & Development working together in harmony■ Not just activity / titre (to select / optimize lead)■ Introduce quality in design / screening. Design product for success!!■ Less of the right (& clean) product is better

■ Face the risk early on■ ‘Killing the trolls’ while they’re still small (Fail early)

Or rather select / design Quality Lead Candidates■ Reduce attrition in later preclinical and clinical development

■ Delivering biopharmaceuticals is more than simply injecting them!!

■ Keep in mind the final treatment at the outset■ Biology of disease■ P3: Payers!! HC Professionals and Patients

■ Get quickly to the patient■ Translational medicine needs to be facilitated■ Current processes too long

RD

28Feb-14

Any Questions?

■ jesus.zurdo@lonza.com

■ Zurdo, J. (2013) Pharmaceutical Bioprocessing. 1(1), 29-50

■ Zurdo, J. (2013) European Biopharmaceutical Review. 195, 50-54

■ The Cell Culture Dish Blog

http://goo.gl/bYKQpd