Enabling Speed to Patient Starting in the Early Biologics Development Space

HENRIK ANDERSEN | BMS BIOLOGICS PROCESS DEVELOPMENT

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BMS Biologics PortfolioBreakthrough Designation & CMC ChallengesGeneral Development Enablement OpportunitiesMolecule Design ConsiderationsClinical Qualification Case StudyHarmonization: Parts of Portfolio Example

PRESENTATION OUTLINE

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BMS Biologics Pipeline

Early Late Marketed

ImmunoscienceImmuno-OncologyVirologyOncologyMetabolicsGenetic Diseases

Indications

Source: www.bms.com Expression Systems: CHO, NS0, and E. coli

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CMC TIMELINE CHALLENGESACCELERATED PROGRAMS

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Current Industry Biologics CMC Challenges

#Trending

IO Accelerate early-phase compounds into late-stage trials

DRIVER:Newer Treatment

Modalities to Patients QuicklyAIDED BY:

Breakthrough Therapy

Designation NNNNNivolumabRapid Progression

Basic Data Sets

In-Licensing

Small Investments

Limited Clinical Data

Expression cell lineCommercial process developmentAnalytical paradigmDesign space and PPQ statusResource considerations

Incomplete CMC

Package

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Processes for Accelerated Approval

Category Applies to Impact toRegulatory Approval Potential CMC Impact

Accelerated Approval Pathway

Allows surrogate endpoint to be used for disease states with substantial unmet clinical need

Completion of confirmatory P3 studies still required

PPQShelf life/stability dataClinical qualification

Fast-TrackDesignation

Serious conditions and unmet medial need

Completion of confirmatory P3 studies still requiredRolling submission allowed

PPQShelf life/stability dataClinical qualification

BreakthroughTherapy Designation

Substantial improvement over existing therapies in early clinical trials

Commercial application does not need P3All benefits of fast-track designation built in(Engage FDA)

Commercial PDAssay validationPPQShelf life/stability dataClinical qualification

Priority ReviewDesignation(can be in parallel)

Filing of commercial application for drugs meeting any of above criteria

Review time is shortened from 10 to 6 months

Shelf life (additional stability data submission during review)

Reference: Adapted from Dye et al. (2015)

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Technical Development & Product Lifecycle

Phase 1 LifecyclePhase 2 Phase 3

On Platform

Readiness forCommercial

Tech Dev/COGs FUMPMC

LifecycleManagement

Launch ProcessDS StabilityDP StabilityPPQ Prep

Clinical Qual

BreakthroughDesignation

Adaptive Trial Design

Emerging Challenge

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Acceleration Challenges, Risks, & Mitigation

Enhance analytical and characterization paradigmExpand early understanding of pCQAs vs. CQAs and associated CPPsPlatform methods throughout development or utilize retainsAlign FIH and commercial process platforms (w/mfg network)Leverage all preclinical and clinical data (platform)Harmonize process and analytics for development programsIncreased interaction with FDA/regulators

Maintain Sensible Stage Appropriate Resource Spend

Commercial Process ReadinessCommercial Launch Site ReadinessStability Data from P3/Commercial Scale LotsProcess characterization/PVClinical Qualification/Support of Specifications

ACCELERATIONRISKS

MITIGATIONSTRATEGY

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Enablement Considerations

Fast to Sequence versus Fast to FIH versus Speed to PatientDesigning the Molecule: DevelopabilityResearch versus Development ToolsInformation ContinuityHarmonizationResource Spending (at risk): Now versus LaterHTS Investment: Lean versus Resource NeutralEnable Clinical Experience: Clinical Qualification

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Key Solutions

• Molecular design• Integrated PD, analytical development, manufacturing, and testing network• Co-operate/leverage Discovery data• Small/sufficient amounts of drug available quickly• Advanced platforms (cell line, methods, specs, processes)• Tox quantities & quality• Launch-capable CMC platform approach at Phase I• Commercial process evaluation• Global focus CM&C package• Platform formulation• Clinical qualification of CQAs• Harmonization of development portfolio (including pearls)• Transfer assets to commercial sites early

Presentation Focus

Strategic driver to stay resource neutral and create efficiencies

Monitored Parameter/

Attribute

PP/PA with alert ranges

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Molecular Design with CMC Development in Mind

Mind your Ps and Qs – Example of IPC Decision Tree

Yes

Yes

Yes

No

No

No

Does the variable impact product CQA?

Variable impact process performance?

Easily Controlled?

CPP / CPA

PP/PA with action ranges

Stability:time, temperature, and concentration variables

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Molecular DesignIntegrated R&D and CMC Development

Mind your Ps and Qs:

Eliminate and evaluate CQA potential up front: Hot spots (oxidation, deamidation, isomerization),

aggregation potential, glycosylation/activity role etc.

FORMULATABILITY

MANUFACTURABILITY

DEVELOPABILITY

• Stability• Homogeneity• Expression system and productivity• Ease of purification

• Manufacturability• Formulatability

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Design Considerations – mAbs (and ADCs)

Reference: Nature Reviews Immunology 10, 345-352 (May 2010)

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CQA Litmus Test

British Dictionary Definition:1. a test to establish the acidity or alkalinity of a mixture2. a critical indication of future success or failure

Cell cultureHeat stressOxidation stressDesialylate/deglycosylate

Risk assess CQA per ICH Q6B

7.1e4 7.2e4 7.3e4 7.4e4 7.5e4 7.6e4 7.7e4 7.8e4 7.9e4 8.0e4 8.1e4 8.2e4Mass, Da

500

1000

1500

2000

2500

3000

3500

4000

4500

5000

5500

6000

6500

7000

7500

Intensi

ty, Co

unts

74869.3696

75031.1213

75187.6236

74915.119674097.7559

75559.508074262.5647 76176.949070916.8502 73937.6528 77733.169176279.6901 81614.129072753.5554 81045.451773636.3956

Reduced

HC G0F

HC G1F

HC G2F

Monitored Parameter/

Attribute

PP/PA with alert ranges

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Molecular OptimizationDesign with CMC Development in Mind

Mind your Ps and Qs – Example of IPC Decision Tree

Yes

Yes

Yes

No

No

No

Does the variable impact product CQA?

Variableimpact process performance?

Easily Controlled?

CPP / CPA

PP/PA with action ranges

No

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CQA Clinical Qualification – Case Study

BackgroundEnable commercial shelf of 2 years at 2-8 ͦC (liquid)Allow for 2 weeks interim storage at 25 ͦC during shipment and packagingMolecule contains “key liability” forming at 0.5% per month at 2-8 ͦC (isoAsp)Product related impurity versus product related substanceDS and DP levels at release are consistently ~ 1%

ChallengeSimple arithmetic: 1% + 24 mos. x 0.5%/mos. + X + Y = ~ 15%Experience and assay variabilityPatient experience at filing versus end of shelf life specifications

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Product Related Substance Evaluation Part 1 - Structural

Dissociation Constants for Molecule P & Molecule P IsoAsp

Sample KD (nM) 95% CI (nM)Molecule P 34 26-43

Molecule P IsoAsp 39 31-47

CD Spectroscopy

Biacore Binding Data

Molecule PMolecule P IsoAsp

Molecule PMolecule P IsoAsp

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Product Related Substance Evaluation Part 2 - Bioactivity

0

0.2

0.4

0.6

0.8

1

1.2

Rel.

to C

ontr

ol

Molecule P 20% IsoAspMolecule P

IsoAspMolecule P

Molecule P20% IsoAsp Molecule PIsoAsp Molecule P

Molecule PDegraded Molecule P

Molecule PIsoAsp Molecule P

Molecule P BioAssay Molecule P BioAssay

Molecule P Primary Cell Assay Molecule P Primary Cell Assay

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Product Related Substance Evaluation Part 3 - PK

0 8 16 24 32 40 48 56 64 720.0001

0.001

0.01

0.1

1

10PEG-rIL-29IsoAsp PEG-rIL-29LLOQ

Time (h)

Mea

n PE

G-r

IL-2

9Se

rum

Con

c. ( µ

g/m

L)

Mea

n M

olec

ule

P Se

rum

Con

c.

(µg/

mL)

Molecule PMolecule P IsoAsp

0.01

0.1

1

10

100

0 7 14 21 28 35 42 49 56 63 70 77 84PE

G-rIL

-29

IsoA

sp(n

g/m

L)Time (d)

PEG-rIL-29 IsoAsp Concentration over Time

240 µg dose in man (DP at EOS)

2.5 mg/kg dose in monkey (DP with 1% IsoAsp)

Mol

ecul

e P

IsoAs

p(n

g/m

L)

Molecule P IsoAsp Concentration over Time

Human Dosing

Cyno Dosing

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Product Related Substance Evaluation

The Tricky Part

Comparable properties as it relates to clinical efficacy and safety (including immunogenicity)

Enable clinical qualification program integrated with

registrational stability study/ shelf life strategy including

planned excursions

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Clinical Qualification Decision Tree

No

Yes

No

Yes

Yes

No

Does themolecule

contain chemical/ structural liabilities (CQAs)?

Does the liability impact

molecular binding / bioactivity?

Send a Thank You note to your Protein

Engineering Group

Are end of shelf life levels

considered significant?

Align acceptability of approach with

regulators

Does clinical/ CMC experience

account for these levels?

Yes

No

Send a smaller Thank You note to your Protein Engineering group

(you’re not off the hook)

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Clinical Qualification Case Study

1Assume FPFD 6 months after DP manufacture, 6 month enrollment, and LPLD 18 months after DP manufacture

Approx. Starting IsoAsp

Levels in DP

Standard logistics paradigm(added)

Approx. IsoAsp

Formation Rate at 2-8 °C (%/mo)

Projected IsoAsp Level Range - Start

to End of Enrollment

Period1

Projected IsoAsp Level

Range by End of

Treatment Period

(~6 mo)1

1% 0.5% 0.5% 4.5-7.5% 7.5-10.5%

Approx. Starting IsoAsp

Levels in DP

Controlled excursion -4 weeks at

25 °C(added)

Approx. IsoAsp

Formation Rate at 2-8 °C (%/mo)

Projected IsoAsp Level Range - Start

to End of Enrollment

Period1

Projected IsoAsp Level

Range by End of

Treatment Period

(~6 mo)1

1% 6% 0.5% 10-13% 13-16%

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Clinical Qualification Enabler

Controlled excursion(s)

Clinical experience with relevant lots

Don’t be afraid to sacrifice weeks for years

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Technical Development Path Integration

Development Aspect R&D Space CLD Space FIH/P2 Space Commercial

SpaceAlignment

Opportunity

Cell LineTransient CHO

HEK293UCOE CHO

DG44 and CHO-S

DG44 and CHO-S DG44 + others Optimal Cell

Line

Upstream Process

DiversePowerCHOFreeStyle

Selection Medium M1 and M3 M1 and M3 +

others M1 +M3

DownstreamProcess

Protein A + Various Mixed Protein A +

Fixed ChromProtein A +

VariousProtein A +

Fixed Chrom

Analytics R&D assays PDA assays PDA and ADT assays

Optimized and validated

PDA and ADT harmonized

Formulation Multiple Multiple or platform Platform Multiple Platform

(harmonized)

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BMS Microbial Portfolio

Program B Program C Program D Program E Program F Program G

Stage of Development Phase 3 Phase 1 Phase 2 Preclinical Phase 2 Phase 1

Place of MFG CMO 2 Partner CMO 5 CMO 2 BMS CMO 4

Inherited Scale (L) ~ 2000 ~ 1500 ~ 100 N/A ~ 300 ~ 300

Protein Size (kDa) ~ 20 ~ 20 ~ 20 ~ 10 ~ 10 ~ 10

E. Coli host ZGOLD5 W3110 W3110B60 W3110B55 BL21*(DE3) BLR(DE3)

Induction IPTG IPTG Arabinose Arabinose IPTG IPTG

Production Type Inclusion body Inclusion body Inclusion body Inclusion body Periplasmic Cytoplasmic

Medium Hydrolysate Hydrolysates Defined Defined Hydrolysates Hydrolysates

Expression Level (g/L) ~ 9 ~ 6 ~ 1 ~ 1 ~ 1 ~ 4

String of Pearls

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BMS Microbial PortfolioPartially Harmonized

Program B Program C Program D Program E Program F

Stage of Development Phase 3 Phase 1 Phase 2 Preclinical Phase 2

Place of MFG CMO 6 CMO 6 CMO 7 CMO 6 CMO 7

Fermentation Scale (L) ~ 2000 ~ 2000 ~ 3000 ~ 2000 ~ 3000

E. Coli host W3110 W3110 W3110 W3110 W3110

Induction IPTG IPTG Arabinose Arabinose IPTG

Production Type Inclusion body Inclusion body Inclusion body Inclusion body Inclusion body

Media Hydrolysates Hydrolysates Hydrolysates Hydrolysates TBD

Expression Level ~9 g/L ~ 6 g/L ~ 5 g/L ~ 5 g/L TBD

Testing SynergiesDNAHCP

Titer Assay

DNAHCP

Titer Assay

DNAHCP

Titer Assay

DNAHCP

Titer Assay

DNAHCP

Titer Assay

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Conclusions

SPEED TO PATIENT

HARMONIZATION & PLATFORMS

DATA

Needs to be enabled as part of early space development design

Needed to manage robust portfolio: Integrate across organization

Enable robust engagement of regulators

Morrey Atkinson, Brendan Hughes, & Annie Sturgess

Leland Paul, Siegfried Rieble, Karen De Jongh & John Fann

Lori Burton, Mark Hill, & Jeff Meyer

Mitchell Tai, Gautam Nayar, & Teri Aldrich

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Acknowledgments