Preclinical Development Preclinical Development Considerations for Biologics – Considerations for Biologics – Phase I Oncology FocusPhase I Oncology FocusODAC Meeting, March 13, 2006, Rockville, MD.ODAC Meeting, March 13, 2006, Rockville, MD.

Preclinical Development Preclinical Development Considerations for Biologics – Considerations for Biologics – Phase I Oncology FocusPhase I Oncology FocusODAC Meeting, March 13, 2006, Rockville, MD.ODAC Meeting, March 13, 2006, Rockville, MD.

James D. Green, Ph.D., DABTSVP – Preclinical and Clinical Development

Sciences Chairman – BioSafe BIOCambridge, MA

James D. Green, Ph.D., DABTSVP – Preclinical and Clinical Development

Sciences Chairman – BioSafe BIOCambridge, MA

J. Green

Background CommentsBackground Comments

Biologic drug developmentBiologic drug development

– Decades of experience across wide range of Decades of experience across wide range of product classesproduct classes

– ICH S6 guidance for preclinical safety evaluation ICH S6 guidance for preclinical safety evaluation programs and approachesprograms and approaches

• Pharmacology, toxicology, pharmacokinetics, unique Pharmacology, toxicology, pharmacokinetics, unique considerationsconsiderations

• Case-by-case approachCase-by-case approach– One program design may not look like another due to One program design may not look like another due to

product specific issues/concernsproduct specific issues/concerns

J. Green

Background CommentsBackground Comments

• FDA organizers asked that I address differences FDA organizers asked that I address differences between preclinical development considerations for between preclinical development considerations for biologics compared to small moleculesbiologics compared to small molecules– Raise for discussion, how would the above influence a Raise for discussion, how would the above influence a

determination of ‘how much preclinical data’ is sufficient to determination of ‘how much preclinical data’ is sufficient to support Phase I trials for a biologic agentsupport Phase I trials for a biologic agent

• Oncology focusOncology focus• Refractory patientsRefractory patients

– Present examples, if possible.Present examples, if possible.

• Provide useful ‘information’Provide useful ‘information’

J. Green

Presentation OutlinePresentation Outline

• Unique development issues for biologicsUnique development issues for biologics– Contrast with small molecule drugsContrast with small molecule drugs– Discussion focused on biologic drugsDiscussion focused on biologic drugs

• For the committee’s information: For the committee’s information: – Utility of toxicology assessmentsUtility of toxicology assessments– Utility of pharmacokinetic assessmentsUtility of pharmacokinetic assessments

• Unique dose response considerations for Phase IUnique dose response considerations for Phase I

• Preclinical development requirements for Phase IPreclinical development requirements for Phase I• SummarySummary

J. Green

Key MessagesKey Messages

• Compared to small molecule drug development programs, Compared to small molecule drug development programs, there are important differences for biologic drugs that affect there are important differences for biologic drugs that affect program designs and assessment parametersprogram designs and assessment parameters

• Well designed pharmacology, toxicology and Well designed pharmacology, toxicology and pharmacokinetic studies are important to support safe use pharmacokinetic studies are important to support safe use conditions for human trials with oncology drugsconditions for human trials with oncology drugs

• Four-week repeat dose toxicology studies with recovery Four-week repeat dose toxicology studies with recovery periods should be adequate to support extended treatment periods should be adequate to support extended treatment of responding and stable disease patients in most casesof responding and stable disease patients in most cases– Case-by-case determination recommendedCase-by-case determination recommended

What Are Important Differences?What Are Important Differences?Typical Antibody ConstructTypical Antibody Construct

Potent effectorPotent effectormolecules, molecules, conjugate, and/orconjugate, and/orglycosylation glycosylation sitessites

Disulfide bond Disulfide bond

Tumor-targeting Tumor-targeting regionsregionsFrom: M. Sanicola, V. BaillyFrom: M. Sanicola, V. Bailly

Comments:Comments:Non oral ROANon oral ROALarge sizeLarge size complex 3-Dcomplex 3-D structurestructureSAR difficultSAR difficultVariant formsVariant formsNo metabolitesNo metabolites

J. Green

What Are Important Differences for What Are Important Differences for Biologics ?Biologics ?

How the biologic drug is made can affect How the biologic drug is made can affect ‘key product attributes’‘key product attributes’– Product attributes govern:Product attributes govern:

• Potency, safety, efficacyPotency, safety, efficacy• Therapeutic ratio and risk estimatesTherapeutic ratio and risk estimates

– Host and process related impurities are Host and process related impurities are related to the production processrelated to the production process

““Process = product” at this Process = product” at this stage of developmentstage of development

J. Green

Unique Issues Effecting the Safety Unique Issues Effecting the Safety Assessment of BiologicsAssessment of Biologics

• Immunogenicity complicationsImmunogenicity complications– Duration of repeat-dose treatment in toxicology studies Duration of repeat-dose treatment in toxicology studies

can can sometimessometimes be limited be limited• Has Has notnot been a major complication in preclinical or clinical been a major complication in preclinical or clinical

studiesstudies

– Changes in pharmacokineticsChanges in pharmacokinetics• Increased or decreased drug clearanceIncreased or decreased drug clearance• Consequent change in dose and potencyConsequent change in dose and potency

– Changes in pharmacologic activityChanges in pharmacologic activity• Blocking or neutralizing Blocking or neutralizing • Hyperpharmacologic response due to extended PK profileHyperpharmacologic response due to extended PK profile• Cross reaction to endogenous factor(s)Cross reaction to endogenous factor(s)

J. Green

Some Important Safety Concerns are Some Important Safety Concerns are Related to ImmunogenicityRelated to Immunogenicity

• Experience to date suggestsExperience to date suggests– Anaphylaxis - rareAnaphylaxis - rare– Serum sickness – rareSerum sickness – rare– Immune complex disease - rareImmune complex disease - rare– Changes in immune function status - rareChanges in immune function status - rare– Immune response generated to the Immune response generated to the

biologic - more commonbiologic - more common

J. Green

General Categories of Immune General Categories of Immune Response to an Exogenous BiologicResponse to an Exogenous Biologic

• Categories:Categories:– BenignBenign

• Growth hormones and insulinsGrowth hormones and insulins– MixedMixed

• huMabs, fusion proteins, interferonshuMabs, fusion proteins, interferons– AutoAuto

• TPO/PEG, blood factors, EPO (Eprex)TPO/PEG, blood factors, EPO (Eprex)

Overall, experience to date suggests that immune SAE’s Overall, experience to date suggests that immune SAE’s are uncommon and most reactions are clinically “benign”are uncommon and most reactions are clinically “benign”

J. Green

Impact of Cited Differences and Impact of Cited Differences and Other Unique Issues ?Other Unique Issues ?

• Interpret preclinical safety data with Interpret preclinical safety data with prior knowledge of ‘unique’ issues prior knowledge of ‘unique’ issues – If preclinical safety assessment is not If preclinical safety assessment is not

compromised, they are of no consequencecompromised, they are of no consequence– Uncertainties or effects communicated to Uncertainties or effects communicated to

physician and patient by usual meansphysician and patient by usual means• FDA review, IB, ICFDA review, IB, IC

J. Green

Utility of Toxicology Assessments: Utility of Toxicology Assessments: Generally Accepted PrinciplesGenerally Accepted Principles

• A range of toxicology responses can be A range of toxicology responses can be observed dependent upon the properties of the observed dependent upon the properties of the moleculemolecule– Toxicity is sometimes non-existent, sometimes Toxicity is sometimes non-existent, sometimes

mild, and occasionally severemild, and occasionally severe– Often, toxicity is limited to an extension of known Often, toxicity is limited to an extension of known

pharmacology; however, severe non-pharmacologic pharmacology; however, severe non-pharmacologic toxicities are sometimes observedtoxicities are sometimes observed

J. Green

Utility of Toxicology Assessments: Utility of Toxicology Assessments: Generally Accepted PrinciplesGenerally Accepted Principles

• Duration of toxicology studies needed Duration of toxicology studies needed to support human use is variableto support human use is variable– Case by case determinationCase by case determination

• Based on planned duration of clinical trialsBased on planned duration of clinical trials– Consider the effects of ‘differences and issues’ previously Consider the effects of ‘differences and issues’ previously

discusseddiscussed

• 4 week repeat-dose studies in one or two 4 week repeat-dose studies in one or two pharmacologically responsive species with recovery pharmacologically responsive species with recovery period are typical across many indications for initial period are typical across many indications for initial INDsINDs

J. Green

Utility of Toxicology Assessments: Utility of Toxicology Assessments: Generally Accepted PrinciplesGenerally Accepted Principles

• Many proteins are also “well-conserved” and Many proteins are also “well-conserved” and pharmacologically active across speciespharmacologically active across species– Rodent models may sometimes be usefulRodent models may sometimes be useful– NHP are frequently used; sometimes other NR modelsNHP are frequently used; sometimes other NR models– Single species safety assessments are sometimes Single species safety assessments are sometimes

scientifically justifiedscientifically justified

• Often, dosimetry and toxicity profiles established Often, dosimetry and toxicity profiles established in animal models are directly relevant to humansin animal models are directly relevant to humans

J. Green

rHurHu RodentRodent PrimatePrimate HumanHumanIL-1IL-1 ++ ++ ++IL-2IL-2 ++ ++ ++IL-3IL-3 +/-+/- ++ ++IL-4IL-4 -- ++ ++IL-5IL-5 +/-+/- ++ ++IL-6IL-6 ++ ++ ++IL-7IL-7 ++ ++ ++IL-8IL-8 ++ ++ ++IL-9IL-9 -- ++IFN-g, IFN-g, -- [+][+] ++TNFTNF ++ ++ ++G-CSFG-CSF ++ ++ ++GM-CSFGM-CSF +/-+/- ++ ++EPOEPO ++ ++ ++TPATPA ++ ++ ++

Clinical CorrelationsClinical Correlations

Modified from Hayes, T.J., 1990

J. Green

Utility of Toxicology Assessments: Utility of Toxicology Assessments: Generally Accepted PrinciplesGenerally Accepted Principles

• Level of initial toxicologic concern extends Level of initial toxicologic concern extends beyond pharmacology and immunogenicitybeyond pharmacology and immunogenicity– Unexpected target organ toxicity and dysfunctionUnexpected target organ toxicity and dysfunction

• Thromboembolic exampleThromboembolic example

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Hemorrhagic Infarctat the margin of the left caudal lobe

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Subacute thrombus within a dissected pulmonary artery

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Occlusive Vasculopathy:mural smooth muscleproliferation resultingin loss of vesselpatency

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Thromboembolic ExampleThromboembolic Example

• Unrelated to expected pharmacologic activityUnrelated to expected pharmacologic activity– Clinically silent in animalsClinically silent in animals

• Observed in animals and in clinical trialsObserved in animals and in clinical trials

• Underscores relevance of well designed and Underscores relevance of well designed and conducted nonclinical studies to identify conducted nonclinical studies to identify relevant human risk factorsrelevant human risk factors

J. Green

Utility of Pharmacokinetic Assessments: Utility of Pharmacokinetic Assessments: Generally Accepted PrinciplesGenerally Accepted Principles

• Clinically relevant disposition profiles can Clinically relevant disposition profiles can routinely be constructed in pharmacologically routinely be constructed in pharmacologically responsive animal modelsresponsive animal models– Studies employ the clinical route and dosing Studies employ the clinical route and dosing

regimenregimen– Studies cover the dose range employed in Studies cover the dose range employed in

toxicology studiestoxicology studies

J. Green

Utility of Pharmacokinetic Assessments: Utility of Pharmacokinetic Assessments: Generally Accepted PrinciplesGenerally Accepted Principles

• Therapeutic ratio supported on basis of Therapeutic ratio supported on basis of weight, surface area and exposure weight, surface area and exposure extrapolationsextrapolations– Interspecies scaling techniques and Interspecies scaling techniques and

toxicokinetics are sometimes usefultoxicokinetics are sometimes useful• Multiples of projected human dose (exposure)Multiples of projected human dose (exposure)

Well-designed pharmacokinetic Well-designed pharmacokinetic studies are important and relevantstudies are important and relevant

J. Green

Non-natural Fusion Construct: Interspecies Scaling Non-natural Fusion Construct: Interspecies Scaling Predicts Human Clearance within Two FoldPredicts Human Clearance within Two Fold

J. Green

Select examples with direct relevance to Select examples with direct relevance to dosimetry considerations in Phase Idosimetry considerations in Phase I

• Non-linearityNon-linearity• Changes in site of injection and ROAChanges in site of injection and ROA

Keep these in mind when Keep these in mind when setting dosing conditionssetting dosing conditions

J. Green

Ref: Ammann, A, et al, 1990

Bell Shaped Dose Response ProfileBell Shaped Dose Response Profile

J. Green

Single Dose huMAB PK in Cynomolgus MonkeysSingle Dose huMAB PK in Cynomolgus Monkeys

1.0

10.0

100.0

1000.0

0 5 10 15 20 25

Time (days)

Mean S

eru

m C

once

ntr

atio

n (

µg/m

L)

1 mg/kg

1 mg/kg

5 mg/kg

10 mg/kg

25 mg/kg

50 mg/kg

Comments:Comments:LD vs. HD ClLD vs. HD ClLong exposureLong exposureTimes above Times above TDRTDR

J. Green

huMAB Low Dose CL ExamplehuMAB Low Dose CL Example

Dose (mg/kg)Dose (mg/kg) CL (ml/min/kg)CL (ml/min/kg)

0.030.03 86.9 86.9 1.0 1.0

0.10.1 7.8 7.8 1.9 1.9

0.30.3 1.4 1.4 0.4 0.4

1.01.0 0.6 0.6 0.2 0.2

3.0 3.0 0.3 0.3 0.04 0.04

J. Green

R

FcRn

Factors Affecting Clearance and Half-Life Factors Affecting Clearance and Half-Life of Antibodiesof Antibodies

Apparent high Apparent high clearance rate at clearance rate at lower doses until lower doses until receptor saturation receptor saturation occursoccursEffect of antigen sinkEffect of antigen sink

FcRn binding FcRn binding decreases decreases clearance and clearance and increases serum increases serum half-lifehalf-life

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Subcutaneous Injection SiteSubcutaneous Injection Site

LEG (F= 0.85)

INTRASCAPULAR (F=0.35)

Time (hours)

0.10

1.00

10.00

100.00

0.00 24.00 48.00 72.00

h

µg

/mL

Seru

m C

onc

(ug/

mL

)

Provided by: Drs. Mark Rogge and Jennifer VisichZymogenetics, Inc.

J. Green

Reference: Mordenti et al, Pharm Res. 13: 1427,1996

J. Green

Can the New Drug Product be Used Can the New Drug Product be Used SafelySafely in Early Clinical Trials? in Early Clinical Trials?

• Typical biologic development program for a cancer Typical biologic development program for a cancer biologic intended for repeat-dose treatment would biologic intended for repeat-dose treatment would include:include:– Example: MABExample: MAB

• Studies to identify ‘relevant’ speciesStudies to identify ‘relevant’ species• Tissue cross reaction study to ID off target binding sitesTissue cross reaction study to ID off target binding sites• SD Pharmacokinetic studies in one or more speciesSD Pharmacokinetic studies in one or more species• SD/RD 4 week toxicology studies SD/RD 4 week toxicology studies ++ recovery is one/two relevant species recovery is one/two relevant species• Total study number: 8-10Total study number: 8-10

– NB: efficacy, MOA studies alsoNB: efficacy, MOA studies also– Timeframe:Timeframe:

• Discovery – 2-3 yrsDiscovery – 2-3 yrs• Preclinical development: 6-12 months.Preclinical development: 6-12 months.

J. Green

Questions and Issues: SafetyQuestions and Issues: Safety

• What does our experience tell us are necessary What does our experience tell us are necessary and reasonable toxicology requirements to and reasonable toxicology requirements to support the repeat-dosing of responding support the repeat-dosing of responding patients in Phase I/ll oncology trials?patients in Phase I/ll oncology trials?– Historically, 4 week repeat-dose studies sufficient for small Historically, 4 week repeat-dose studies sufficient for small

molecule development programsmolecule development programs– Historically, 4 week repeat-dose studies have been viewed as Historically, 4 week repeat-dose studies have been viewed as

sufficient to treat responders for biologics drug development sufficient to treat responders for biologics drug development programs (e.g., Rituxanprograms (e.g., Rituxan®®, Herceptin, Herceptin®®))

• Recently for biologics, 3 month repeat-dose toxicology studies Recently for biologics, 3 month repeat-dose toxicology studies are being required to support treatment beyond one monthare being required to support treatment beyond one month

J. Green

Questions and Issues: SafetyQuestions and Issues: Safety

• Are the cited differences between small molecules Are the cited differences between small molecules and biologics of sufficient concern to warrant and biologics of sufficient concern to warrant additional requirements warranted for biologics in all additional requirements warranted for biologics in all cases? cases? – This should not be a mandatory requirement for all biologic This should not be a mandatory requirement for all biologic

drugs for Phase I trialsdrugs for Phase I trials• Case by case determination is recommendedCase by case determination is recommended

– Agreement with FDA medical and pharmtox reviewers prior Agreement with FDA medical and pharmtox reviewers prior to initiation of IND supporting studiesto initiation of IND supporting studies

– Importance of open, early and frequent dialogue with FDA Importance of open, early and frequent dialogue with FDA scientists to assure program alignment and avoid scientists to assure program alignment and avoid unnecessary program delaysunnecessary program delays

J. Green

SummarySummary

• Compared to small molecule drug development programs, Compared to small molecule drug development programs, there are important differences for biologic drugs that affect there are important differences for biologic drugs that affect program designs and assessment parametersprogram designs and assessment parameters

• Well designed pharmacology, toxicology and Well designed pharmacology, toxicology and pharmacokinetic studies are important to support safe use pharmacokinetic studies are important to support safe use conditions for human trials with oncology drugsconditions for human trials with oncology drugs

• Four-week repeat dose toxicology studies with recovery Four-week repeat dose toxicology studies with recovery periods should be adequate to support extended treatment periods should be adequate to support extended treatment of responding and stable disease patients in most casesof responding and stable disease patients in most cases– Case-by-case determination recommendedCase-by-case determination recommended

J. Green

AcknowledgementsAcknowledgements

• BIO’s BioSafe Expert Nonclinical Safety Assessment BIO’s BioSafe Expert Nonclinical Safety Assessment Committee Members: Committee Members: – Drs. J. Cavagnaro, M. Cosenza, J. Green (Chair), S. Heidel Drs. J. Cavagnaro, M. Cosenza, J. Green (Chair), S. Heidel

(Vice-chair), C. Horvath, A. Levin, M. Rogge (Sec.), (Vice-chair), C. Horvath, A. Levin, M. Rogge (Sec.), R. Soltys, J. Stoudemire, T. Terrell, G. Treacy, G. Warner, P. WorkingJ. Stoudemire, T. Terrell, G. Treacy, G. Warner, P. Working

• Biogen Idec Colleagues: Biogen Idec Colleagues: – Drs. B. Adelman, J. Clarke, D. Hutto, L. Klunk, M. Li, A. Drs. B. Adelman, J. Clarke, D. Hutto, L. Klunk, M. Li, A.

Molina, M. Subramanyan, J. Woodworth, C. TenHoorMolina, M. Subramanyan, J. Woodworth, C. TenHoor