human pharmacology for biologicals – first into man studies daren austin phd clinical pharmacology...

Human pharmacology for biologicals – First into man studies

Daren Austin PhDClinical Pharmacology Discovery Medicine

GlaxoSmithKline

27/04/2007 AGAH/Club Phase I Annual Mtg 2

London - March 13, 2006


London - March 13, 2006


Some perspective Developing new medicines is a collaborative effort

– industry, academia and regulatory bodies

FTIH studies are generally very safe

– protocols represent a high standard of science and medicine

TGN1412 underscores the importance of translational science, clinical pharmacology and study design for safe drug development

Most antibodies are very safe

– At least one marketed antibody has the same cytokine profile as TGN1412


A few successes…


Applications of therapeutic antibodies

AbciximabBasiliximabDaclizumabEfalizumab

NatalizumabPalivizumab

AdalimumabBavacizumab

EtanerceptInfliximab

Omalizumab

GemtuzumabozogamacinIbritumomab

tiuxetanTositumomab

AlefaceptCetuximabMuronomabMuronomab

Trastuzumab

DESTROYDESTROYTARGET CELLSTARGET CELLS

ALTER CELLALTER CELLFUNCTIONFUNCTION

TARGETED DRUGTARGETED DRUGDELIEVRYDELIEVRY

NEUTRALIZE “TOXINS”NEUTRALIZE “TOXINS”IMMUNOTOXICOTHERAPYIMMUNOTOXICOTHERAPY


The wrong way …We’ve got a new wonder

drug! … we give it to you and wonder what it will do


The right way…Outline Understand the mechanism

Understand the pharmacology

Design the right study (theory)

Define the right dose

Understand the population

Design the right study (practice)

Conduct the study right

www.prairierivers.org


Understand the mechanism

Soluble or cell-associated target Pleiotropy Redundancy Potential for biological amplification Downstream signalling Tissue expression and homeostasis Translation plan for human systems


Understand the pharmacologyBig molecules – small differences?

Characteristic Small Molecule Antibody

Molecular weight < 700 150,000 (300x higher)

Potency pM – nM (agonist/antagonist)

pM – nM(typically antagonists)

Clearance Linear at low doses, Non-linear at high doses

Non-linear at low doses, linear at high doses

Volume Wide range, < 1000 L/kg 70 ml/kg, 2x plasma

Bioavailability 0 – 100%, predictable from Phys Chem properties

0% via oral, 30 – 90% via sub-cut

PK/PD timeframe PD slower than PK PK slower than PD

Preclincal NOAEL Dose limiting, non-specific, off-target binding

Exaggerated pharmacology

FTIH design Multi-cohort, cross-over design

Multi-cohort, parallel group design


Understand the pharmacology Antagonists

– possess affinity without activity acts by blocking a receptor, occupying or

inhibiting messenger

Agonists– possess affinity with efficacy,

binds and activates a response via downstream signalling

Hence, an agonist activates a receptor, an antagonist binds but doesn’t activate it (i.e., it blocks access of agonist)


Design the right study (theory)What dose range? What starting dose?

www.pbase.com


Dose ranges: are they adequate?Data from 100 GSK FTIH studies

Median of 6 dose levels (8 periods)

Cumulative escalation is 60x (2–20000x)

Distribution is different to industry benchmark#

# Buoen et al. (2005) J. Clin Pharm 45: 1123-1136

0

5

10

15

20

25

30

2 4 8 16 32 64 128 256 512 1,024 2,048 4,096 8,192 16,384 32,768

Log2 (Dose range)

Per

cen

t Data

BPCEDD

Industry


Design the right studyTypical GSK FTIH designs

For small molecules typically five period (incl. placebo) with repeated dose across cohorts and 2-3 fold escalations:– P, X, 2X, 4X, 8X then P, 8X, 16X, 32X, 64X– 23 x 23 = 64-fold– 3 x 3 x 2 x 2 x 1.5 x 1.33 = 72-fold

For large molecules typically six period parallel group with log/semi-log decreases– X, 10X, 10X, 3X, 3X, 3X– 102 x 33 = 2700-fold

Overall dose range defined by number of cohorts Define starting dose to give top dose


Exposure ranges for responses Agonists are very

efficient at signalling (80/20)

Antagonists must block most receptors before signal is turned off

0%

20%

40%

60%

80%

100%

120%

0.001 0.01 0.1 1 10 100 1000

Relative Dose

Rel

ativ

e R

esp

on

se

Shallow

Antagonist

Agonist

Switch

Desired response

Exposure Ratio Shallow

Anta-gonist Agonist "Switch"

90% ED90/ED10 4 2 1 <1

95% ED95/ED5 5 3 1 <1

99% ED99/ED1 8 4 2 1

Orders of magnitude for exposure rangeGOOD (<100x)POSSIBLE (100 – 1000x)IMPOSSIBLE (>1000x)





0%

20%

40%

60%

80%

100%

120%

0.001 0.01 0.1 1 10 100 1000

Relative Dose

Rel

ativ

e R

esp

on

se

Shallow

Antagonist

Agonist

Switch

Desired response



90% ED90/ED10 4 2 1 <1

95% ED95/ED5 5 3 1 <1

99% ED99/ED1 8 4 2 1




http://pixelsoap.com/photos/album32/roulette


Define the right dose What starting dose?

Define No Observable Adverse Effect Level

Safety cover for top dose (1 – 5x)

Low dose basedon enhanced cover

(100 – 500x)

Low dose basedon expected

pharmacology

For NMEs, low dose will be typically 100x lower based on design arguments


Define lowest level of biological activity preclinically Equivalent to “Minimally effective” Phase IIB dose Will require downward preclinical dose titration for antibodies

Define NOAEL

Safety cover fortop dose (1 – 5x)

Safety cover forlow dose

(100 – 500x)

Low dose based on pharmacology

Define MABEL

Low dose = Min(MABEL, NOAEL/cover, Binding)

Minimally Active Biological Effect Level

Define the right dose What starting dose?


MABEL based on PD/PD of orthologues

Raptiva™ targets CD11a did not bind to preclinical species muM17 is an anti-mouse CD11a Mab developed as a surrogate

molecule to assess reproductive toxicity in mouse Mechanistic PK/PD model used to determine dose equivalence to

humans

Wu (2006) J Pharm Sci 96 (6) 1258


PK/PD and orthologues

Wu (2006) J Pharm Sci 96 (6) 1258


PK/PD and orthologues model validation

Wu (2006) J Pharm Sci 96 (6) 1258


Allometric scaling of proteins

Established for small and larger molecules Assumes conservation of clearance pathway across species For monoclonal antibodies this assumption is frequently violated

– Human target may only be shared by primate species– Single species allometry– Consider target expression and target mediated clearance

http://www.elephants.com/sharma_photos.htm

Mordenti et al (1991), Pharm Res 8, 1351


Scaling capacity-limited binding to humans

MUC-18 cell surface adhesion (melanoma)

Fit parallel linear and non-linear binding elimination pathways

Assume Vmax and Km are predictive of humans

Residual clearance allometrically scaled

Simulate human PK profiles

Ignores neutralisationhttp://www.abgenix.com/documents/ASCPT2004%20poster.pdf


Define the right dose Large molecules bind to a target at nanomolar

concentrations– 150kD implies equates to 0.15µg/ml for 50% binding

That’s about 0.01 mg/kg

Antibody binding is normally antagonistic– High binding required to suppress signaling pathways– 80-90% binding equates to 1 – 2µg for biological effect

That’s about 0.1 mg/kg

Guiding simplification– Starting dose of Kd[nM]/200Kd[nM]/200 [mg/kg] will give about 50% binding

[Duff pg. 29] Scale for smaller proteins according to MWT and Vdss



Proposed (and approved) Suggested (for agonist)

100x lower starting dose and smaller escalations*Assumes Cmax/Kd is correlated with functional responseRo ~ (Cmax/Kd)/(1+(Cmax/Kd))

*

Dose (mg/kg)

Cmax (ug/ml)

AUC(0-inf)

(ug.h/ml)Cover DOSE

Ratio Cmax

Kd Ro

0.1 2.309 428 500x 8.2 89%

0.5 11.55 2142 100x 40.9 98%

2 46.2 8567 25x 163.8 99%

5 115.5 21418 10x 409.5 100%

Dose (mg/kg)

Cmax (ug/ml)

AUC(0-inf)

(ug.h/ml)Cover DOSE

Ratio Cmax

Kd Ro

0.001 0.023 4.28 50000x 0.08 8%

0.003 0.069 12.8 16667x 0.25 20%

0.008 0.185 34.2 6250x 0.7 40%

0.012 0.277 51.4 4167x 1.0 50%

0.025 0.577 107 2000x 2.0 67%

0.05 1.155 214 1000x 4.1 80%


Understand the population ICH guidelines Benefit outweighs the risk

– HVTs do not benefit– Risk must be managed

accordingly

Mixed populations?– HVTs (S&T/PK) then

escalate in patients

Mild patients?– Neither HVTs nor mild

patients may predict eventual populationhttp://www.noaddedsugar.org/images/gordon/crowd.jpg


Healthy subjects or patients?

Points to consider Comments

Expression of target protein Healthy subjects may not predict safety and tolerability

Safety profile in patients may vary with disease severity

Determination of optimal biological dose

May only be possible in patients

Presence of co-morbidities Detection and interpretation of safety signals more difficult

Long half life Extended follow-up not always feasible in healthy volunteers

Opportunity for investigating pharmacodynamic activity

Risk assessment May preclude healthy subjects

Immunogenicity May limit future choice of therapy


Not all created equal …

Intrinsic variability– drug-target interactiondrug-target interaction

– type of transduction

– drug access at biophase

– delivery & input rate

– metabolism pheno/genotype

– disease & homeostasis

– placebo response

Extrinsic variability– drug-drug interactions

– interactions with endogenous substances


Part 1 – Healthy subjectsSafety, tolerability

PK

Part 2 – PatientSafety, tolerabilityPK, PD

Increasing dose

Bridging dose

Mixed study population


Design the right study (practice)

Stronger drive to deliver more information earlier: MTD with Proof of PharmacologyProof of Pharmacology– early call on therapeutic index– define MTD in relevant populations (target expression?)– early go/no-go decisions

Fusion designs in Phase I– combination of study objectives

Adaptive designs in Phase I– say how you will decide to do something


Proof of pharmacology

Safety signalSafety signal from known class of compounds (e.g. cortisol suppression)

Receptor occupancy signaloccupancy signal from ex vivo assay (e.g. CD11B from neutrophils)

Imaging signalImaging signal (e.g. fMRI or PET studies) Transcriptomics for evidence of signal transductionsignal transduction Clinical surrogateClinical surrogate signal (e.g. airway conductance) Clinical signalClinical signal (e.g., fasting plasma glucose)


Design the right study: Phase I Fusion designs

FTIH

SingleDose

RepeatDose

FoodEffect

Drug-DrugInteraction

PatientPopulation

HumanPharmacology


Safe and well-tolerated?FTIH study objectives

Part A To investigate the safety and tolerability of single escalating doses of

GSK123456 in healthy subjects. To characterize the preliminary pharmacokinetics of single escalating

doses of GSK123456 in healthy subjects.Part B To investigate the safety and tolerability of a single oral dose of

GSK123456 in mild to moderate patients To characterize the preliminary pharmacodynamics of single and repeat

doses of GSK123456 as assessed by in an appropriate model

…GSK123456 is safe, well-tolerated, pharmacokinetics, response in patients…

Summarise and report results of Part A and justify doses in Part B

Will we establish a Maximum Tolerated Dose?


Summary biopharmCEDD FTIH/FTIP studies

Criteria Syncra® GSK1 GSK2 GSK4

Indication Diabetes Rheumatoid arthritis

Severe asthma Neuro-degeneration

Target GLP-1 Soluble cytokine Soluble cytokine Soluble protein

Precedence Yes No Semi No

Population HVT HVT HVT/Patients Patients

Design Parallel 2-dose adaptive AUC-

based escalation

Parallel SDadaptive follow-up

Parallel SD/RDPart A/B

Parallel SD/RD D-optimal adaptive

dose escalation on target inhibition

Escalation 416x 10,000x 10,000x 800x

Proof of Pharmacology

Fasting glucose compared to active control (enabling)

Target binding and ex vivo LPS

inhibition

Allergen challenge Target binding and inhibition


GSK123456 Pop-PK analysis (0.03 – 1.0 mg/kg) during ongoing trial

10

100

1000

10000

100000

1000000

0 7 14 21 28 35 42

Time [days]

Co

nc

en

tra

tio

n [

ng

/ml]

Population Mean Individual Predictions GSK123456

Population PK analysis ongoing to predict time to follow-up


Conduct the study rightEnsure clinical excellence

All FTIH studies conducted in a

hospital based Unit

Integrated emergency response system and access

to ITU

Determine if additional measures or clinical expertise is needed

Assure staff training and experience

Shared medical accountability between site (PI) and sponsor

(medical monitor)

Dosing staggeredInterval hrs -

days

Staff and facilities to handle medical

emergencies


Summary Understand the mechanism

– Translational medicine plan

Understand the pharmacology– Same principles, different size, High/Low risk molecule?

Design the right study (theory)

– Think escalations not doses, start low, end slow

Define the right dose– MABEL, Cmax/Kd, Preclinical PKPD, Allometry

Understand the population– HVTs and/or/then Patients? Target? MTD?

Design the right study (practice)– Fusion designs with Proof of Pharmacology for FIM expected

Conduct the study right– Hospital site, staggered dosing


Acknowledgements GSK biopharmCEDD GSK riCEDD Ruth Oliver, CPDM Colin Dollery, GSK

“Laugh when you can, it’s good medicine” Lord Byron

© Mike Baldwin

human pharmacology for biologicals – first into man studies daren austin phd clinical pharmacology...

Documents

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