Human pharmacology for biologicals first into man studies
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Human pharmacology for biologicals – First into man studies. Daren Austin PhD Clinical Pharmacology Discovery Medicine GlaxoSmithKline. London - March 13, 2006. London - March 13, 2006. Some perspective. Developing new medicines is a collaborative effort

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Human pharmacology for biologicals first into man studies

Human pharmacology for biologicals – First into man studies

Daren Austin PhD

Clinical Pharmacology Discovery Medicine

GlaxoSmithKline


London march 13 2006

London - March 13, 2006

AGAH/Club Phase I Annual Mtg


London march 13 20061

London - March 13, 2006

AGAH/Club Phase I Annual Mtg


Some perspective

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

AGAH/Club Phase I Annual Mtg


A few successes

A few successes…

AGAH/Club Phase I Annual Mtg


Applications of therapeutic antibodies

Adalimumab

Bavacizumab

Etanercept

Infliximab

Omalizumab

Applications of therapeutic antibodies

ALTER CELL

FUNCTION

DESTROY

TARGET CELLS

Abciximab

Basiliximab

Daclizumab

Efalizumab

Natalizumab

Palivizumab

Alefacept

Cetuximab

Muronomab

Trastuzumab

Gemtuzumab

ozogamacin

Ibritumomab

tiuxetan

Tositumomab

TARGETED DRUG

DELIEVRY

NEUTRALIZE “TOXINS”

IMMUNOTOXICOTHERAPY

AGAH/Club Phase I Annual Mtg


The wrong way

We’ve got a new wonder drug! … we give it to you and wonder what it will do

The wrong way …

AGAH/Club Phase I Annual Mtg


The right way outline

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

AGAH/Club Phase I Annual Mtg


Understand the mechanism

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

AGAH/Club Phase I Annual Mtg


Understand the pharmacology big molecules small differences

Understand the pharmacologyBig molecules – small differences?

AGAH/Club Phase I Annual Mtg


Understand the pharmacology

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)

AGAH/Club Phase I Annual Mtg


Design the right study theory what dose range what starting dose

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

www.pbase.com

AGAH/Club Phase I Annual Mtg


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#

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

# Buoen et al. (2005) J. Clin Pharm45: 1123-1136

AGAH/Club Phase I Annual Mtg


Design the right study typical gsk ftih designs

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

AGAH/Club Phase I Annual Mtg


Exposure ranges for responses

Exposure ranges for responses

  • Agonists are very efficient at signalling (80/20)

  • Antagonists must block most receptors before signal is turned off

AGAH/Club Phase I Annual Mtg


Exposure ranges for responses1

Exposure ranges for responses

  • Agonists are very efficient at signalling (80/20)

  • Antagonists must block most receptors before signal is turned off

AGAH/Club Phase I Annual Mtg


Exposure ranges for responses2

Exposure ranges for responses

  • Agonists are very efficient at signalling (80/20)

  • Antagonists must block most receptors before signal is turned off

AGAH/Club Phase I Annual Mtg


Define the right dose

Define the right dose

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

AGAH/Club Phase I Annual Mtg


Define the right dose what starting dose

Define the right doseWhat starting dose?

Define No Observable Adverse Effect Level

Safety cover for top dose (1 – 5x)

Low dose based

on enhanced cover

(100 – 500x)

Low dose based

on expected

pharmacology

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

AGAH/Club Phase I Annual Mtg


Define the right dose what starting dose1

Define the right doseWhat starting dose?

Define NOAEL

Define MABEL

Minimally Active Biological Effect Level

Safety cover for

low dose

(100 – 500x)

Safety cover for

top dose (1 – 5x)

Low dose based on pharmacology

  • Define lowest level of biological activity preclinically

  • Equivalent to “Minimally effective” Phase IIB dose

  • Will require downward preclinical dose titration for antibodies

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

AGAH/Club Phase I Annual Mtg


Mabel based on pd pd of orthologues

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

AGAH/Club Phase I Annual Mtg


Pk pd and orthologues

PK/PD and orthologues

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

AGAH/Club Phase I Annual Mtg


Pk pd and orthologues model validation

PK/PD and orthologues model validation

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

AGAH/Club Phase I Annual Mtg


Allometric scaling of proteins

Allometric scaling of proteins

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

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

  • 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

AGAH/Club Phase I Annual Mtg


Scaling capacity limited binding to humans

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 neutralisation

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

AGAH/Club Phase I Annual Mtg


Define the right dose1

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]/200 [mg/kg] will give about 50% binding

      • [Duff pg. 29]

      • Scale for smaller proteins according to MWT and Vdss

AGAH/Club Phase I Annual Mtg


Define the right dose2

Define the right dose

Proposed (and approved)

Suggested (for agonist)

*

100x lower starting dose and smaller escalations

*Assumes Cmax/Kd is correlated with functional response

Ro ~ (Cmax/Kd)/(1+(Cmax/Kd))

AGAH/Club Phase I Annual Mtg


Understand the population

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 population

http://www.noaddedsugar.org/images/gordon/crowd.jpg

AGAH/Club Phase I Annual Mtg


Healthy subjects or patients

Healthy subjects or patients?

AGAH/Club Phase I Annual Mtg


Not all created equal

Not all created equal …

  • Intrinsic variability

    • drug-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

AGAH/Club Phase I Annual Mtg


Mixed study population

Mixed study population

Bridging dose

Part 1 – Healthy subjects

Safety, tolerability

PK

Part 2 – Patient

Safety, tolerability

PK, PD

Increasing dose

AGAH/Club Phase I Annual Mtg


Design the right study practice

Design the right study (practice)

  • Stronger drive to deliver more information earlier: MTD with Proof 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

AGAH/Club Phase I Annual Mtg


Proof of pharmacology

Proof of pharmacology

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

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

  • Imaging signal (e.g. fMRI or PET studies)

  • Transcriptomics for evidence of signal transduction

  • Clinical surrogate signal (e.g. airway conductance)

  • Clinical signal (e.g., fasting plasma glucose)

AGAH/Club Phase I Annual Mtg


Design the right study phase i fusion designs

Food

Effect

Drug-Drug

Interaction

FTIH

Design the right study: Phase I Fusion designs

Single

Dose

Patient

Population

Repeat

Dose

Human

Pharmacology

AGAH/Club Phase I Annual Mtg


Safe and well tolerated ftih study objectives

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 pharmacodynamicsof 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?

AGAH/Club Phase I Annual Mtg


Summary biopharm cedd ftih ftip studies

Summary biopharmCEDD FTIH/FTIP studies

AGAH/Club Phase I Annual Mtg


Gsk123456 pop pk analysis 0 03 1 0 mg kg during ongoing trial

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

Population PK analysis ongoing to predict time to follow-up

AGAH/Club Phase I Annual Mtg


Conduct the study right ensure clinical excellence

Conduct the study rightEnsure clinical excellence

Staff and facilities to handle medical emergencies

All FTIH studies conducted in a hospital based Unit

Assure staff training and experience

Integrated emergency response system and access to ITU

Dosing staggered

Interval hrs - days

Shared medical accountability between site (PI) and sponsor (medical monitor)

Determine if additional measures or clinical expertise is needed

AGAH/Club Phase I Annual Mtg


Summary

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

AGAH/Club Phase I Annual Mtg


Acknowledgements

Acknowledgements

© Mike Baldwin

  • GSK biopharmCEDD

  • GSK riCEDD

  • Ruth Oliver, CPDM

  • Colin Dollery, GSK

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

AGAH/Club Phase I Annual Mtg


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