Role of biomarkers in drug development

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Role of biomarkers in drug development

• Venkatesh Atul Bhattaram
• Pharmacometrics
• Office of Clinical Pharmacology and
  Biopharmaceutics,
• CDER/FDA

My remarks today do not necessarily reflect the
official views of FDA.
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Types of BiomarkersBased on Pathophysiology

• Biochemical
• in vivo
• PK, BMD, CD4,SGPT Estradiol, Cholesterol
• ex vivo
• ACE, AChE activity
• Anatomical / Morphological
• Tumor Size, Artery Diameter, Results of PET,
  CT-Scan, MRI

• Histological
• Biopsy, WBC
• Symptoms/Signs/ Others
• BP, PCWP, Exercise HR, Hospitalization, Rescue
  Medication, Pain Relief, QT, HEM/CYT Response
  rate, Genetic status

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Types of Indications

• Symptom / Sign Benefit
• pain relief, angina relief, BP lowering, improved
  cognition
• Morbidity / Mortality Benefit
• Reverse Disease
• Tx of pediatric leukemia
• Retard Disease
• Tx of CHF, Some cancers, Reno-, Cardio-protection

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Objectives

• Biomarkers can be effectively used to improve
  dose/regimen selection
• dose range for symptom/sign related indications
  (Exp-Resp in pivotal trials)
• dose(s) for mortality/morbidity indications
• Value of biomarkers is enhanced for drugs with
  approved indications
• new target populations, new dosing regimens, new
  routes of delivery

Jadhav et al. Amer.Pharm.Rev. 2004
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Case Studies
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Initial Dosing Regimen Selection

• Case Study Aromatase Inhibitors
• chemoprevention of breast cancer
• Mortality/Morbidity benefit
• biomarker driven dose/regimen probably more
  rational (than PK)
• Case Study ACE / A2 Inhibitors
• anti-hypertensives
• Symptom/Sign benefit
• select dose range based on ex-vivo activity

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Pathway of E2 formation
Kelloff GJ, et al. Aromatase inhibitors as
potential cancer chemopreventives. Cancer
Epidemiol Biomarkers Prev 1998 Jan 7(1)65-78).
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Pharmacokinetics
Duan Gobburu, 2001
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PK Driven Dosing Regimen

• Terminal half-life is about 1 day
• Dosing frequency every t1/2
• Kinetics of pharmacologic response not considered

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Irreversible Physiologic PD Model
Estradiol (E2)
kf,E2
kdeg,E2
Aromatase (AR)
kf,AR
kdeg,AR
kbin? Cp
Duan Gobburu, 2001
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Effects on Estradiol (E2)
Duan Gobburu, 2001
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PD Driven Dosing Regimen

• Terminal half-life is about 1 day
• Dosing frequency every t1/2
• Kinetics of pharmacologic response not considered

• Regeneration of aromatase is the rate-limiting
  step
• Estradiol reaches baseline levels in about 20
  days (not in 1day)

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Optimizing Dosing Regimen
1 mg 2.5mg 5 mg 10 mg 25 mg 50 mg
qd
1 mg 2.5mg 5 mg 10 mg 25 mg 50 mg
E2 Level (nmol/mL)
q 48h
1 mg 2.5mg 5 mg 10 mg 25 mg 50 mg
q 72h
Duan Gobburu, 2001
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Value to Drug Development

• Offset of E2 suppression critical, not PK
• Relationship between the clinical outcome and E2
  levels has not been explored
• Supra-optimal E2 suppression could lead to
  undesired skeletal events
• Undesired toxicity can be avoided by optimal
  dosing regimen
• Biomarker model helps in dose selection

Duan Gobburu, 2001
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Initial Dosing Regimen Selection

• Case Study Aromatase Inhibitors
• chemoprevention of breast cancer
• Mortality/Morbidity benefit
• biomarker suggested dose/regimen probably more
  rational (than PK)
• Case Study ACE / A2 Inhibitors
• anti-hypertensives
• Symptom/Sign benefit
• select dose range based on ex-vivo activity

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ACE / A2 Inhibitors

• Ex vivo activity is used to select a dose range
  to conduct pivotal trials
• BP reduction increases beyond maximal ex vivo
  activity
• Pivotal trials almost always are dose ranging,
  have been the basis for approval

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ACE / A2 Inhibitors
Dose, mg
Gobburu Lipicky, 2003
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Value to Drug Development

• Ex vivo activity clearly aids in avoiding too
  low, high doses
• Reasonable estimate of the step size between
  doses obtained
• Also, provides proof-of-concept

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Case Studies
?
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Target Population

• Case Study Herceptin (Trastuzumab)
• a recombinant DNA-derived humanized monoclonal
  antibody that selectively binds to HER2.
• Treatment of patients with metastatic breast
  cancer
• Patients whose tumors over-express HER2 protein
  (3 score) benefit

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Herceptin TTP
Anthracycline Taxol
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Herceptin TTP
Anthracycline Taxol
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Herceptin Cardiotoxicity
Anthracycline Taxol
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Herceptin

• Considerable cardio-toxicity exists (28)
• Patients with HER2 over-expression seem to
  benefit more
• Benefit/Risk different for 2 and 3
• Prospective target population identification is
  clearly important
• Identifying responders may improve dose-response
  (benefit/risk) relationship

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6-Mercaptopurin

• Over 50 years of use
• Patients with inherited deficiency of TPMT
  (thiopurine methyltransferase)
• high accumulation of intra-cellular thioguanine
  nucleotides
• prone to myelosuppression
• substantial dosage reductions needed

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6-MP and TPMT
Relling et al JNCI, 1999
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Value to Drug Development

• Prospective identification of patients with low
  TPMT activity is beneficial
• avoid undesired toxicity
• Prospective testing of effective doses in such
  patients
• Could minimize number of dropouts in clinical
  trials due to toxicity

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Case Studies
?
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New Population (Sotalol in Pediatrics)

• Section 505 A, FDAMA
• Sotalol approved in adults for VT,SVT
• mortality/morbidity benefit
• Studies using Biomarkers (QTc, HR)
• available in peds and adults (original)
• Population neonates to 12 yr
• Model-dependent analysis performed
• Is PKPD in peds predictable from adults ?
• Any dosage adjustments ?

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PK in Pediatrics
Shi J et al JPKPD, 2001
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Effect on QTc Pediatrics
Shi J et al JPKPD, 2001
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Effect on QTc Adults
Peds 8 Adults 7.5
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Effect on HR Pediatrics Adults
Adults EC50 804 ug/L
Peds EC50 790 ug/L
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Value to Drug Development

• PKPD in peds predictable from adults
• assessed using biomarkers
• Led to dosing recommendations in peds
• Regulatory buy-in of model dependent analysis
• Less burden to the sponsor to show similar
  benefit in pediatrics as in adults

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Case Studies
?
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Metoprolol XL

• IR dosing b.i.d.
• XL dosing q.d. (convenient dosing)
• Immediate release (IR) approved for treating
  angina, hypertension in adults
• easily demonstrable, titratable effects
• directly related to beta-blockade
• IR also approved for prevention of MI, death
  (mortality/morbidity benefit)
• not solely related to beta-blockade
• not titratable

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Metoprolol XL Angina

• New drug application (IR)
• Two trials in angina patients
• ITT analysis
• New formulation (XL)
• One trial with healthy patients
• Concentration-HR relationship

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Metoprolol and Attentuation of Exercise HR IR, XL
Abrahamsson et al, CPT
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Value to Drug Development

• Knowledge from IR used as prior
• Beta blockade demonstrated with a simple trial in
  healthy subjects
• Concentration-?HR compared between IR and XL
• particularly the duration of effect
• used to project effects in angina patients
• Less burden to the sponsor to show similar
  outcome between XL and IR

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Biomarkers in Drug Development

• Biomarkers can be effectively used to improve
  dose/regimen selection
• dose range for symptom/sign related indications
  (DR in pivotal trials)
• dose(s) for mortality/morbidity indications
• Value of biomarkers is enhanced for drugs with
  approved indications
• new target populations, new dosing regimens, new
  routes of delivery

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References

• Jadhav, Mehta, Gobburu. How biomarkers can
  improve clinical drug develoment.
  Amer.Pharm.Rev., 7(3), 62-64, 2004.
• Lesko et al. Use of biomarkers from drug
  discovery through clinical practice Report of
  the Ninth European Federation of Pharmaceutical
  Sciences Conference on Optimizing Drug
  Development. Clin.Pharmacol.Ther.,73284-291,
  2003.
• Temple RJ. Are surrogate markers adequate to
  assess cardiovascular disease drugs?
  JAMA,282(8)790-793, 1999.
• Guidance for Industry. Exposure-response
  relationships-study design, data analysis and
  regulatory applications
• Peck, Rubin, Sheiner. Hypothesis A single
  clinical trial plus causal evidence of
  effectiveness is sufficient for drug approval.
  Clin.Pharmacol.Ther. 73481-490, 2003.
• Colburn WA. Optimizing the use of biomarkers,
  surrogate endpoints and clinical endpoints for
  more efficient drug development.
  J.Clin.Pharmacol.401419-1427, 2000.
• ICH E5 and Pediatric drug development.

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Acknowledgements

• Dr Joga Gobburu
• Dr Patrick Marroum
• Dr. Mehul Desai, DCRDP

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