biomarkers

biomarker definition

• indicator of normal biologic state or response that can be measured objectively or quantifiably

  • indicator of normal biologic, pathogenic or pharmacologic processes/responses to a therapeutic intervention

examples of biomarkers

• proteins

• physiological responses eg blood pressure

• imaging techniques as long as they are objectively measured and for the purposes in the definition

what can biomarkers be used for

• diagnostic

• susceptibility or risk

• predictive

• prognostic

• pharmacodynamic

• monitoring

• safety

predictive biomarker

identified who is likely to have an unfavourable effect

prognostic biomarker

predict or monitor reoccurrence / progression of the disease

general framework for developing disease related biomarkers

• biomarker discovery

• validation

• qualification

• establishment of clinical utility or implementation

why do we need bioamarkers in drug development

• quicker and more accurate health diagnoses

• improve clinical management

• reducing time for discovery

• evaluation of new treatments

translational medicine

• conditions and prerequisites for the transfer of in vitro and in vivo findings int ohuman application

what increases probability of successful progression through clinical drug development

• biomarkers

translatable biomarkers

• test of validity petameters such as sensitivity, specificity and reproducibility in animal and human data

• predictions about candidate drugs are more accurate

forward translation

• from basic research to clinical research, view drug development as customer

reverse translation

from clinical research to basic research, feed back clinical needs and samples

examples of translational biomarkers

• toxicity biomarkers

• target engagement

• mechanism biomarker

• outcome biomarker

toxicity biomarker and examples

• used to stop decision for a candidate compound

• eg QT prolongation and hERG channel blockade

• raised liver enzyzmes

• glomerular filtration rate of kidney

aim of target engagement

• tell us the candidate compound is interacting with the macromolecular target of interest

• present early in pathophysiological cascade and inform on biological interactions with molecular target of drug

imaging techniques used for target engagement

• PET

• SPECT

  • no functional activity directly

Example of target engagement

• receptor occupancy

• translational as it can be measured in rodents and humans using imaging techniques based on radioligand binding

  • PET and SPECT in humans

mechanism biomarker definition

• physiological impact of the candidate compound

  • easier in preclinical drug development

  • functional activity - happening downstream from target engagement

mechanistic biomarkers

enzyme activity, gene/protein expression, behavioural changes, blood conc of specific channels

example of mechanistic biomarker in practice

• drugs acting as agonists or antagonists at GPCR

• cAMP levels can be measured from blood by elisa or mass spectrometry

outcome biomarker

• link with the disease that predicts candidate compound efficacy

• can be biochemcical, physiological eg changes in bp or sleep induction

• late pathophysiological cascade

biomarker discovery and development timeline

• discovery

• analytical validation

• clinical validation

• qualification - FDA review

analytical validation for biomarker discovery

• involves testing in large number of samples

• confirms biomarker sensitivity but also begins to consider biomarker specificity

• alterations to improve sensitivity

clinical validation of biomarker

• ability of biomarker to predict important clinical outcome

• must be tested in population of patients different to the population the biomarker was originally identified within

advantage of using a biomarker in support of clinical evidence

• level of validation required is lower compared to it being the complete substitute

what is the main challenge in biomarker field?

distinguish between a potential biomarker and reliable biomarker that can be universally used to guide important clinical and commercial decisions

how do biomarkers help in drug development

• to speed up development and approval of new drugs

• improved prediction of drug efficacy over conventional clinical endpoints

• help identify candidate drugs that are likely to fail earlier in the process

Requirements to determine clinical utility of the drug

• need to treat for extensive period of time

• wait a long time to get to clinical endpoint clinical surrogacy

how did biomarkers aid the HIV/AIDS outbreak?

• drugs needed to be developed faster

• assay of CD4+ cell count standardised as surrogate endpoint for clinical trials acting as a pharmacodynamic biomarker

• zidovudine approved by FDA

was CD4+ assay completely foolproof for HIV/AIDS?

• no

• GIV plasma RNA quantification as an alternative and better surrogate endpoint was more specific

• but CD4+ cell count allowed drugs to be developed faster

surrogate endpoint

• indirect clinical benefit eg HIV viral load decreases

• predict clinical benefit eg development of AIDS

example where biomarkers were not effective in drug discovery and development

• rofecoxib was a COX2 specific inhibitor withdrawn for inc heart disease and stroke

• cardiac safety biomarker would not have prevented this

• correct screening for selectivity would have prevented it, increased risk was caused by COX1 inhibition in endothelial cells

prevention of serious adverse effects in clinical trials example of using a biomarker

• TGN1412 is a CD28 specific monoclonal antibody superagonist

  • causes severe cytokine release from T cells, leading to multiorgan failure

• IL-2 and IFN-gamma release could be used as biomarkers for this adverse response

advantages of biomarkers in drug discovery

• easily measured

• time efficient

• quantitative

• objective

• highly reproducible

• clinical relevance and reliability across heterogenous patient population

negatives for biomarker suitability in drug development

• difficult to measure

• expensive to implement

• require long experiments

• difficult to reproduce

biomarkers in clinical decisions and disease management

• pharmacogenomic biomarker

• diagnostic biomarker

• companion + complementary diagnostics

Pharmacogenomic biomarker

• informative for clinical setting

• possess or lack target

• metabolism of drugs

  • inform on effective dosing on whether they are fast or slow metabolites

what can genomic biomarkers describe

• Drug exposure and clinical response variability

• Risk for adverse events

• Genotype-specific dosing

• Mechanisms of drug action

• Polymorphic drug target and disposition genes

• Trial design features

Diagnostic biomarker

• Primarily used in clinical setting

• Can also be used in preclinical in vivo setting

• Identify whether disease present or not

• Identify risk of disease

• Identify progression / regression of the disease

• Identify disease before manifestation of symptoms

companion and complementary diagnostics

• essential to identify patients who will benefit from a medicine before it is prescribed or whether a medicine is safe or not

• complementary diagnostics are not essential, but may inform on level of side effects or efficacy of a particular drug

• associated with a particular drug and marketed with them

precision medicine and benefits

• Use of an individual’s unique molecular and genetic characteristics to allow

  • improved diagnosis

  • predict susceptibility to disease or treatment

  • refine doses to maximise successful outcome

  • minimise adverse reactions

Measurement of the levels of HER2 has been suggested as a potential biomarker for breast cancer patients. Which would describe this use of a biomarker?

predictive

Identification of a mutation in the HER2 gene was developed as an alternative biomarker. If used prior to prescribing, what kind of biomarker would this be classed as?

companion diagnostic

True or False: KRAS mutations are predictive biomarkers for the efficacy of drugs acting via HER1and HER2.

False

• if both receptors can activate KRAS, blocking one route would not be enough

What do we need to know about these variants SNPs for warfarin in order for them to be safety biomarkers:

what the functional consequence of the variant is