The Medical and Economic Roles of Pipeline Pharmacogenetics: Alzheimer's Disease as a Model of Efficacy and HLA-B*5701 as a Model of Safety

Abstract

Pharmacogenetics (PGX) is the study of drug response as a function of an individual's DNA. PGX is often viewed as an extension of disease association genetics, and although this information may be related, it is not the study of drug response. Although medicines are used to treat diseases, the value of strategies that identify and incorporate DNA biomarkers associated with clinical efficacy, or DNA biomarkers for untoward clinical responses, can be applied directly to pharmaceutical pipelines. The growth of adverse event PGX studies involving marketed medicines generally uses relatively large numbers of affected patients, but has been productive. However, the two critical strategies for pipeline genetics must make use of fewer patients: (1) the early identification of efficacy signals so that they can be applied early in development for targeted therapies and (2) identification of safety signals that can subsequently be validated prospectively during development using the least number of patients with adverse responses. Assumptions are often made that large numbers of patients are necessary to recognize PGX hypotheses and to validate DNA biomarkers. In some ways, pipeline pharmacogenetics may be viewed as the opposite of current genome-wide scanning designs. The goal is to obtain PGX signals in as few patients as possible, and then validate PGX hypotheses for specificity and sensitivity as development trials go forward--not using hundreds of thousand of markers to detect strong linkage disequilibrium signals in thousands of patients and their controls. Drug development takes 5-7 years for a drug candidate to traverse to registration--and this is similar to the timeframe for validating genetic biomarkers using sequential clinical trials. Two important examples are discussed, the association of APOE genotypes to the demonstration of actionable efficacy signals for the use of rosiglitazone for Alzheimer's disease; and the identification of HLA-B(*)5701 as a highly sensitive and specific predictive marker for abacavir treated patients who will develop hypersensitivity syndrome (HSS). The rosiglitazone study prevented pipeline attrition by changing the interpretation of a critical Phase IIB proof of concept study (2005) from a failed study, to a positive efficacy response in a genetically predictable proportion of patients. Now, three years later, a Phase III program of clinical trials using pharmacogenetic designs is months away from completion (late08). If successfully registered (early09), millions of patients could benefit, and efficacy PGX would have achieved its first prospective block-buster. The use of safety candidate gene association genetics in patients who received abacavir therapy and developed HSS starting in 1998 culminated in a double blind clinical trial that determined sensitivity > 97% and specificity >99% in 2007. Clinical consensus panels rapidly recommended abacavir as the preferred therapy along with HLA-B(*)5701 pre-testing, immediately increasing the market share of abacavir with respect to ot...

Pharmacogenetics: Matching the Right Foundation at Personalized Medicine in the Right Genomic Era

“…(Trent, 2010) The increased benefit-to-risk ratio and the economic consequences of HLA-B*5701 pre-screening of HIV-infected patients before abacavir treatment's initiation were demonstrated in a prospective double-blinded clinical trial sponsored by GSK. (Mallal et al, 2008;Roses, 2009; Moreover, consistent data support the association of the HLA class II allele HLA-DRB*0101 with an increased risk of nevirapine-induced hepatotoxicity, as well as genotype-related peripheral neuropathy, hyperlipidaemia, lipodystrophy to HAART, nucleoside reverse transcriptase inhibitors-related pancreatitis and tenofovir-associated renal proximal tubulopathy. (Tozzi, 2010) Other recent examples of important HLA associations with drug hypersensitivity include HLA-B*1502 and Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) that are associated with carbamazepine in Han Chinese; HLA-B*5801 and SJS/TEN and drug-induced hypersensitivity syndrome/drug reaction with eosinophilia and systemic symptoms associated with allopurinol; HLA-B*5701 and flucloxacillin-induced liver injury.…”

“…However, standardized methodologies should be established regarding: specification of sample source, standardization of diagnostic systems and treatments, adequate monitoring, sufficient length of observation, inclusion of possible confounding factors. (Roses, 2009;Spraggs et al, 2009) The cost of pipeline pharmacogenetics is much lower in comparison with the cost of clinical trials and drug attrition. The advantages of large public-private partnerships at all stages of drug development in order to accelerate new medicines approval and biomarkers qualification and validation for selection of patients for clinical trials, monitoring drug effects and safety risk, regulatory guidelines harmonization and implementation, are illustrated by Eck and Paul.…”

“…For example, Eli Lilly has applied the tailored therapy strategy for drugs Xigris andStrattera. (Lechleiter, 2009, as cited in Fackler &McGuire, 2009;Roses, 2009) Stingl and Brockmöller realize a comparative analysis of a variety of pharmacogeneticsrelated study designs integrated in all phases of drug development and clinical practice, evaluating the following issues: type and quality of evidence gained by each category of study design, their appropriated timeliness, as well as their pros and cons. The authors underline the necessity for new study designs for the clinical application of pharmacogenetics knowledge, as well as for mandatory requirements for the comprehensive characterization of relevant genetic variation in drug development.…”

Pharmacogenetic Considerations in the Treatment of Alzheimer’s Disease

“…APOE is a pleio tropic gene with multifaceted activities in physiological and pathological conditions, and the presence of the APOE4 allele is determinant in AD pathogenesis [ hyperphosphorylation of tau protein and neurofibril lary tangle formation, reducing choline acetyltransfer ase activity, increasing oxidative processes, modifying inflammationrelated neuroimmunotrophic activity and glial activation, altering lipid metabolism, lipid transport and membrane biosynthesis in sprouting and synaptic remodeling and inducing neuronal apoptosis and premature neuronal death [2,3,19,20]. Multiple stud ies over the past two decades have demon strated that APOE variants may affect the therapeutic response to antidementia drugs [2,3,5,6,11,12,19,[21][22][23][24][25]. At least 20 major phenotypic features illustrate the biological disadvantage of APOE-4 homozygotes and the poten tial consequences that these patients may experience when they receive pharmacological treatment for AD and/or concomitant pathologies [1][2][3]11,18,22,26].…”

“…At least 20 major phenotypic features illustrate the biological disadvantage of APOE-4 homozygotes and the poten tial consequences that these patients may experience when they receive pharmacological treatment for AD and/or concomitant pathologies [1][2][3]11,18,22,26]. In over 100 clinical trials for dementia, APOE has been used as the only gene of reference for the 10 [2,20,[23][24][25]27,28]; however, controversial results are frequently found due to methodological problems, study design and patient recruitment in clinical trials. The major con clusion in most studies is that APOE-4 carriers are the worst responders to conventional treatments [2,3].…”