June 12-13, 2009 Dr. Cattaneo Stresa, Italy
7th Symposium DRUG DISCOVERY DEVELOPMENT PIPELINE New Developments in Clinical Pharmacy and Clinical Pharmacology June 13, 2009 – Stresa, Italy
Pharmacogenetics and Drug Development
Dario Cattaneo, Ph.D. Unit of Clincal Pharmacology “Luigi Sacco” University Hospital, Milan – Italy This is a large hurdle for academia and many pharmaceutical companies. Nevertheless, this costly and time-consuming process not always provides optimal results… Ospedale Luigi Sacco AZIENDA OSPEDALIERA – POLO UNIVERSITARIO - Roses, Nat Rev Drug Disc 2008 -
No medicine is perfect!
Drug Class Efficacy balancing efficacy with toxicity… contraceptive pills 97% NSAIDs 80% Anti-asthmatics 60% Anti-arrhythmic agents 60% Anti-depressants 60% Anti-diabetic agents 55% Anti-migraine agents 50% Anti-virals 45% Drugs for Alzheimer 30% Anti-neoplastic agents 25%
7th Symposium New Development in Clinical 1 Pharmacy and Clinical Pharmacology June 12-13, 2009 Dr. Cattaneo Stresa, Italy
ADVERSE DRUG REACTIONS ARE THE FOURTH SERIOUS ADVERSE DRUG REACTIONS (ADRs) LEADING CAUSE OF DEATH IN U.S.A. REPORTED TO THE FDA, 1998 – 2005
60 15107 cardiovascular (+170%) 50 diseases Drug use * 100000 16000 (5.5%) 40 80000 89842 12000 DRs of death (%) of 30 A (+1 150%)50%) cancer 60000
20 8000
Cause 5519 40000 Death
smoking Seriuous 10 others medical car alcool 34966 errors accident 4000 suicide 20000 0
* Illegal substances were excluded 0 0 1998 1999 2000 2001 2002 2003 2004 2005 Over 2 millions hospitalized patients experienced adverse drug reactions… Year
- Lazarou, JAMA 1998 - - Moore, Arch Intern Med 2007 -
Nearly 40 drugs were withdrawn from market Who wins, who loses? The case of torcetrapib since 1990… Adderall (death and stroke) Natalizumab (leukoencephalopathy) Tuesday, December 05, 2006 Alosetron (ischemic colitis) Nefazodone (hepatotoxicity) Alpidem (hepatotoxicity) Pemoline (hepatotoxicity "After spending more than 100 +106% !! Astemizole (QT prolongation) Rapacuronium (bronchospasm) Bendazac (hepatotoxicity) Remoxipride (aplastic anemia) $800 million to develop a ** 80 Bromfenac (hepatotoxicity) Rofecoxib (CV events) successor for its block buster (rhabdomyolysis) (QT prolongation) Cerivastatin Sertindole Lipitor Pfizer, the world's 60 /dL) Chlormezanone (hepatotoxicity) Sorivudine (myelotoxicity) ltdkhltdlargest drug maker, halted g Cisapride (QT prolongation) Temafloxacin (renal failure) development on Saturday of 40 Dexfenfluramine (pulmonary hypertension) Terfenadine (QT prolongation) its top experimental medicine HDL (m Dilevalol (hepatotoxicity) Terodiline (TdP) 20 Droperidol (QT prolongation) Tolcapone (hepatotoxicity) the cholesterol drug Ebrotidine (hepatotoxicity Tolrestat (hepatotoxicity) torcetrapib, due to safety 0 Fipexide (hepatotoxicity) Triazolam (psychiatric effects) concerns ( CVD events)” baseline 4w-treatment
Flosequinan (death) Troglitazone (hepatotoxicity) - Brousseau, NEJM 2004 - Grepafloxacin (QT prolongation) Trovafloxacin (hepatotoxicity) Mibefradil (rhabdomyolysis) Valdecoxib (CV events)
- Need, Nat Gen 2005 - This is a failure for both big pharm and patients…
7th Symposium New Development in Clinical 2 Pharmacy and Clinical Pharmacology June 12-13, 2009 Dr. Cattaneo Stresa, Italy
PHARMACOGENETICS AND DRUG DEVELOPMENT: THE PATH TO A SAFER AND MORE EFFECTIVE DRUGS?
Emerging pharmacogenetic approaches can be used:
What can we do to • for the identification of novel drug targets ithii?improve this scenario? •to idffidfdidlimprove drug efficacy and safety during development • to optimize the response of already marketed drugs • as a complementary tool for pharmacovigilance • to save money for both industry and academia •….
- Roses, Nat Rev Drug Disc 2008 -
GENETIC STRATEGIES TO IDENTIFY DRUG TARGETS: Genome-wide studies and Alzheimer’s disease
Such associations can provide a scientific rationale for a drug discovery program di rected to a specific human disease.
- Li et al, Arch Neurol 2008 -
7th Symposium New Development in Clinical 3 Pharmacy and Clinical Pharmacology June 12-13, 2009 Dr. Cattaneo Stresa, Italy
The issue of Phase IIA clinical trials Pharmacogenetics and drug development: the case of rosiglitazone in patients with Alzheimer’s disease Phase IIA is the first time that a molecule is tested for its desired clinical (phase IIb trial) effects in humans (usually compared versus placebo). There are essentially 3 types of results:
Comparison (treatment vs pl.) Action taken
clear clinical efficacy Druggppg development program continues
no appreciable efficacy Stop of the development program
efficacy only in a treated subgroup More supportive data required* No effect: Highly significant negative study! Efficacy effect!!
*owing to the huge costs of development, those programs with borderline efficacy are generally stopped. However, the cost of additional trials might be reduced if the population of responders and non-responders could be segmented on the basis of their genetic profiles early in Phase IIA and IIB. - Risner et al, Pharmacogenomics J 2006 -
Pharmacogenetics and drug development: the case of rosiglitazone in patients with Alzheimer’s disease (phase IIb trial) These data formed the rationale for the design of genotype-specific treatment groups in Phase III clini cal tiltrialsof 48 weeksof treatment duration (results are No effect: Highly significant anticipated in 2009). negative study! Efficacy effect!!
- Risner et al, Pharmacogenomics J 2006 -
7th Symposium New Development in Clinical 4 Pharmacy and Clinical Pharmacology June 12-13, 2009 Dr. Cattaneo Stresa, Italy
RELATIONSHIP BETWEEN NON-RESPONSE AND PHARMACOGENETICS AND COMPANION DIAGNOSTICS TRIAL SIZE
Hp: 30% diff. drug vs placebo sample size: 120 patients (α=0.05, β=0,9) Sales and prices of novel Hp: 90% diff. drug vs placebo sample size: 30 patients (α=0.05, β=0,9) oncology therapies
1400 1200
1000 ize (n) 800 600
Sample s Sample 400
200 0 0 20% 40% 60% 80% 100% Non-responders (%)
Assuming an average cost of $20,000 per patient, the use of pharmacogenetic biomarkers would results in savings of $1.8 million, or a 75% reduction in cost!!
- Kirk et al, Exp Biol Med 2008 - - Million, Nat Rev Drug Disc 2004 -
KRAS MUTATIONS AND SUSCELPTIBILITY TO CETUXIMAB AND PANITUMUMAB IN COLORECTAL CANCER
Panitumumab (vectibix) and cetuximab (Erbitux) are two human anti-EGFR PG analyses done after gefitinib was marketed showed that efficacy was antibodies recently approved for the treatment of CRC. greater in patients whose tumors contained specific mutations of EGFR. - Jmeno et al, Cancer J 2009 -
7th Symposium New Development in Clinical 5 Pharmacy and Clinical Pharmacology June 12-13, 2009 Dr. Cattaneo Stresa, Italy
THIOPURINE METABOLISM: an example of phase II enzymes
AZATHIOPRINE 12 298 Unrelated Adults
TPMTH/TPMTH Pharmacogenetics 8 jects
6-MERCAPTOPURINE b anddd drug sa fe tty TPMTL/TPMTH Thiopurine Methyltransferase 4 (TPMT) TPMTL/TPMTL % ofSu
6-METHYL MERCAPTOPURINE 0 0 5 10 15 20 TPMT Activity, Units/ml RBC
- Weinshilboum, Am J Hum Genet 1980 -
Azathioprine-induced fatal myelosuppression in a TPMT alleles and protein degradation renal transplant who carried TPMT mutations
TPMT Protein (% Remaining) 100 12 3 4 5 6789 10 TPMT*1 (wild type)
VNTR TPMT*3A
VNTR G460A A719G Ala154Thr Tyr240Cys 50 TPMT*3B
VNTR G460A Ala154Thr TPMT*3C WT VNTR A719G *3A Tyr240Cys 0 Patients with poor or intermediate TPMT activity may tolerate 0 10 20 only 1/10th to 1/2 of the average AZA dose. Time, hours - Tassaneeyakul, Transplantation 2003 -
7th Symposium New Development in Clinical 6 Pharmacy and Clinical Pharmacology June 12-13, 2009 Dr. Cattaneo Stresa, Italy
ZiagenR (Abacavir)
Abacavi r ildlidis a commonly used nucleoside analogue with potent antiviral activity against HIV-1. About 5% of patients treated with abacavir develop a hypersensitivity reaction characterized by multisystem involvement than can be fatal in some cases…
Pharmacogenetics of cyclosporine IMPACT OF ABCB1 SNPs ON RENAL GRAFT FUNCTION 40 70 ° 30.9%*^ °°* 60 ° °
30 ) In the clinical practice, cyclosporine (CsA) monitoring is usually 2 50 * * based on periodical evaluation of whole blood drug levels. 40 ° 20 ° However, some patients may experience suboptimal CsA 30 12.7% GT+TT ° ° response despite they fell within therapeutic drug 10 20 Exon 21 GG 10 GFR (ml/min/1.73m concentrations. DGF (%) of Frequency
0 0 12345678 1 6 12 18 24 30 36 42 48 54 60 66 72
CsA can lead to a wide spectrum of complications both early 40 70 ° * * ° ° 60 and in the long-term post-transplant, including acute and 29.9%*^ )
30 2 50 chronic nephrotoxicity, opportunistic infections and cancer. * * * 40 * 20 * 30 13.2% CT+TT * 10 20 * Polymorphisms in genes encoding for drug transporting * Exon 26
CC GFR (ml/min/1.73m 10 proteins may play a pivotal role in predicting individual DGF (%) of Frequency 0 0 response to pharmacotherapy. *p<0.001 12345678 1 6 12 18 24 30 36 42 48 54 60 66 72 days post-Tx months post-Tx ^Multivariate logistic analyses confirmed the independent predictive role of ABCB1 SNPs on DGF, together with cold ischemia time and donor age. - Cattaneo et al, JASN in press 2009 -
7th Symposium New Development in Clinical 7 Pharmacy and Clinical Pharmacology June 12-13, 2009 Dr. Cattaneo Stresa, Italy
Kaplan-Meyer analysis for CMV episodes …and many other examples !!
Drug Clinical outcome Gene(s) 50 exon 21 GT/TT2677 50 exon 26 CT/TT2677 simvastatin Miopathy, rhabdomiolyis SLC01B1 40 40 irinotecan Anemia, leukopenia UGT1A1 HR 3.2 (CI: 1.5-6.8) p=0.003 HR 2.2 (CI: 1.1-4.6) p=0.03 warfarin bleeding CYP2C9, WKORC1 30 Log-Rank Test: p=.0.01 30 Log-Rank Test: p=.0.03 MV (%) MV
C lapatinib Skin rash, diarrhoea CYP2C19
20 20 efavirenz dyslipidemia CYP2B6
Pts with exon 26 CC2677 atazanavir Efficacy/safety UGT1A1 exon 21 GG2677 10 10 fluoropirymidine Anemia, leukopenia DPYD tamoxifen efficacy CYP2D6 0 0 0 6 12 18 60 66 72 0 6 12 18 60 66 72 methotrexate Anemia, leukopenia TSER Months post-Tx Months post-Tx tacrolimus efficacy CYP3A5
- Cattaneo et al, JASN in press 2009 -
Conclusions Main Barrier to Implementation
PGx may contribute to drug development by defining the Ethical committees are often reluctant to accept PGx subpopulation of patients who experience efficacy (as opposed to evaluations during registrative trials. However, regulatory those who will not respond) thus avoiding dependence on the agencies should kept in mind that access to patients during average response of the whole treated population. clinical trials, including their DNA, will be crucial for exploiting the full potential of PGx, as will be the involvement PGx testing can also help address the safety issues that are of PG expertise much earlier in the development process. paramount in drug development, at both pre-approval and post- approval stages. By coupling PGx studies with pharmacovigilance A comprehensive surveillance system that maintains programs patients at risk will be increasingly identified before the need to dose the patient. individual privacy but provides the basis for PGx analyses of well-documented patient data is, therefore, vital to the objective prediction of drug response. PGx offers at the same time the potential to reduce sample size and trial costs by pre-selecting subpopulations for which a In other words…. therapy is known to elicit greater response.
7th Symposium New Development in Clinical 8 Pharmacy and Clinical Pharmacology June 12-13, 2009 Dr. Cattaneo Stresa, Italy
No DNA, no party!!!
7th Symposium New Development in Clinical 9 Pharmacy and Clinical Pharmacology