# Presentation: 010674

## Pipeline pharmacogenetics: efficacy and safety applications

** **
- Allen D. Roses, MD, FRCP [Hon]
- GSK Genetics Research
- FDA Hepatotoxicity, 28 January 2005

- FDA/CDER-AASLD-PhRMA HepTox Steering Group

- 28 January 2005

## Asset Risk Management during Development

- The earlier an AE can be recognized during development, the earlier that risk can be effectively managed
- Observations during clinical trials mimics practice in that patients present sequentially
- This presentation will cover:
- The differences between efficacy PGx and safety Pgx
- Examples of AEs recognized and characterized during development
- A taxonomic strategy for risk management using Genetics

- FDA/CDER-AASLD-PhRMA HepTox Steering Group

- 28 January 2005

## Prospective efficacy pharmacogenetics

**Target selection**
**Pathway analysis**

**Predictive **
**Toxicology**

**Prospective efficacy**
**Identifying**
**non-responders and**
**hyper-responders**

**Risk Management**
**Post Marketing**
**Surveillance**

**Identifying AEs during full development**

**Prospective efficacy pharmacogenetics**

- FDA/CDER-AASLD-PhRMA HepTox Steering Group

- 28 January 2005

## All published Efficacy Pharmacogenetics is Retrospective

**ADME PGx literature relating to drug metabolism - dosage**
**Corticotropin-releasing hormone receptor (*****CRHR1*****) sequence variants and improved lung function with inhaled steroids in asthmatics **[HumMolGen 2004]
**Insulin receptor substrate-1 associated with increased risk of sulfonylurea treatment in Type 2 Diabetes** [DiabetesCare, 2004]
**Growth hormone receptor polymorphism associated with increased responsiveness** [Nat Gen 2004]
**Activating mutations of Epidermal Growth Factor Receptor underlying responsiveness of non-small cell lung cancer to Gefitinib** [NEJM 2004, Science 2004]
**Herceptin for breast cancer**
**Polymorphism CYP3AP1*1 linked to time to achieve Tacrolimus concentrations after kidney transplantation** [AmJTransplant 2004]

- FDA/CDER-AASLD-PhRMA HepTox Steering Group

- 28 January 2005

## Prospective efficacy and safety pharmacogenetics

**The earlier PGx hypotheses can be tested - the highest value to the pipeline **
**A chemical asset that fails after Phase III is very expensive and any PGX salvage *****post-hoc***** hypotheses must be tested in new expensive trials**
**Years are lost and more expenses added**
**The value comes from proving prospective efficacy PGx hypotheses early – or by killing the asset early**

- FDA/CDER-AASLD-PhRMA HepTox Steering Group

- 28 January 2005

## Prospective efficacy pharmacogenetics

**There are only three outcomes from Phase IIA proof of concepts studies**
**1-  There is no clinical efficacy – ****kill the compound**
**2-  There is obvious clinical efficacy – ****progress the   ****	****compound to Phase IIB**
**3-  There are ****ambiguous**** results with some patients, but confidence in going forward for expensive trials is weak – ****apply efficacy PGx to define non-****	****responders and responders**

- FDA/CDER-AASLD-PhRMA HepTox Steering Group

- 28 January 2005

##                  1,1	               1,2		              2,2

- FDA/CDER-AASLD-PhRMA HepTox Steering Group

- 28 January 2005

## Effect of genotype on absolute mean weight loss (Kg) for combined (capsule and tablet) high dose groups

- FDA/CDER-AASLD-PhRMA HepTox Steering Group

- 28 January 2005

## Mechanics of prospective efficacy and AE pharmacogenetics in the pipeline

**All patients in clinical trials can provide DNA sample following specific informed consent, including commercial uses.**
**All samples maintain the usual GLP train of custody, although investigative [hypothesis generating] PGx is not performed under GLP conditions.**
**PGx analyses are available to assist development decisions and regulatory consultation**
**The same DNA samples are available to study AEs**

- FDA/CDER-AASLD-PhRMA HepTox Steering Group

- 28 January 2005

## Prospective Safety Pharmacogenetics

**Target selection**
**Pathway analysis**

**Predictive **
**Toxicology**

**Prospective efficacy**
**Identifying**
**non-responders and**
**hyper-responders**

**Risk Management**
**Post Marketing**
**Surveillance**

**Identifying AEs throughout development**

**Prospective Safety Pharmacogenetics**

- FDA/CDER-AASLD-PhRMA HepTox Steering Group

- 28 January 2005

## Adverse event profiles are personalized

**AE - the classic example of environmental interaction with an individual’s genetic make-up**
**To experience an AE, a patient must receive the drug and develop a defined phenotype within a recognized time period. **
**PERSONALIZED: “**_***Will I***_** get an adverse event?”**

- FDA/CDER-AASLD-PhRMA HepTox Steering Group

- 28 January 2005

## Retrospective Safety PGx: avoiding SAEs

- Ziagen (abacavir) is a highly-effective treatment for HIV/AIDS ... but 4-5% of patients have hypersensitivity reactions (HSR)

- Exploratory study of 114 genetic markers in 85 abacavir-treated patients who developed HSR *vs.* 115 patients without such responses

- There are large ethnic differences

- FDA/CDER-AASLD-PhRMA HepTox Steering Group

- 28 January 2005

## Is the association of HLA B-57 found in minority samples? (CNA30032 Subjects: Summary of Allelic Test Results)

- FDA/CDER-AASLD-PhRMA HepTox Steering Group

- 28 January 2005

## Two genes detected in initial candidate screen ~ 150 Kb apart over >3 LD blocksEXTENDED LINKAGE DISEQUILIBRIUM

**HLA-B**

**MICA**

**TNFa-238**

- FDA/CDER-AASLD-PhRMA HepTox Steering Group

- 28 January 2005

## AD vs Controls:  A high density SNP map around APOE					Lai et al, 1998

- Low allele freq (2-3%)

- intron

- intron

- 22 kb

- PEREC1-X2

- PEREC1-X5

- PEREC1-Int5

- PEREC1-X6

- APOE-X1

- APOC1

- FDA/CDER-AASLD-PhRMA HepTox Steering Group

- 28 January 2005

**Notes:**
A fine map and case-control analysis of the 40 kb APOE region. The region of high significance (p< E-10) span over 20 kb.

## Is the locus B57? or another locus due to ethnic-specific recombination in the B57-TNF --> extended LD region?

**Caucasians**

**Blacks**

**X**

**X**

**HLA-B57**

**TNFa-G308A**

- FDA/CDER-AASLD-PhRMA HepTox Steering Group

- 28 January 2005

## PRESTO Trial - Example of prospective AE PGx during Phase III

**Use of Tranilast to treat re-stenosis after percutaneous transluminal coronary revascularisation**
**Double-blind placebo trial of 11,500 patients**
**4% of patients in the trial developed hyperbilirubinemia **
**Why was this not observed in Phase II studies?**

- FDA/CDER-AASLD-PhRMA HepTox Steering Group

- 28 January 2005

## Hyperbilirubinemia with Tranilast – candidate gene panel tested during Phase III 

**The 7- repeat polymorphism in the TATAA box of *****UGT1A1  (*****UDP-glucuronosyltransferase 1) - a form of Gilbert’s syndrome – highly associated with hyperbilirubinemia in trial subjects**
**Double blind control trial – after the trial completed- 96% of the hyperbilirubinemia patients were 7/7 homozygous [4%, 6/7]**
**None of the 7-7 patients receiving placebo developed hyperbilirubinemia**

- FDA/CDER-AASLD-PhRMA HepTox Steering Group

- 28 January 2005

## Tranilast AE Pharmacogenetics

**Tranilast AE Pharmacogenetics**
**Distribution of Bilirubin Levels in Hyperbilirubinemia Cases (>2mg/dl, n=146) and Controls (n=1085)**

- FDA/CDER-AASLD-PhRMA HepTox Steering Group

- 28 January 2005

## How few patients does it take to recognize a SNP profile related to an AE during a drug trial?

**Mathematical analysis reflects taxonomy principles**
**Also highly dependent on the number and the ethnicity of “controls”**
**Theoretical projections are that differences in SNP LD patterns can be recognized **_***prospectively***_** as statistically significant with as few as 10-20 patients**
**Experimental support for these data exists**

- FDA/CDER-AASLD-PhRMA HepTox Steering Group

- 28 January 2005

## Can Safety SNP profiles be identified during trials using as few as 10-20 AE patients?    Yes

-  4 **SNPs flanking UTP1A1 locus of tranilast hyperbilirubinemia **
** ****Cases from tranilast clinical trial (US Caucasian) **
** ****3,000 White controls from Aberdeen UK (Caucasian)**
** ****Fisher’s exact test**

- FDA/CDER-AASLD-PhRMA HepTox Steering Group

- 28 January 2005

## Why do PGx AE surveillance and how to do it?

**Why**
- Rare adverse events = slow accumulation of cases
- Pressure on GSK to make interim decisions long before traditional significance/power achieved
- Genetics may give clues to rapidly explore
- ‘One at a time’ thinking is the tactic of *‘*_*Focus on *__***this***__* patient*_*’*
- Let’s make decisions as ‘evidence based’ as possible
- Need to be sample sparing (prudent insurance for the future)
**How**
- Assesses how likely **each case** is to be classified as genetically distinct from the controls
- Requires large no. of well characterised controls
- Cases **must** come from the same population as controls
- Method ‘steps along the genome’ using the presence/absence data of **all** the single nucleotide (SNP) markers available at that time to form an ‘extreme’ hypothesis
- Offers a ‘traffic light’ alarm          to signal possible genetic correlate to follow-up at **earliest** juncture

- FDA/CDER-AASLD-PhRMA HepTox Steering Group

- 28 January 2005

## Imagine a large control population

- Cases arrive - when do _**you**_ think there is a skin & eye correlate of AE?

- Skin/eye ‘profile’ appears different =>
- Possible genetic correlate with adverse event - invariably pale eyes & pale skin

- With invariably brown skin & brown eyes

- FDA/CDER-AASLD-PhRMA HepTox Steering Group

- 28 January 2005

## An analogy for why the PGx method works => classify to nearest centre of gravity, stop when enough information has accumulated

- An *analogy* for why the PGx method works => classify to nearest centre of gravity, **stop** when enough information has accumulated

**STOP !**

*<= Control*

*<= Case*

- SNP based genotype or Character 1

- SNP based genotype or Character 2

- FDA/CDER-AASLD-PhRMA HepTox Steering Group

- 28 January 2005

**Notes:**
Nearest (updated centre of gravity) to classify case, 
but note 
strength of prediction is Manhattan distance to red star - distance to blue star 
and only keep if positive.. Closest in difference in log allele frequencies
 conditional on allele in that case

## Pharmacogenetics: correcting misperceptions

**PGx will not increase costs of drug development – but will provide new safe and effective drugs for more people**
**PGx will provide the opportunity to find effective drugs for definable [and perhaps overlapping] segments of the patient population **
**PGx will reduce attrition in the late pipeline, significantly translating to more safe and effective therapies**
**PGx diagnostics will be standardised and less expensive than the one-off diagnostic models currently being imagined and debated**
**PGx is applicable to patient populations in developing countries, decreasing the potential for disparity of differentiated medicines**
**There are ethical challenges that can be evaluated, based on other secure data management systems**
**Differentiation of medicines makes risk/benefit sense and is cost/effective**

- FDA/CDER-AASLD-PhRMA HepTox Steering Group

- 28 January 2005

## AcknowledgementsGSK R&D Executive Genetics Research TeamMedical GeneticsUK and US Discovery GeneticsBioinformaticsApplied PharmacogeneticsGenomics & Proteomic SciencesAll the Drug Discovery and Clinical Development (especially WW Regulatory) Teams

- FDA/CDER-AASLD-PhRMA HepTox Steering Group

- 28 January 2005

**Notes:**
Specifically, Linda, David B., David Y., Maha and Mike Moore for providing data.

## GSK Human Genetics Resource

**	**

**>****80,000 subjects**** recruited (*****DNA, full prospective clinical data, informed consent for commercial purposes*****)**
**>****18 disease**** collections initiated since 1997 and continue in 2004**
**Association studies usually use ~500 affected patients and ~500 ****	****controls, confirmed by a second 500p/500c (each ****larger**** than most published disease association studies)**
**Clinically assessed by > 190 academic clinical investigators in 18 disease-focused world-wide ****	****networks collected over six+ year period**

- FDA/CDER-AASLD-PhRMA HepTox Steering Group

- 28 January 2005