# Presentation: 793310

## Case Study of Ximelagatranand Hepatotoxicity

- Mark Avigan, MD CM
- Director, Division of Drug Risk Evaluation
- Office of Drug Safety
- CDER, FDA

- January 28, 2005

- FDA/CDER-AASLD-PhRMA HepTox Steering Group

- 28 January 2005

## Overview

- Clinical Hallmarks of DILI/ISLI
-  FDA experience – troglitazone & bromfenac
-  Ximelagatran clinical development program & spectrum of hepatotoxicity in study patients
-  Projected safety issues after marketing & impact of   serum ALT monitoring
-  Summary & Future Directions

- FDA/CDER-AASLD-PhRMA HepTox Steering Group

- 28 January 2005

## Clinical Hallmarks of Drug-Induced Severe Liver Injury

- Depend on:
- Mechanism(s) of Toxicity
- Type of Injured Cells and Organelles
- Mechanism(s) of Protection/Adaptation
-  Range between:
- Idiosyncratic rare events
- acute/subacute hepatocellular injury
- High Probability events  (influenced by dose/exposure)
- acute/subacute/chronic hepatocellular injury
- other pathologic processes

- FDA/CDER-AASLD-PhRMA HepTox Steering Group

- 28 January 2005

## Rules of the Game (1)

- Hy’s law cases in clinical trials portend idiosyncratic serious liver injury (ISLI)/ALF cases after marketing.
-  caveats include absence of biliary obstruction, other etiologies of injury
-  among cases with jaundice, progression to ALF and/or death is approximately 10% - 15%
-  When ALT/AST elevations with no increases of bilirubin occur in clinical trials, an increased risk of ISLI/ALF cannot be ruled in/out.
-  The degree or *incidence* of isolated ALT/AST elevations does not always predict the level of risk for ISLI/ALF.

- FDA/CDER-AASLD-PhRMA HepTox Steering Group

- 28 January 2005

## Rules of the Game (2)

- The relationship of onset of liver injury with duration of drug exposure is not predictable.  The hazard may be ‘frontloaded’, constant or develop after a threshold period of exposure.
-  There are no measures that predict *a priori* whether injury will resolve or progress if a hepatotoxic drug is continued/discontinued.
-  The tempo of injury is a characteristic both of individual drugs and patients.   Rapid acceleration of liver injury in some individuals diminishes the value of periodic LFT monitoring.

- FDA/CDER-AASLD-PhRMA HepTox Steering Group

- 28 January 2005

## Troglitazone

- Approved in US 1/97 in US
-  US Clinical studies (Rx n=2510)
-  0.2% ALT > 30 X (n=5; 2/5 also developed jaundice)
-  *Median onset of injury: 4 months; range 1-8 months*
-  NIH Diabetes Prevention Trial (n = 585)
- 3.0% ALT > 3 X ULN; 1 patient developed ALF 94 days after Rx began (Day 57: ALT ~ 2.2 X ULN)
-  Withdrawn 3/00 - 94 liver failure cases; *rapid acceleration of injury in 19/94 (< 1 month)*

- FDA/CDER-AASLD-PhRMA HepTox Steering Group

- 28 January 2005

## Bromfenac SodiumExtended Use Despite Labeling for Short Term Use

- Approved 7/97; Recommended Rx < 10 days and LFT monitoring if > 4 weeks
-  Single dose (n=1000) and 1 week (n=500) Rx studies
-  no safety problem observed; 0.4% ALT > 3 X ULN
-  Chronic OA and RA studies (n = 830)
- 2.8% ALT > 3 X ULN; 2.3% 3 X - 8 X ULN; 0.5% > 8 X ULN; dose-related effects, majority within 90 days after starting RX & reversible upon D/C; jaundice not noted
* *Post-marketing liver failure cases - most Rxed 2-8 months; 12 deaths or transplants

- FDA/CDER-AASLD-PhRMA HepTox Steering Group

- 28 January 2005

## Ximelagatran Proposed Indications & Exposures

*Long-term Use (months - years)*
-  Secondary prevention of VTE; 24 mg bid
-  Prevention of AF associated stroke/systemic thromboembolism; 36 mg bid
*Short-term Use (7-12 days)*
-  Prevention of VTE post TKR surgery;  36 mg bid

- FDA/CDER-AASLD-PhRMA HepTox Steering Group

- 28 January 2005

## Ximelagatran Development ProgramPharmacologic Properties of Drug

- FDA/CDER-AASLD-PhRMA HepTox Steering Group

- 28 January 2005

## Ximelagatran Development Program Human Pharmacokinetics of Drug

- Pro-drug half-life  -  5 hr
- Peak bioconversion to melagatran – 3 hr; CYP450 enzymes play minor role
- <15% plasma protein binding; polar compound
-  Fixed dose; 3 - 4 fold variation of melagatran’s AUC *among* Afib patients
- Elimination 80% renal; 5% biliary

- FDA/CDER-AASLD-PhRMA HepTox Steering Group

- 28 January 2005

## Ximelagatran Development ProgramClinical Studies

- FDA/CDER-AASLD-PhRMA HepTox Steering Group

- 28 January 2005

## Ximelagatran Development ProgramDrug Exposure

***Long-term studies ***
- 6,931 patients Rxed with ximelagatran;          mean 1 yr  (5,024 > 6mo; 3,509 > 1 yr)
-  ***Short-term studies                 ***
- 2,689 patients Rxed with ximelagatran;           range 7-12 days (1,927 patients 36 mg bid,        762 patients 24 mg bid)
- 1,915 patients Rxed with warfarin

- FDA/CDER-AASLD-PhRMA HepTox Steering Group

- 28 January 2005

## ALT > 3X in Long Term Trials Cumulative Risk Over Time

- FDA/CDER-AASLD-PhRMA HepTox Steering Group

- 28 January 2005

## Severe Liver Injury - Long term RxAll randomized patients

- Concurrent increase of total bilirubin > 2x ULN within 30 days of ALT rise > 3x ULN
-  37/6,948* (0.5%) in ximelagatran Rx groups vs 5/6,230 (0.08%) in warfarin Rx groups
-  Relative risk 6.6 (95% CI 2.6 – 16.9)
-   3 liver injury associated deaths
- * Mean Exposure in Long-term Experience (LTE) trials – 357 days

- FDA/CDER-AASLD-PhRMA HepTox Steering Group

- 28 January 2005

## Severe Liver Injury - Long term RxInvestigator Attributed as ‘Related’ Cases

- Causality assessment of ‘related’ cases constrained by clinical/diagnostic info
- 19/6,948 ximelagatrin Rx group vs 2/6,230 comparator group
- Relative risk 8.5 (95% CI 2.0 – 36.6)

- FDA/CDER-AASLD-PhRMA HepTox Steering Group

- 28 January 2005

## Ximelagatran-induced Liver InjuryImportant Characteristics

- Time to event: ALT > 3x ULN
-  Mild injury outcomes
-  Severe injury outcomes
-  Adaptation (Rx continued vs d/ced)
-  Percentage of all cases with liver injury
-  Time until ALT normalizes
-  Dose effect on risk
-  Transition time between mild and severe injury

- FDA/CDER-AASLD-PhRMA HepTox Steering Group

- 28 January 2005

## Number of Patients with ALT > 3x ULN by month since randomization Time to Event Analysis

- FDA/CDER-AASLD-PhRMA HepTox Steering Group

- 28 January 2005

## Time of Early Liver Injury in Patients who Later Developed Severe Injury

-  Days to ALT
-     > 3 x ULN   Cases (N)	   Related Cases
-           1-7	       	1	          1
-           8-15	       	1	          0
-         16-30	       	4	          3
-         31-45	       	4	          4
-         46-90	      	11	          7
-           >90	      	16	          4
-          Total	      	37	         19

- FDA/CDER-AASLD-PhRMA HepTox Steering Group

- 28 January 2005

## Number of Long-term Ximelagatran Treated Patients with Maximal ALT > 3x ULN by Magnitude of Last Recorded ALT

- FDA/CDER-AASLD-PhRMA HepTox Steering Group

- 28 January 2005

## Mean Number of Days between 1st Elevation of ALT > 3x ULN and Normalization Ximelagatran Treated Patients

- FDA/CDER-AASLD-PhRMA HepTox Steering Group

- 28 January 2005

## Cumulative Incidence of Ximelagatran Treated Patients with Elevated ALT by Dose Study TPC-0001 (6 month study post ACS)

- FDA/CDER-AASLD-PhRMA HepTox Steering Group

- 28 January 2005

## Sponsor’s Proposed Monitoring Scheme

*Short-term Rx for TKR prophylaxis*
-  No monitoring
-  Assume intended treatment not to exceed 12          days
* **Long-term Rx*
-  Baseline and monthly monitoring
-  Discontinuation if ALT>5x ULN anytime, or >3x after 4 wks, or symptoms of hepatic injury

- FDA/CDER-AASLD-PhRMA HepTox Steering Group

- 28 January 2005

## Monitoring EffectivenessElements Which Have Impact

- Tempo of liver injury
- Compliance with monitoring
- Reversibility of injury if drug d/ced

- FDA/CDER-AASLD-PhRMA HepTox Steering Group

- 28 January 2005

## Severe Liver Injury CasesProtocol Compliance and Tempo of Injury

- Compliance with study protocols
- 14/36 patients (39%) failed to discontinue study drug as specified in algorithm
- Rapid tempo of liver injury
-  serum ALTs rose to high levels in <30 days
-  rises of total bilirubin occurred after stopping drug

- FDA/CDER-AASLD-PhRMA HepTox Steering Group

- 28 January 2005

## Case 1: 80 yr old male

**Day ****	****Event**
- 1		ALT: 16, *start ximelagatran 36 mg bid for AFib*
- 30		ALT: Normal
- 56		ALT: 2X ULN
- 85		ALT: 20X ULN; *D/C ximelagatran*
- 100	ALT: 30X ULN; T. Bili 2.4; AP 154; Serologic testing for Hepatitis A, B, C, CMV, EBV, HSV, CEA, ANA, liver imaging   all unremarkable
- 108 	Liver Bx: Acute submassive necrosis
- 114	INR: 1.7, Alb 2.9, T. Bili 10.7, PT 16.3
- 119	INR: 1.8, Alb 2.5, T. Bili 17.1
- 145	Died: duodenal ulcer bleed with coagulopathy
*Autopsy: small, friable and diffusely mottled liver with extensive    liver necrosis, hepatocyte dropout and bile duct proliferation*

- FDA/CDER-AASLD-PhRMA HepTox Steering Group

- 28 January 2005

## Case 1 -  Fatal Liver Injury

- FDA/CDER-AASLD-PhRMA HepTox Steering Group

- 28 January 2005

## Case 2: 73 yr old maleHx of SLE, HTN, diabetes

**Day ****	****Event**
- 1		ALT: 1.9x ULN, *start ximelagatran 36 mg bid for DVT*
- 12		ALT: 4.5x ULN
- 18		ALT: 7.8x ULN, + HBsAg, +HBeAg, +HBcAb
- 22		ALT: 367, T. Bili: 1.8
- 24		*D/C ximelagatran*
- 26		ALT: 518, T. Bili: 4, INR: 2.3
- 42		ALT: 189, T. Bili: 26.8, *hepatic encephalopathy*
- 44		Died: *liver failure*

- FDA/CDER-AASLD-PhRMA HepTox Steering Group

- 28 January 2005

## Case 3: 77 yr old male

**Day  ****	****Event**
- 1      	ALT: Normal, Alb: 3.6, s*tarted ximelagatran 36 mg  **	**bid*
- 30		ALT: Normal
- 63  	ALT: 216, Alk P 156, T. Bili: 1.3
- 67		Test result not available
- 81		GI bleed, BP 76/45, Hgb: 7, PT: 37, INR 3.4, Plasma 	melagatran: 0.25M, ALT 569, Alk P 173, Albumin: 	2.0; *treated with pRBC, FF plasma, cryoprecipitate, **	**fluids, vitamin K*
- 82 	T. Bili: 6.2, death: *pre-anastomotic (Bilroth II) GI **	**bleed, coagulopathy, shock; no autopsy*

- FDA/CDER-AASLD-PhRMA HepTox Steering Group

- 28 January 2005

## Projected ISLI/Death Risk Based on Long Term Trials

- LFT monitoring in clinical trials most likely
- best-case scenario in ‘real world’
-  ISLI incidence ~ 1/200 in clinical trials (n=6,900)
-  predict ~ 3 cases of ALF, liver Xplant or death
-  observed ~ 3 liver related deaths
-  If 1 death was causally related to ximelagatran, 1 fatal injury/6,900 Rxed patients

- FDA/CDER-AASLD-PhRMA HepTox Steering Group

- 28 January 2005

## Summary (1)

- ISLI causally related to ximelagatran Rx
-  Basis of conclusion:
-  imbalance in both severe and mild injury cases; ximelagatran vs comparator Rx arms
-  causality assessments
-  Liver injuries may be dose independent, often occur within 6 mos. & frequently limited (adaptation response)
-  Specific chemical interaction(s) and precise mechanism of injury are unknown

- FDA/CDER-AASLD-PhRMA HepTox Steering Group

- 28 January 2005

## Summary (2)

- Rapid acceleration of liver injury in some
-    individuals limits protective value of monitoring
- Strategy to prevent extended Rx after TKR
-    in absence of LFT monitoring must be
-    reliable

- FDA/CDER-AASLD-PhRMA HepTox Steering Group

- 28 January 2005

## Future Directions

- Seek to develop pre-clinical models of ISLI
- Elucidate chemical interactions leading to injury
- Elucidate protective pathways that are basis of adaptation & reversible injury
- Elucidate biochemical/genetic basis of susceptibility to ISLI
- Seek biomarkers that detect early injury & predict adaptation/lack of adaptation
- Determine structure/function models which isolate the potential for inducing injury from desired therapeutic activity.  If predictive, such modeling would greatly enhance drug design.

- FDA/CDER-AASLD-PhRMA HepTox Steering Group

- 28 January 2005

## Acknowledgements

*Division of Drug Risk Evaluation/ODS*
* *Kate Gelperin, MD, MPH
-  Allen Brinker MD, MPH
*Division of Gastrointestinal and Coagulation Drug Products/OND*
-  Ruyi He, MD

- FDA/CDER-AASLD-PhRMA HepTox Steering Group

- 28 January 2005

## BACK-UP SLIDES

- FDA/CDER-AASLD-PhRMA HepTox Steering Group

- 28 January 2005

## Cumulative Incidence of Ximelagatran- Treated Patients with Elevated ALT by Dose Study TPC-0001 (6 month study post ACS)

- FDA/CDER-AASLD-PhRMA HepTox Steering Group

- 28 January 2005

## Cumulative Incidence of Patients with Elevated LFTs; Ximelagatrin vs Comparator

- FDA/CDER-AASLD-PhRMA HepTox Steering Group

- 28 January 2005

## Cumulative Incidence of Ximelagatran Treated Patients with Elevated ALT by Study

- FDA/CDER-AASLD-PhRMA HepTox Steering Group

- 28 January 2005

## Cumulative Incidence of Patients with ALT > 3x ULN by Study

- FDA/CDER-AASLD-PhRMA HepTox Steering Group

- 28 January 2005

## Cumulative Incidence of Comparator Treated Patients with Elevated ALT by Study

- FDA/CDER-AASLD-PhRMA HepTox Steering Group

- 28 January 2005

## Concomitant Elevations of ALT > 3X ULN and Bilirubin > 2x ULN by Study

- FDA/CDER-AASLD-PhRMA HepTox Steering Group

- 28 January 2005

## Conundrums

- There are no currently validated ‘biomarkers’ 100% specific for ISLI (that specifically tag bad drugs, toxic mechanisms or vunerable patients)
-   ISLI association with ‘weak’ signals can only be ruled out empirically by large-scale exposure to the drug in question with *adequate* surveillance
-  Absence of a ‘strong’ signal prior to drug approval does not guarantee that ISLI will not become apparent during large-scale exposure

- FDA/CDER-AASLD-PhRMA HepTox Steering Group

- 28 January 2005

## Responding to Uncertainty Whether Drug Causes ISLI/ALF

*Issues to consider:*
-  Probability that there is *no* association with ISLI (based on signal profile)
-  Treatment benefit & alternative Rx options
-  Best/Worst case scenarios of ISLI/ALF incidence & severity that may occur)
-  Practicality/effectiveness of monitoring large numbers of patients

- FDA/CDER-AASLD-PhRMA HepTox Steering Group

- 28 January 2005

## Tacrine Hydrochloride

- Cholinesterase inhibitor for Rx of Alzheimer’s
-  Clinical Studies revealed:
-  50% subjects developed ALT increases; Median time to onset - 6 wks
-  25% ALT > 3 X ULN; 7% ALT > 10 X ULN
-  ALT increases managed by protocol of LFT monitoring and dose reduction; permanent drug withdrawal if ALT > 5 X ULN
* **Despite biopsy evidence of hepatocellular necrosis, jaundice or clinically serious liver injury is very rare*

- FDA/CDER-AASLD-PhRMA HepTox Steering Group

- 28 January 2005

## Simvastatin

- Statin for Rx of hypercholesterolemia linked to increased risk for atherosclerosis-related events
-  ~5% treated subjects - AST > 1.5 X ULN
-  Long-term Rx studies
-  Include the ‘4S’ Study - Median F/U 5.4 yrs; Simvastatin 20 - 40 mg daily: n = 2,221
-  ALT > 3X ULN -  0.7%  vs  0.6% placebo (more than once); No ALT changes after 6 months of constant Rx
-  Recommended monitoring up to 1 yr (if normal ALT)
* **No association of ALT elevations with jaundice/hepatitis*

- FDA/CDER-AASLD-PhRMA HepTox Steering Group

- 28 January 2005

## Clinical Scales of CausalityGeneral Criteria

- Temporal relationship between Rx and liver injury
-  Exclusion of alternative Causes
-  caveat: drug-induced toxicity might aggravate injury of underlying chronic liver disease
-  Extrahepatic manifestations of hypersensitivity
-  Dechallenge/Rechallenge
-  Risk factors
-  Bibliographic information
*Although limited because of incomplete info, it is often useful to assign each AERS report of ISLI/ALF/death a ‘score’ to establish likelihood of causality.*

- FDA/CDER-AASLD-PhRMA HepTox Steering Group

- 28 January 2005

## CIOMS Diagnostic Scale*

_*Individual Criteria                                         Range of Scores*_
- Time from start of Rx until event		              +1 to +2
- Time from stop of Rx until event                                 	0 to +1
- Course after stop of Rx                                          	               -2 to +3
- Age                                                                             	0 to +1
- Alcohol/Pregnancy                                                         	0 to +1
- Concomitant Rx                                                                    -3 to   0
- Non drug-related causes			               -3 to +2
- Previous drug information                                               	0 to +2
- Dechallenge/Rechallenge			               -2 to +3
_*Causality Assessment: Total Scores*_
- Highly Probable: 8-10;  Probable: 6-8;  Possible: 3-5;  Unlikely: 1-2
- *Danan & Benichou, J. Clin. Epidemiol.; 1993

- FDA/CDER-AASLD-PhRMA HepTox Steering Group

- 28 January 2005

## Attribution of Causality to Drug(s) in AERS Reports of Hepatotoxicty

- Rules of differential dx are no different than in pre-marketing studies or at bed-side
- Analysis of causality requires informative reports
- Accuracy of attribution is enhanced by
-  use  of consistent criteria (e.g. CIOMS, CDS or M&V scales)
-  proactively pursuing patient info including medical records
- Absence of adequate info/patient histories is major stumbling block.   Lack of critical info does not imply lack of causality!
- Presence of underlying liver disease may cause confusion

- FDA/CDER-AASLD-PhRMA HepTox Steering Group

- 28 January 2005