Positive Rechallenge: What Clinical Trial Data Tell Us Julie Papay, Pharm.D. UCB BioSciences Global Patient Safety

Transcription

1 Positive Rechallenge: What Clinical Trial Data Tell Us Julie Papay, Pharm.D. UCB BioSciences Global Patient Safety Drug-Induced Liver Injury (DILI) Conference XVI Wednesday 23 March 2016

2 The comments provided here are solely those of the presenter and are not necessarily reflective of the positions, policies, or practices of UCB BioSciences 2

3 Challenge Drug induced liver injury (DILI) Dechallenge Recovery from injury with drug discontinuation Rechallenge Suspect drug readministered Positive ALT doubles Alk phos or bili doubles Negative

4 Rechallenge Points to Consider Pros Enables lifesaving drug use Positive rechallenge can confirm DILI diagnosis Negative rechallenge may imply adaptation (e.g., isoniazid, statins, tacrine) Clinical trial data may inform which subjects more safely rechallenged Cons 2-13% fatal (e.g., halothane) FDA advises avoidance 1 Rapid onset of liver injury Frequently inadvertent High risk without rigorous clinical monitoring 1 FDA Guidance for Industry, July 2009,

5 Drug Induced Liver Injury (DILI) and Rechallenge in Clinical Trials: Sparse Data Clinical Monitoring / Stopping Criteria Preclinical Screening Rechallenge Criteria Sparse information

6 Positive Rechallenge in Clinical Trials: Recent New Drug Approvals Improved preclinical screening/testing yields safer therapeutics Rigorous safety with drug stopping criteria Provides most optimistic data on drug rechallenge

7 Positive Rechallenge in Clinical Trials: Recent New Drug Approvals Drug / Indication Daclatasvir/asunaprevir Hepatitis C (n=747) 1 Alirocumab (Praluent) Cholesterol lowering (n=3499) Notes 3 of 4 (75%) positive rechallenge: ALT>10xULN without bilirubin elevation or eosinophilia 1 case of concurrent rash 2 positive rechallenge 1. Trial 7028 phase 3 multicohort study (HALLMARK-DUAL) in 18 countries Medical reviews available at

8 Daclatasvir/Asunaprevir: 75% Positive Rechallenge All re-administration occurred within 24 days Event 1: Mean 66 days (42-84 days) Event 2: Mean 5 days (3-6 days) ALT>10xULN with rechallenge in 3 subjects 1 case of concurrent rash no bilirubin elevations or eosinophilia 2 of 4 recovered; 2 recovery unreported Medical review for Daklinza available at

9 Fuji et al. Hepatology 2015;61 (1): ; Shibata et al Hepatology 2015; Suga et al. World J Clin Cases 2015 December 16; 3(12): Daclatasvir/Asunaprevir: Immunoallergic Injury? 3 Subsequent case reports in Japanese patients 57 y/m HSRx with liver injury & jaundice, fever, eosinophilia Fever resolved after drug d/c, but liver injury continued No rechallenge due to concerns of possible drug-resistant mutations (non-responder to previous peginterferon/ribavirin) 57 y/f Developed fever (possibly due to influenza viral infection), eosinophilia, and IgE. Rapidly developed hepatic failure with ascites, jaundice, and low prothrombin index. Recovered without liver transplantation. 66 y/m DRESS syndrome in treatment naïve patient: eosinophilia & systemic symptom syndrome, including concomitant hepatic/renal deterioration, and rash on trunk and limbs After d/c drug, labs & clinical manifestations gradually improved, without recurrence

10 Alirocumab : 2 Positive Rechallenge Case 1 st Event Rechallenge 42 year old female (BMI 36.3 kg/m 2 ) ALT increase mild intensity on day 68 Treatment interrupted, ALT returned to BL Upon re-introduction, peak ALT 3.6x ULN on day 97 Led to permanent discontinuation 36 year old male* *history of fatty liver also confirmed on liver ultrasound peak ALT 5.4x ULN 28 days after 1 st injection (normal bilirubin, AlkP) Negative viral serologies Treatment interrupted for 5 weeks, ALT returned to BL 4 weeks after discontinuation Upon re-introduction, 5 additional episodes of ALT (>2x ULN but 3x ULN) Treatment continued & completed study

11 Positive Rechallenge in Clinical Trials: Published Literature Drug Aplaviroc or GW CCR5 antagonist - HIV (n=342) Lapatinib (Tykerb) Breast cancer (n=20) Pazopanib (Votrient) Renal cell carcinoma, Soft tissue sarcoma (n=103) Rechallenge One positive rechallenge 2 Hy s Law events 6% had ALT 2.5-5xULN Ph III program terminated 55% positive rechallenge 38% positive rechallenge Nichols et al. Antimicrobial Agents and Chemotherapy 2008;52(3): ; Spraggs, et al. Pharmacogenomics (Apr. 2013): p541; Powles et al. Eur J Cancer 2015;51:

12 Positive Aplaviroc Rechallenge in HIV Clinical Trials (n=342) Subject First ALT Elevation/ Time to Onset Recovery 2 nd ALT Elevation/ Time to Onset Recovery 37 y/m 5.7x / wk 12 Normal bilirubin ALT returned to baseline Negative viral serologies 9x / 2 weeks Permanently discontinued & ALT normalized 2 other Hy s Law severe liver injury events with: ALT 66x ULN, bilirubin 7x ULN (therapy-naïve) ALT 17x ULN, bilirubin 3x ULN (treatment-experienced) 6% had ALT 2.5-5xULN Phase III program terminated

13 Pazopanib: 103 Patients Rechallenged in 9 Prospective Phase II/III Studies (n=2080) Liver chemistry: Entry criteria: ALT/AST 2.5ULN and total bilirubin 1.5ULN Post-baseline liver chemistry tests every 3 or 4 weeks Rechallenge considered for isolated ALT >8x ULN Powles et al. Eur J Cancer 2015;51: and

14 Pazopanib: 103 Patients Rechallenged in 9 Prospective Phase II/III Studies (n=2080) Rechallenged only if clinical benefit was observed and all criteria were met: ALT 2.5x ULN Total bilirubin <1.5xULN or direct bilirubin 35% No hypersensitivity signs or symptoms Subject reconsented Required reduced dose & close monitoring Powles et al. Eur J Cancer 2015;51: and

15 Pazopanib Positive Rechallenge Occurs More Rapidly: Injury More Common with HLA-B*57:01 38% positive rechallenge suggests adaptation? Recurrence of transaminitis happened soon after reintroduction of treatment (median 9 days) Upon rechallenge: no ALT >20 ULN ALT elevation >8 ULN noted in 21% ALT>5-8x ULN noted in 79% No cases of liver failure after rechallenge HLA-B*57:01 associated with liver injury Rechallenge should only be undertaken with close monitoring of liver chemistry 15

16 Lapatinib: 55% Positive Rechallenge: Immunoallergic Injury Lapatinib monotherapy study in breast cancer (n=1194): 2% developed ALT >5x ULN 55% positive rechallenge with lapatinib reinitiation (n=20) HLA DQA1*02:01 and DRB1*07:01 markers increase risk of liver injury events with: 8% developing ALT >5x ULN when carrying HLA alleles vs. 0.5% exhibiting ALT >5x ULN without HLA markers HLA markers present in 15-25% of Caucasian, Asian, African and Hispanic; 1% in Japanese Spraggs C, et al. Pharmacogenomics. 2013:14(5):541.

17 Lapatinib: 55% Positive Rechallenge: Immunoallergic Injury U.S. Prescribing information has boxed warning: Hepatotoxicity may be severe and deaths have been reported Hy s Law severe liver injury in clinical trials (<1%) Immunoallergic and autoimmune features are uncommon, but linked to specific HLA alleles Tykerb U.S. Prescribing information. Revised March

18 High positive rechallenge rates in recent clinical trials Despite rigorous monitoring and state of the art preclinical, clinical, & genetic understanding of a drug Physician Patient Sponsor Regulator

19 Real world rechallenge higher morbidity/mortality likely in uncontrolled rechallenge even fatal positive rechallenge could be unknown by physician, sponsor, regulators? Patient??

20 Real World Positive Rechallenge (n=88) 73% serious adverse events, including 2 fatalities Most exhibited symptomatic jaundice or hepatitis, hepatocellular injury, < 1 month from initial DILI (many <1wk) 14% Hy s Law events with jaundice on DILI or rechallenge Most recurred upon rechallenge Most (82%) received multiple meds besides suspect drug Papay JI. Regul Toxicol Pharmacol 2009;54:84-90

21 Real World Positive Rechallenge (n=88) Real world drug rechallenge can be prevented with: recognition of initial drug-induced liver injury & communication to patient record DILI in electronic health records (as per allergies) and prevent possible rechallenge Papay JI. Regul Toxicol Pharmacol 2009;54:84-90

22 Summary Up to 75% positive rechallenge in recent clinical trials & many with immunoallergic injury Rechallenge requires a systematic benefit:risk assessment: Has efficacy been observed in this patient? Are there other therapeutic alternatives? Has dechallenge occurred? Key drug safety liabilities relevant to this patient: HLA markers, hypersensitivity, other meds? Patient well-informed of benefit:risks & consents?

23 Conclusions Rechallenge should generally be avoided due to potential for serious injury and fatalities Rechallenge of critical medications requires use of a standardized rechallenge benefit:risk checklist

24 Acknowledgements John Senior, Lana Pauls, FDA Hepatotoxicity Meeting Christine Hunt, Nancy Yuen, Dawn Clines, Rezvan Rafi, Susan Britt, John Walsh, Roger Brown Thank you

25 Recent New Drug Approvals: Rechallenge in the Label Kynamro: cholesterol lowering agent for *rare, severe disorder hepatic fat 10% Available via REMS program Esbriet- idiopathic pulmonary fibrosis *prevalence 1:160,000 to 1:1,000,000). Most individuals with HoFH experience severe CHD by their mid-20s. The rate of either death or coronary bypass surgery by the teenage years is high. Severe aortic stenosis is also common.

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28 All subjects achieved sustained virologic response (SVR12), defined as HCV RNA less than the lower limit of quantification (LLOQ) 12 weeks after discontinuation of treatment Daclatasvir and Asunaprevir: 4 Positive Rechallenge in Trial 7028 Subject y/f y/f y/m /F First ALT Elevation/ Time to Onset Recovery 2 nd ALT Elevation/ Time to Onset Recovery 503 / Day / Day / Day 56 Last dose day 57 normal ALT day / Day / Day / Day 71 NR 864 / Day / Day / Day 95 Last dose day 102 normal ALT day / Day / Day / Day 112 NR No eosinophilia or increases in bilirubin

29 Pazopanib: 38% Positive Rechallenge (n=103) Negative Rechallenge (ALT <3xULN) n = 62 (60%) Age, yrs (mean, SD) 59.1 (10.85) 62.8 (9.42) Male 35 (55%) 19 (49%) Peak category of the first elevation Positive Rechallenge (ALT >3xULN) n = 39 (38%) ALT>3-5xULN 23 (36%) 10 (26%) ALT>5-8xULN 19 (30%) 9 (23%) ALT>8-20xULN 16 (25%) 18 (46%) ALT>20xULN 4 (6%) 2 (5%) 2 nd ALT >3xULN 31 (79%) 8 (21%) 0 Reduced dose 73% 87% 2 (2%) lacked follow-up data

30 Pazopanib Positive Rechallenge Occurs More Rapidly; Injury More Common with HLA-B*57:01 Days to first ALT>3xULN Mean (SD) Time to ALT>3xULN with rechallenge Negative Rechallenge (ALT <3xULN) n = 62 (60%) Positive Rechallenge (ALT >3xULN) n = 39 (38%) 55.5 (73.28) 48.3 (36.92) (5-248) Days to recovery of first ALT>3xULN 23.3 (25.54) 30.1 (28.91) HLA-B*57:01 associated with liver injury Powles et al. Eur J Cancer 2015;51: ; Xu et al.