Therapies for DILI: NAC, Steroids or NRF-2 activators?

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1 Therapies for DILI: NAC, Steroids or NRF-2 activators? William M. Lee, MD Professor of Internal Medicine Meredith Mosle Chair in Liver Diseases UT Southwestern Medical Center at Dallas Drug-Induced Liver Injury: Getting the Medicine and Science Together March 24-25,

2 Acute Liver Failure Fulminant Hepatic Failure Most severe form of liver injury but rare Devastating: survival <10% in earlier era UNOS Status 1 Fascinating Frustrating Hard to treat Difficult to study

3 Acute Liver Failure Study Group Rationale: Network to study a rare disease Began in 1998, once 23, now 13 adult, 15 peds sites 1,600 cases in adult, 931 in pediatric registry Three directions: Prospective clinical data, sera, plasma, DNA, tissue Numerous ancillary studies in progress Therapy trials: NAC trial done, others on the way Funding: NIDDK U-01 through 2010

4 Etiology of ALF in the USA Adult Registry (N=1,551) 46% More than half of all US ALF is drug-related 12% 15%

5 Comparison of Different ALF Etiology Groups N = 1,551 APAP Drug Indeterminate HepA/HepB All Others n=719 n=180 n=206 n=36/114 N=296 Age (median) /42 44 Sex (% F) /44 73 Jaundice (Days) (median) /5 4 Coma 3 (%) /54 40 ALT (median) / Bili (median) / Tx (%) /42 29 Spontaneous Survival (%) Overall Survival (%) / /61 65

6 Therapies for the overall condition ALF Therapy Rationale Result Total body washout Detoxify No help; harmful Heparin DIC No help; harmful Steroids Inflammation No help Prostaglandins Cytoprotection No help Activated charcoal Clear toxins No help Plasmapheresis Clear toxins Possible Cell systems Replace liver May improve coma Cell transplants Replace liver Not enough data

7 Drug-Induced Liver Injury: Herbalife Hepatotoxicity 38 yo housewife, took 3 tabs per day as tea for 3 weeks for weight loss. Noted nausea, dark urine, jaundice. Two wks later: TB 14.2, AST 2,624, INR 1.9. Recovered after drug withdrawn. Two Herbalife series: Elinav F. J Hepatol 2007;47:514; Schoepfer AM, et al. J Hepatol 2007:47:521

8 Black cohosh hepatotoxicity: autoimmune hepatitis 35 yo woman, began a mail order pill one/day. Admitted 4 wks later with coma. TB 19.3, AST 835/ALT 674, INR 3.9, ANA 1:640. Transplantation required.

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10 Autoimmune hepatitis/dili Stopping the drug may or may not be enough Use of steroids seems logical But when? If given early, not certain what you are treating If one waits, is there a point that is too late?

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12 Transplant-free survival by etiology and coma grade APAP 65% 56% Hep A 68% Ischemia 55% 26% 26% 27% 25% AFLP Hep B Autoimmune Drug-induced Indeterminate Coma I-II Coma III-IV Coma grade I-II patients had ~50% better survival than III-IV

13 Study Design NAC Trial A multi-center, randomized, double blind study of IV NAC vs. placebo for non-acetaminophen ALF (NAALF) Does IV NAC over 72 hrs improve survival in NAALF? 173 patients enrolled from 828 screened over 8 yrs Main groups: AIH, DILI, Hep B, Indeterminate Randomized by site, coma grade (I-II vs III-IV) Continued with standard care including OLT Primary outcome: overall survival at 3 weeks Secondary outcomes: transplant-free survival, transplantation rate, length of ICU/hospital stay, no. of organ systems failing Initial prediction was for overall survival ~57% PLB, improved to 75% for the NAC group

14 Primary/secondary outcomes in the NAC trial Overall survival p< 0.28 Transplant-free survival *p< 0.04 Transplant free I-II *p< 0.01 Transplant-free III-IV p< 0.09 Transplanted 3wk p< 0.09 *p< Transplanted 1 yr The most impressive difference was in transplant free survival in coma grades I-II. * = statistically significant NAC PLB

15 NAC Results by Etiology Overall survival Transplant free survival PLB NAC PLB NAC DILI 17/26 15/19 7/26 11/19 N=45 65% 79% 27% 58% AIH 10/15 7/11 4/15 1/11 N=26 67% 64% 27% 9% HBV 6/12 19/25 2/12 10/25 N=37 50% 76% 17% 40% Indeterm 18/26 9/15 6/26 6/15 N=41 69% 60% 23% 40%

16 Cox proportional hazards model by treatment and coma grade NAC I-II differed from all other groups

17 Cox proportional hazards model: time to transplant by treatment and coma grade

18 Summary/Conclusions IV NAC for non-acetaminophen ALF No improvement in overall 3 wk survival with IV NAC vs PLB Significant improvement in transplant-free survival (0.04). Particularly for coma grade I-II (p=0.01, 2/3 of patients were coma I-II) NAC was generally well tolerated ALFSG is now performing an open label NAC trial and looking at ALI, a less severe form, although not doing NAC in this grp NAC can be recommended, particularly for early stage ALF May have a special role in DILI or in Hepatitis B

19 Rationale for NAC trial in DILI DILI is severe, has significant mortality DILI is often prolonged NAC appears to be of benefit: anti-oxidant? NAC is safe: both IV and oral forms End point: time to recovery This would be a carrot for DILIN enrollment But there are many obstacles to such a trial

20 Few if any controlled trials except for NAC Are milder DILI cases likely to benefit? Is there an oral form that would be acceptable? Are there alternatives to NAC? No evidence to support corticosteroids What about new classes of medications? NRF-2 activation Summary/Conclusions Treatment for DILI 2010

21 Nrf2 Activation is Anti-Inflammatory and Tissue Protective AIMs target Keap1 and activate Nrf2 Nrf2 regulates 250+ antioxidant and detoxification enzymes Increases cellular antioxidant content Activates detox/export pathways Keap1 suppresses IKKβ-NFκB Potent anti-inflammatory effect Reduces cytokine production Reduces oxidative stress AIMs mimic cyclopentenone prostaglandins (cypgs) Promote resolution of inflammation Protects host from inflammationinduced damage Broad anti-inflammatory and tissue protective effects Science (1995) 270: 296; FASEB J, (1997) 11:118 Am.J.Phys. (1998) 275:1640; J.Imm (2004) 172:2522

22 Nrf2 Protects Against Hepatic Damage Challenge Nrf2 Status Outcome KO lethality and necrosis Acetaminophen Induction with RTA 403 Hepatoprotective in WT but not Nrf2 KO mice KO ROS, inflammation, and liver necrosis Concavalin A Induction with RTA 403 Prevented immune-mediated hepatotoxicity KO neoplastic lesions and weight loss Aflatoxin Induction with RTA 403 aflatoxin-dna adduct formation by ~90% and preneoplastic lesions by over 99% FAS or TNF-a KO hepatocyte apoptosis; hemorrhagic foci Ischemiareperfusion KO Hepatic Effects of Nrf2 Hepatic effects of genetic or pharmacologic manipulation of Nrf2 studied extensively Genetic deletion of Nrf2 enhances hepatic damage from a variety of injurious stimuli Pharmacologic induction protective against many hepatotoxic stimuli AIMs protect against APAP hepatotoxicity via activation of Nrf2 RTA 403 Protects Against APAP Hepatotoxicity antioxidant response and hepatocyte damage D-Gln/LPS Faa Induction with RTA 402 Induction with RTA 403 survival Protected against formation of hepatocellular carcinomas

23 RTA 402 Suppresses Hepatitis In Vivo 100% 80% Survival LFT Changes ALT % control AST % control Survival 60% 40% % Control % 50 0% Vehicle D-Gln/LPS RTA 402 (mg/kg) mg/kg D-Gln and 10 ug/kg LPS 0 Vehicle D-Gln/LPS RTA 402 (mg/kg) mg/kg D-Gln and 10 ug/kg LPS Hepatitis induced in BALB/c mice by administration of 700 mg/kg of D-galactosamine and 10 mg/kg of LPS IP Vehicle or RTA 402 administered at indicated doses 4 hours post-d- Gln/LPS and surviving animals sacrificed 16 hours post-d-gln/lps N=10/group for controls and 9/group for RTA 402-treated groups

24 Induction of Nrf2 is hepatoprotective Genetic or pharmacologic induction of Nrf2 and increase in ALT is associated with hepatoprotection upon ConA challenge Genetic Induction of Nrf2 is Hepatoprotective in ConA Challenge Aim induction of NRF2 is hepatoprotective in ConA challenge Serum ALT (U/L) Keap1 WT Keap1 KO Serum ALT (U/L) Vehicle RTA Vehicle ConA Keap1 WT Vehicle ConA Keap1 KO 0 Vehicle ConA Nrf2 WT Vehicle ConA RTA 403

25 New possible therapeutic trial: NRF-2 activators Nrf2 activator RTA 402 is in clinical trials for diabetic nephropathy, already early phase III Could it be considered for a trial in ALF or in DILI? Oral once a day Lowers bilirubin and ALT levels Increases in ALT are transient, due to muscle

26 Summary: Therapy for DILI 2010 Although some evidence for autoimmunity in DILI, no evidence suggests that corticosteroids of value NAC appears safe and effective for severe early DILI New strategies are needed: we are intrigued by the promise of Nrf2 activators