Treatment of Unique Populations Raymond T. Chung, MD

Transcription

1 Treatment of Unique Populations Raymond T. Chung, MD Director of Hepatology and Liver Center Vice Chief, Gastroenterology Kevin and Polly Maroni Research Scholar Mass General Hospital

2 Disclosures Research Grants (Clinical Trials): Gilead, Abbvie, Merck, BMS, Mass Biologics

3 The Rising Tide Has Lifted Nearly All Boats Genotype 1 Naive Nonresponders Genotype 2 (essentially) Genotypes 4, 5, 6 HCV / HIV

4 Who s Left Behind? Possible Gaps Genotype 3 (and a little bit of 2) Cirrhosis, including decompensated disease Post-liver transplant Acute HCV Renal failure* DAA class failures* PI containing regimens NS5A containing regimens

5 Genotypes 2, 3 as Low-Hanging Fruit We ve historically lumped GT3 with GT2 in IFN+RBV studies Excellent SVR rates associated with PEG/RBV for GT2/3 Not surprisingly, DAA efforts therefore focused principally on GT1

6 Sofosbuvir in Treatment-Naive GT 2, 3 Patients: split, don t lump! FISSION Sofosbuvir 400 mg + ribavirin daily x 12w PEG-2a weekly + ribavirin 800 mg daily x 24w SVR % n = Overall GT GT3 Lawitz E et al., NEJM 2013; 368:

7 Sofosbuvir/Ribavirin for Treatment-Naive and Experienced Patients with GT 2 or 3: VALENCE SVR 12 G2 (blue), G3 (red) Phase 3 trial in Europe Amended to treat GT3 for 24 weeks SOF/RBV x 12W (GT2, n = 73) or 24W (GT3, n = 250) Cirrhosis, 14% 23% 50 Treatment experienced, 58% 25 0 No cirrhosis Cirrhosis Overall Zeuzem et al, N Engl J Med 2014; 370:1993

8 All-Oral Combination of Daclatasvir (NS5A) and Sofosbuvir in Patients with GT 3: ALLY-3 ALLY-3 0 Weeks EOT SVR Treatment-naive 19% w/ cirrhosis N = 101 Daclatasvir + sofosbuvir 99% 90% Prior treatment 25% w/ cirrhosis N = 51 Daclatasvir + sofosbuvir 99% 86% SVR F0-F3 = 96% (105/109) SVR F4 = 63% (20/32) No SAEs related to treatment, no premature D/C due to AEs RAVS: Y93H detected in 13 (9%) SVR 54% Nelson D et al, Hepatology 2015;61:1127

9

10

11

12

13 SOF/RBV vs SOF/PEG/RBV in gt 3 and 2 : BOSON Foster G et al, Gastro 2015; 49:

14 BOSON: Overall SVR12 Foster G et al, Gastro 2015; 49:

15 Gt 3 SVR12 rates by Subgroup Foster G et al, Gastro 2015; 49:

16 SOF + Velpatasvir (NS5A) for Genotype 3: ASTRAL-3 Foster G et al, NEJM 2015;373:2608

17 ABT-493 (PI) + ABT-530 (NS5A) for Genotype 3 (noncirrhotic)

18 ABT-493 (PI) + ABT-530 (NS5A) for Genotype 3

19 Phase-2, Open-label Studies of ABT-493 (PI*) + ABT-530 (NS5A*) in Treatment Naive Pts with GT3: Noncirrhotic (8 wks) and Cirrhotic (12 wks) 69% F0-F1 *pangenotypic, high-potency % with SVR 12 mitt analyses (excl. 1 nonvirologic failure) 28/28 Noncirrhotic 8 wks 24/24 Cirrhotic 12 wks ITT analysis Muir AJ, et al ( SURVEYOR-II ). J Hepatol 2016;64(Suppl 2):S186. EASL 2016 Abstract PS098. Kwo P, et al ( SURVEYOR-II, part 2 ). J Hepatol 2016;64(Suppl 2):S208. EASL 2016 Abstract LB01.

20 Genotype 3 Higher rates of relapse in treatment-experienced, cirrhotic patients May need longer durations of currently available compounds, RBV or both PEG may still be of utility (cirrhotics, TE) Pangenotypic approaches likely to supplant current measures

21 The Cirrhotic Patient Limited success seen in cirrhotics with PEG/RBV, PEG/RBV/TVR or BOC Explanations: Structural: limited drug delivery (portal HTN, nodules) Impaired innate, adaptive immunity Until now, no successful, safe strategies in the decompensated cirrhotic How to overcome?

22 Sofosbuvir + Ledipasvir (NS5A) in Gt 1 Experienced Cirrhosis: ION-2 Phase 3 trial of FDC +/- RBV x wks for gt 1 HCV (n = 440) Tx-experienced (P/R or triple Rx) 88 compensated cirrhotics evenly divided among 4 groups FDC x 12 wks FDC + RBV x 12 wks FDC x 24 wks 25 FDC + RBV x 24 wks 0 FDC 12wks FDC/R 12wks FDC 24wks FDC/R 24wks Afdhal, N Engl J Med 2014;370:

23 Decompensated Cirrhosis and Post-Liver Transplant HCV IFN-based regimens contraindicated once liver failure has supervened Can all-oral regimens stabilize decompensated liver disease? Paradigm of nucs (LAM) in decompensated HBV Allograft HCV historically a major problem SVR, tolerability, DDIs

24 Sofosbuvir/Ledipasvir + RBV in Decompensated Cirrhosis: Preliminary Results of a Prospective, Multicenter Study n = 99 Randomized to SOF + LDV + RBV (600 mg w/escalation) for 12 or 24 wks Patients with GT 1 or 4 and decompensated cirrhosis Median albumin = g/l; median platelets = 71-88K 12 Weeks 24 Weeks Flamm, Abst# 239, AASLD /52 42/ /30 24/27 19/22 18/20 Overall CPT B CPT C

25 Sofosbuvir/Ledipasvir + RBV in Patients with Decompensated Cirrhosis: Improved Clinical Status SAE = 10%-42% (only 4 considered treatment-related) 5 deaths: septic shock (4), renal failure/cardiac arrest Changes in MELD CPT B CPT C 12 wk (n=30) 24 wk (n=29) 12 wk (n=23) 24 wk (n=24) 5 n=5 n= CPT B 2 1 n=3 n= CPT B Albumin 12 Weeks 24 Weeks BL PT Wk4 Baseline PT Wk CPT C BL PT Wk4 0 Baseline PT Wk4 Flamm, Abst# 239, AASLD 2014

26 Sofosbuvir/Ledipasvir + RBV in Patients With Post-Transplant Recurrence: SOLAR-1 n = 223 (214 reported) Randomized to SOF/LDV + RBV (600 mg w/escalation) for 12 or 24 weeks Post-transplant patients with GT 1 or 4, including cirrhotics Most cirrhotic patients with MELD > 10 (60%) Median platelets = K, median albumin = g/dl SVRT2 (%) Weeks 24 Weeks Changes in MELD (n=41) CP-B 12 Wk CP-B 24 Wk n=4 n= /55 55/56 25/26 24/25 22/26 15/18 3/5 2/3 F0-F3 CPT A CPT B CPT C Reddy, Abs t# 8, AASLD

27 Liver Transplant Recipients With Recurrent HCV Gt1 Receiving Paritaprevir/r/Ombitasvir + Dasabuvir + RBV Post-LT (~4 yrs) allograft HCV treated x 24 wks (n = 34) Non-cirrhotics, Gt1a 85% RBV dosing mg Drug-drug interactions: 7-fold in TAC half-life 3-fold in CsA half-life Tacrolimus dosing 0.5 mg q week or 0.2 mg q 3 days CsA dosing 1/5 of daily prestudy dose Adverse events Fatigue and headache 1 early discontinuation 100% 80% 60% 40% 20% 100% 100% 100% Mantry, Abst # 198, AASLD % Week 4 EOTR SVR12

28 ALLY-1: SOF + DCV in decompensated cirrhosis/post-lt Poordad F et al, Hepatology 2016

29

30 The Cirrhotic and Post-LT patient Extending therapy appears to provide the additional potency to overcome barriers in the experienced cirrhotic patient DAA combinations can be given safely, even in decompensated patients and can improve hepatic function Careful monitoring still warranted in decompensated disease Post-LT disease can be managed successfully, with successful navigation of DDIs

31 Acute HCV Prior literature had suggested shorter courses of IFN-based regimens in ahcv matched performance of longer duration regimens for chronic HCV Can abbreviation of DAA-based regimens succeed in acute HCV?

32

33 SOF-LDV for 6 wks for acute HCV in HIV-infected persons N=26, 18 gt 1, 8 gt 4 Well controlled HIV, CD4 mean 675 All but one on ART SOF/LDV x 6 wks SVR12 = 77% (20/26) 4 VFs, 2 lost to FU No relapses in pts with HCV RNA< 6.9log10 Rockstroh J et al, CROI 2016, 154LB

34 DAA Failures The most recent unmet need Resistance-associated variants (RAVs) against PIs and NS5A inhibitors Problem of cross-resistance between PIs PI RAVs recede, but NS5A RAVs persist Can addition of another DAA class overcome the challenge of these RAVs?

35 More is better: rescue of DAA failures with addition of another DAA class Regimen LDV/SOF/RBV SOF + PrOD +/- RBV Grazoprevir/ Elbasvir/SOF/ RBV Class NUC/NS5A NUC/NS5A/PI /NNI Failed Regimen SOF/RB V PEG/RB V/SOF PrOD + RBV Duration (weeks) SVR % % PI/NUC/NS5A GRZ/ELB % Wyles D, Hepatology 2015 Poordad F, AASLD 2015 Lawitz E, AASLD 2015

36 Summary Advent of DAAs has brought prosperity to nearly all HCV subgroups Remaining pockets had included GT3, compensated and decompensated cirrhosis, post-lt disease, renal failure, acute HCV, treatment of PWID, DAA failures All of these can now be successfully treated by going longer or adding RBV Pangenotypic approaches will provide further help We are developing increasingly successful approaches for multiclass DAA failures

37