New combination EBR/GZR: The end of an era for the difficult to treat?

Transcription

1 New combination EBR/GZR: The end of an era for the difficult to treat? Ioannis Goulis Associate Professor in Gastroenterology Aristotle University of Thessaloniki, Greece 9 th International Congress of Internal Medicine Athens, March 2017

2 Declaration of conflict of interest Speaking/Teaching: Abbvie, Bristol-Myers Squibb, Gilead, Merck Grant/Research support: Abbvie, Bristol-Myers Squibb, Gilead, Μerck, Regulus

3 Which patients are difficult to treat? 1. Chronic Kidney Disease (& patients under hemodialysis) 2. Patients with Inherited Blood Disorders 3. Patients who inject drugs 4. HCV/HIV co-infection 4

4 EBR/GZR Phase 3 clinical trials on Special Populations n=913 ±cirrhosis Study Population Number of patients Treatment & Duration C-EDGE TN (double blind) C-EDGE TE (open-label) GT 1,4,6 TN + κίρρωση GT 1,4,6 TE + κίρρωση N= 316 N= 105 N=105 & 105, N= 104 & 106, EBR/GZR : 12 weeks Placebo - 12 wks EBR/GZR : 12 /16 wks EBR/GZR + RBV : 12 /16 wks C-EDGE COINFECTION (open-label) C-EDGE CO-STAR (double-blind) GT 1,4,6 TN + cirrhosis HCV/HIV-1 co-infection GT 1, 4, 6 TN + cirrhosis, + HIV-1 /PWID N= 218 EBR/GZR :12 wks N=201 σε ITG*, N=100 placebo (DTG) (ITG)EBR + GZR : 12 wks placebo -12 weeks C-SALVAGE~ (open-label) GT 1 TE επί Pis + κίρρωση N=79 EBR + GZR + RBV : 12 wks C-EDGE IBLD (double-blind) GT 1,4,6 TN, TE +/-cirrhosis N=107 in ITG N=52 in DTG ITG = EBR + GZR for 12 weeks C-SURFER (double-blind) GT 1 TN of TE + cirrhosis CKD N=122 N=113 EBR + GZR : 12 wks Placebo : 12 wks H-2-H (open-label) GT 1, 4,6 TN, TE + κίρρωση N=129 EBR/GZR N=126 SOF/PR EBR/GZR 12 wks, vs SOF/PR 12wks * ITG= immediate tx group **DTG = deferred tx group,= 12 weeks followed by 12 weeks of open-label EBR + GZR, OPAT= opiate agonist therapy, IBLD=inherited blood disorders Zeuzem S et al, Ann Int Med 2015, Kwo P et al, Gastroenterology 2016; Forns X, Journal of Hepatology 2015, Roth D et al. Lancet Hezode et al EASL 2016 sat-128; Dore GJ et al. Annals of Internal Medicine 2016 Rockstroh et al Lancet 2015, Sperl at al. Journal

5 Patients with Chronic Kidney Disease (+hemodialysis) 5

6 Chronic hepatitis C increases the risk of ESRD

7 CKD increase the risk of HCV complications Kaiser Permanente Database HCV pts vs 2179 HCV+CKD (egfr<60) ESRD associated with increased risk of: Death: 1.61 ( ) Arrythmia: 1.89 ( ) Myocardial infarction: 2.39 ( ) Transient ischemic attack: 1.97 ( ) Cardiac failure: 3.58 ( ) ESRD increase the risk of cardiac death or death from any cause among HCV pts Tartof et al, EASL 2016

8 HCV treatment in patients with CKD

9 What is the unmet clinical need in HCV patients with CKD? In patients with GFR<30 ml/min/1,73m 2 the SOF based regimens are not recommended Insufficient data on the efficacy/safety of DAAs in this population Significant commorbidity- many concomitant medications-need for close monitoring of possible DDIs

10 Sofosbuvir-Containing Regimens Have Been Linked to Worsening of Renal Function in HCV-TARGET 1 HCV-TARGET is an ongoing prospective observational cohort study characterizing the use of direct-acting antivirals across clinical practices in North America and Europe Baseline Characteristic egfr 30 ml/min/1.73 m 2 Started Tx N=19, (n) *Includes acute or chronic renal insufficiency, outcome abstracted from treatment documentation egfr ml/min/1.73 m 2 Started Tx N=63, (n) Prior HCV Treatment Experience 58% (11) 56% (35) Prior PI Therapy Failure 5% (1) 8% (5) Cirrhosis History of decompensation MELD 10 Treatment 42% (8) 32% (6) 26% (5) 68% (43) 48% (30) 41% (26) SOF/PegIFN/RBV 5% (1) 6% (4) SOF/RBV 26% (5) 24% (15) SOF/SMV 58% (11) 51% (32) SOF/SMV/RBV 11% (2) 19% (12) Selected Adverse Events Worsening renal function* 29% (5/17) 11% (6/56) 1. Saxena V et al. Presented at: 50 th Annual EASL Meeting; April 2015; Vienna, Austria.

11 % Patients Achieving SVR Treatment With OBV/PTV/r + DSV ± RBV in 20 Patients with Advanced CKD: RUBY-1 1 Most common AEs included: Anemia was reported in 69% of patients receiving RBV Diarrhea occurred in 14-31% AEs related to DAAs were reported in 29-62% of patients SVR mitt SVR12 Event GT1a OBV/PTV/r + DSV + RBV N=13 GT1b OBV/PTV/r + DSV N=7 Any AE 13 (100) 6 (86) Any AE assessed as being related to DAAs 8 (62) 2 (29) Serious AE 3 (23) 1 (14) AE leading to study drug discontinuation AE leading to RBV dose reduction (69) NA Death 1 (8) 0 AEs occurring in 15% of patients overall Anemia 9 (69) 0 Fatigue 5 (38) 2 (29) Diarrhea 4 (31) 1 (14) Nausea 5 (38) 0 Headache 3 (23) 0 1. Pockros PJ et al. Gastroenterology Mar 11. pii: S (16) doi: /j.gastro

12 C-SURFER ΕΒR/GZR in CKD

13 C-SURFER : CKD patients/ + hemodialysis n=111 GZR 100 mg / EBR 50 mg Follow-up n=113 R Placebo *GZR 100 mg / EBR 50 mg n=11 GZR 100mg / EBR 50mg (PK) Followup D 1 TW4 TW8 TW12 FUW4 FUW8 FUW12 FUW16 Randomized multi-center double blind trial Ν= 224, gen 1, naïve & experienced N= 11 PK samples collected 1. Roth D et al. Lancet. 2015;386: ; 2. Roth D et al. Poster presented at: Kidney Week 2015; November 2015; San Diego, CA.

14 Gender, n (%) Male Female Race, n (%) White African-American Asian Other HCV genotype, n (%) G1a G1b G1 other Prior treatment history, n (%) Naive Experienced Patient demographics: 75% on hemodialysis GZR + EBR (ITG + PK group) 12 weeks (n = 122) 92 (75) 30 (25) 61 (50) 55(45) 5 (4) 1 (<1) 63 (52) 58 (48) 1 (<1) 101 (83) 21 (17) Placebo (DTG) 12 weeks (n = 113) 80 (71) 33(29) 48(43) 53(47) 9 (8) 3 (3) 59 (52) 53 (47) 1 (<1) 88 (78) 25 (22) Cirrhosis, n (%) 7 (6) 7 (6) Diabetes, n (%) 44 (36) 36 (32) Dialysis, n (%) 92 (75) 87 (77) CKD stage, n(%) stage 4 stage 5 22 (18) 100 (82) 22 (19) 91(81) DTG = deferred treatment group; ITG = immediate treatment group; PK = Intensive PK group Roth D et al. Lancet. 2015;386: ;

15 Patients, % SVR12: >94% with EBR/GZR 12wks without RBV Full analysis set Modified full analysis set 100% 94.3% 99.1% 95.1% 98% 75% 50% 25% 0% Immediate treatment Deferred treatment Relapse 1 a 1 2 c 2 D/c unrelated to study medication /122 /116 /102 /99 6 b 0 3 d 0 1. Roth D et al. Lancet. 2015;386: ; 2. Roth D et al. Poster presented at: Kidney Week 2015; November 2015; San Diego, CA.

16 C-Surfer conclusions The first phase 3 trial with a large number of patients (n=224) including hemodialysis and cirrhotic patients EBR/GZR <1% renal excretion-no need for dose adjustment SVR12=94-95%, regardless of fibrosis stage or stage of CKD Low rates of anemia-no RBV

17 Patients with Inherited Blood Disorders

18 EASL Guidelines for IBLD patients

19 Prevalence of HCV in IBLD patients in Greece

20 LDV/SOF+RBV in limited number of patients with Hemophilia All the patients received LDV 90 mg and SOF 400 mg /day and RBV according to their weight, twice a day for 12 wks SVR12 was the primary endpoint All 14 patients achieved SVR12. Treatment was well tolerated

21 What gaps exist in the HCV treatment for IBLD patients? HCV treatment in IBLD patients is complicated: The risk of hemolytic anemia due to RBV and the common comorbidities have limited the use of interferon based treatments in this population The published data refer mostly on the DAAs treatments in patients with hemophilia Data on HCV patients with thalassemia are limited The progression of fibrosis is accelerated in these patients because of co-incident iron load. Priority for treatment?

22 22 C-EDGE-IBLD: ΕΒR/GZR in patients with inherited blood disorders (hemophilia, thalassemia, sickle cell anemia)

23 C-EDGE IBLD : patients with Inherited Blood Disorders Double-blind, randomized study Ν=159, γον 1,4,6 naïve & experienced 24% cirrhotic, 38% thalassemia, 35-44% gen 1α Hezode et al EASL 2016 sat-128

24 Demographic characteristics, 38% with thalassemia Gender, n (%) Male Female Race, n (%) White African-American Asian Other HCV genotype, n (%) G1a G1b G1 other G4 G6 Prior treatment history, n (%) Naive Experienced GZR + EBR (Immediate) 12 weeks (n = 107) 80 (74.8) 27 (25.2) 81 (75.7) 19 (17.8) 6 (5.6) 1 (0.9) 47 (43.9) 46 (43.0) 2 (1.9) 12 (11.2) 0 (0) 53 (49.5) 54 (50.5) Placebo (Deferred) 12 weeks (n = 52) 39 (75.0) 13 (25.0) 40 (76.9) 9 (17.3) 3 (5.8) 0 (0) 18 (34.6) 27 (51.9) 0 (0) 6 (11.5) 1 (1.9) 27 (51.9) 25 (48.1) Cirrhosis, n (%) 26 (24.3) 12 (23.1) HIV coinfected, n (%) 6 (5.6) 4 (7.7) IL28B CC, n (%) 27 (25.2) 9 (17.3) Blood disorder, n(%) Sickle Cell Anemia ß Thalassemia von Willebrand / Hemophilia A/B 19 (17.8) 41 (38.3) 47 (43.9) 10 (19.2) 20 (38.5) 22 (42.3) Hezode et al EASL 2016 sat-128

25 SVR12 SVR12: 93.5% EBR/GRZ 12 wks, without RBV (ITT) 100% 93.5% 75% 50% 25% 0% 100/107 Full analysis set Breakthrough 0 Relapses 6 Treatment discontinuation 1 Discontinued due to non-compliance and did not continue within the study Full analysis set includes all patients who received 1 dose of study medication Hezode et al EASL 2016 sat-128

26 SVR12 based on patients characteristics: 97.6% in b-thalassemia Hezode et al EASL 2016 sat-128

27 CONCLUSIONS The first phase 3 study focused on this population 97.6% SVR12 in thalassemic patients Absence of RBV is an advantage No change in hematologic parameters/ no need for change in concomitant medication

28 People who inject drugs (PWIDs)

29 HCV Transmission Among PWID Continues Assessment of data reported to CDC from regarding young people ( 30 yrs of age) with HCV Change in HCV Incidence Among Young PWID, Change in Incidence (%) Insufficient data No change or decrease < 100% increase 100% to 199% increase 200% increase Suryaprasad AG, et al. Clin Infect Dis. 2014;59:

30 PWIDs:What do we know about the treatment of these patients? Data mainly from pooled analysis, retrospective studies Long-term rates of reinfection? Adherence rates? The EASL& AASLD guidelines encourage the treatment of these patients 1. HCV Guidance: Recommendations for Testing, Managing, and Treating Hepatitis C. Accessed January 28, 2016; 2. EASL. J Hepatol. 2015;63: EASL Recommendations on Treatment of Hepatitis C 2016

31 SVR12 (%) Retrospective analysis of SVR12 with LDV/SOF in PWID 1,2 SVR Rates for Subjects on OAT Compared With Those Not on OAT in the ION 1,2,3 Trials No concomitant OAT Concomitant OAT / 6/ 492/ 29/ 311/ 10/ 195/ 6/ 308/ 10/ 320/ 5/ weeks 12 weeks 24 weeks 8 weeks 12 weeks 24 weeks LDV/SOF LDV/SOF + RBV 70 patients on substitution treatment No cases of reinfection 24 weeks post end of treatment No interaction with methadone 2 1. Grebely J, Mauss S, Brown A, et al. 4th International Symposium on Health Care in Substance Users, Sydney, 2015; 2. SOF/LDV SmPC;

32 % Patients Achieving SVR % Patients Achieving SVR SVR12 with PTV/r/OBV + DSV ± RBV in PWID (pooled analysis) Pooled Analysis of Genotype 1 Patients on Stable OAT Phase II Study in Genotype 1 Patients on Stable OAT , , / % naïve 98% non-cirrhotic 10 37/ % naïve 100% non-cirhotic No need to change methadone/buprenorphine dose 1. Puoti M. AASLD 2014, #1938; 2. Lalezari J, Sullivan JG, Varunok P et al. J Hepatol. 2015;63(2):

33 CΟ-SΤΑR: ΕΒR/GZR in PWIDs

34 CO-STAR: patients on opiate agonist therapy Double blind, Νaïve, gen 1, 4, 6 On opiate agonist therapy (methadone, buprenorphine, naloxone) 3 months 20% cirrhotic, 7% HIV/HCV, 76% gen 1a 55% VL> IU/ml Baseline positive urine drug screen results in 58% of patients Immediate Treatment Arm EBR / GZR, n = 201 Unblinding Follow-up for 24 weeks Deferred Treatment Arm Placebo, n = 100 Unblinding EBR / GZR Follow-up for 24weeks D1 W4 W8 W12 W16 W22 W28 W36 W52 Dore GJ. Annals of Internal Medicine 2016.

35 Subjects Achieving SVR, % SVR12: 92% EBR/GZR 12 wks without RBV 100% 90% 80% 70% 60% 50% 40% 30% 20% 10% 0% Overall SVR 92% SVR by Genotype 94% 93% 92% Relapse(n) Reinfection (n) n/a Other c (n) % mfas a 96 % n N GT1a b GT1b GT4 GT6 a Excludes lost to follow up or discontinued unrelated to virologic failure and reinfection. b Includes one subject with mixed infection (GT1a and GT1b) who achieved SVR12. c Other includes subjects who were lost to follow-up or discontinued Dore GJ. Annals of Internal Medicine 2016.

36 Adherence, % High rates of Adherence 80% adherence (>67 doses) 95% adherence (>79 doses) 90% adherence (>76 doses) 100% 90% 80% 70% 60% 50% 40% 30% 20% 10% 0% 100% 99% 97% 100% 100% 100% n N Immediate Treatment Arm (N=199) Deferred Treatment Arm (N=97) In both treatment arms, 97% of subjects took at least 81 of 84 doses despite continued drug use in more than half of subjects throughout treatment Dore GJ. Annals of Internal Medicine 2016.

37 Dore et al. EASL 2016 #163 Reinfection Rates

38 C-EDGE CO-STAR: Impact of Baseline Drug Use on SVR Treatment-naive F0-4 PWID with GT1/4/6 HCV who were on OAT were treated with grazoprevir/elbasvir (N = 301) > 40% had injection drug use during therapy (excluding cannabinoids) Overall SVR12: 91.5% Subgroup n/m SVR12 (95% CI) Positive drug screen Negative drug screen 123/136 61/ SVR12 (%) (Mean, 95% CI) 90.4 ( ) 93.8 ( ) Dore GJ, et al. Ann Intern Med. 2016

39 SVR12 92% in PWIDs CO STAR CONCLUSIONS High adherence % in patients with concurrent drug use Low number of reinfections (8/201) No interactions with methadone/buprenorphine

40 Patients with HCV/ΗΙV coinfection Available data on DAAs

41 SVR12, % ION-4: SVR 12 with LDV/SOF 1 Overall Naive vs Experienced Cirrhosis Status Race P< LDV/SOF 12 wk Naive Experienced No Cirrhosis Cirrhosis Non-Black Black 8/8 of patients with GT4 achieved SVR; overall SVR rate in GT1 was 96% (313/327) 1. Naggie S et al. N Engl J Med. 2015;373:

42 PTV/r/OBV + DSV ± RBV in Coinfected Patients: TURQUOISE-I SVR12, % wk wk 1. Sulkowski M et al. JAMA. 2015;313:

43 SVR12, % ASTRAL-5: SOF/VEL in HCV/HIV patients relapse 1 LTFU 1 withdrew 1 LTFU consent Total 1a 1b GT 1. Wyles D et al. EASL 2016, PS104.

44 Limitations in the concurrent use of DAAs and HIV agents Frequent DDIs- Cautious when choosing the HCV regimen (Liverpool DDIs) There are several case reports of interaction between tenofovir-based and Sof-based regimens (possible nephrotoxicity)

45 C-EDGE CO-INFECTION: EBR/GZR in HCV/HIV

46 C-EDGE CO-INFECTION EBR 50 mg / GZR 100 mg Follow-up D 1 TW4 TW8 TW12 FUW4 FUW8 FUW12 FUW24 Ν=218 HCV GT1, 4 or 6, HCV treatment naive, HIV-1 infected On suppressive ART with CD4 >200 cells/mm3, or not on ART with CD4 >500 cells/mm3 and HIV-1 RNA <50,000 c/ml Efavirenz and HIV PIs not allowed Multicenter, single-arm, open-label phase 3 trial of EBR/GZR 12 wk Rockstroh et al Lancet 2015

47 Demographic characteristics All Patients N = 218 Age, years mean (SD) 48.7 (8.9) Male sex, n (%) 183 (83.9) Race, n (%) White 167 (76.6) Black or African-American 38 (17.4) Asian/Other 13 (6.0) HCV genotype, n (%) 1a 144 (66.1) 1b 44 (20.2) 4 28 (12.8) 6 2 (1.0) Cirrhotic, n (%) 35 (16.1) Antiretroviral therapy, n (%) 211 (96.8) Baseline CD4 (cells/µl); median (1 st 3 rd quartile) 568 ( ) Antiretroviral therapy, NRTI, n (%) Abacavir containing regimen 47 (21.6) Tenofovir containing regimen 164 (75.2) Antiretroviral therapy, 3 rd agent, n (%) Raltegravir 113 (51.8) Dolutegravir 59 (27.1) Rilpivirine 38 (17.4) Rockstroh et al Oral Presentation AASLD 2015#210

48 SVR12, % SVR12: 95% in HCV/HIV co-infection με EBR/GZR 12wks without RBV All Patients GT1a GT1b GT4 27 Reasons for Non-SVR LTFU or DC a Breakthrough Relapse Reinfection aunrelated to virologic failure. 1. Rockstroh JK et al. Lancet HIV. 2015;2:e319 e327.

49 Patients, % SVR24: 93.1% in HCV/HIV coinfection with EBR/GZR 12wks without RBV ITT analysis 100% 93.1% 93.1% 93.2% 92.9% 75% 50% 25% 0% 203/ / / 44 26/ 28 All Patients GT1a GT1b GT4 All GT GT1a GT1b GT4 Relapse, n (%) 5 (2.4) 4 (2.8) 0 (0) 1 (3.6) Other Failure Criteria, n (%) 10 (4.6) 6 (4.2) 3 (6.8) 1 (3.6) Reinfection, n LTFU or discontinued unrelated to VF, n *2 patients with GT6 infection were also included; both patients achieved SVR12. GT = genotype; LTFU = lost-to-follow-up Rockstroh et al Lancet 2015

50 C-EDGE Co-Infection conclusions 95% SVR12 with EBR/GZR 12wks no RBV Same efficacy regardless of HIV regimen It can be co-administered with tenofovir-based HIV regimen

51 General Conclusions High SVR12 rates in all patients populations EBR/GZR 12 wks without RBV was used in all the studies 3 dedicated studies were conducted for the first time in specific patient groups Well tolerated regimen despite the high comorbidity rate of these populations No need for dose adjustment in CKD Limited number of DDIs between EBR/GZR and concomitant medication

52

53 CKD and hemodialysis patients with chronic HCV infection must be evaluated for treatment European Association for the Study of Liver: Clinical Practice Guidelines 1 In patients with CKD 4/5 EBR/GZR OBV/PTV/r are recommended for gen 1 & 4