New Approaches to Hepatitis B Therapy

Transcription

1 ew Approaches to Hepatitis B Therapy YSGE Course 2016 Ira M. Jacobson, M.D. Chairman, Department of Medicine Mount Sinai Beth Israel Professor of Medicine Icahn School of Medicine at Mount Sinai

2 Themes HBV reactivation with HCV DAA therapy: Is it real? What should we do about it? The introduction of tenofovir alefenamide () Data from phase 3 trials When to use it ovel therapeutic approaches to HBV infection

3 Hepatitis B Reactivation Associated With DAA HCV Therapy: Review of Spontaneous Post-Marketing Cases FAERS database search 11/22/13 10/15/16 29 cases identified (5 in USA, 17 Japan, 5 other) 3 decompensated: 2/3 death; 1/3 LT Mean time to reactivation 53 days (most 4 8 wks) o specific culprit DAA regimen BL HBV viral parameters utcome HBsAg (+) n=13 HBsAg (-) n=4 HBsAg not reported n=12 HBcAb (+) n=6 HBcAb not reported n=23 HBsAg (-) n=3 HBsAb not reported n=26 HBV DA undetectable n=16 HBV DA detectable n=9 HBV DA BL either not reported or detectability unclear n=4 Death n=2 Transplant n=1 Hospitalization n=6 ther n=20 16/29 initiated HBV therapy 7/16 delayed (7-60 days) with 1 death Bersoff-Matcha SJ, et al. AASLD 2016, Boston. #LB-17

4 Hepatitis B reactivation associated with DAA therapy for hepatitis C: A review of spontaneous post-marketing cases

5 HBV Testing and Monitoring During HCV DAA Therapy: AASLD/IDSA Guidance Test all pts initiating HCV therapy for HBsAg, anti-hbc, and anti-hbs o HBV markers: VACCIATE (this is not new!) HBV markers present: HBV DA detectable HBV DA meets criteria for treatment in AASLD HBV guidelines Treat with HBV drug HBsAg positive HBV DA low or undetectable Monitor for reactivation; treat if HBV DA level meets AASLD HBV guideline treatment criteria HBsAg negative; Anti-HBc positive (± anti-hbs) Insufficient data to provide recommendations AASLD/IDSA. HCV guidance. September hcvguidelines.org ctober 2016.

6 Tenofovir Alefenamide () Approved for HBV Infection ovember 10, 2016

7 HBV Treatment Landscape in 2016 Peginterferon alfa-2a Lamivudine Entecavir Tenofovir DF Interferon alfa-2b Adefovir Telbivudine Tenofovir Alefenamide ()

8 ext-generation Delivery System of Tenofovir P H 2 P H 2 P H H 2 H H TFV TDF Tenofovir Tenofovir Disoproxil Fumarate Tenofovir Alafenamide Improved stability in plasma: Enhanced delivery of active form (TFV-DP) to hepatocytes Lower doses are used (25 mg vs 300 mg) Systemic exposures of TFV reduced Agarwal K et al. AASLD 2013, Poster #973; Murakami E et al. HepDART 2013, Abstract 104

9 A ovel Prodrug Bi of Tenofovir DIAI ESTER GI TRACT TFV (tenofovir) TDF (tenofovir disoproxil fumarate) 300 mg (tenofovir alafenamide) 25 mg REAL TUBULAR CELL PLASMA ~90% LWER PLASMA TFV TFV TFV AT 1 & 3 HEPATCYTE short plasma half-life TFV HBV longer plasma half-life - greater plasma stability TFV-DP AMIDATE REAL TUBULAR CELL AT 1 & 3 TFV T 1/2 based on in vitro plasma data - TDF = 0.4 minutes, = 90 minutes. Lee W et. Antimicr Agents Chemo 2005;49(5): Birkus G et al. Antimicr Agents Chemo 2007;51(2): Babusis D, et al. Mol Pharm 2013;10(2): Ruane P, et al. J Acquir Immune Defic Syndr 2013; 63: Sax P, et al. JAIDS Sep 1;67(1):52-8. Sax P, et al. Lancet Jun 27;385(9987): Agarwal K et al. J Hepatology 2015; 62: ; Buti EASL 2016, ral 9 - GILEAD CFIDETIAL AD PRPRIETARY DRAFT. FR ITERAL USE LY. T FR DISTRIBUTI R PRMTI. GS06; Chan, EASL 2016, ral GS12 9

10 Randomized 2:1 HBV Phase 3 Program Two phase 3, randomized, double-blind studies Primary Endpoint* Wk 48 Wk 72 Baseline Wk 144 Wk 384 Double-blind Wk 96 Study 108 HBeAg- (=425) Study 110 HBeAg+ (=873) 25mg TDF 300mg pen-label 25 mg Primary endpoint (non inferiority margin of 10%): HBV DA <29 IU/mL at Week 48 Key secondary endpoints ALT normalization at Week 48 Renal parameters and bone mineral density at Week 48 95% retention rate through Week 48 Inclusion criteria: HBV DA 20,000 IU/mL; ALT >60 U/L (males), >38 U/L (females), egfr CG >50 ml/min *on-inferiority margin of 10% Buti M et al. Lancet G&H 2016; doi: /S (16) Chan HLY et al. Lancet G&H 2016; doi: / /S (16)

11 Proportion of Patients, % (95% CI) Antiviral Efficacy of and TDF at Week 72 Rates of Viral Suppression HBV DA <29 IU/mL HBeAg- HBeAg TDF : 92.6% TDF: 92.1% : 71.6% TDF: 71.9% Treatment difference +0.6 (-5.3, +6.4); p= Treatment difference: 0.9 ( 7.0, 5.2); p= Week Seto, AASLD 2016, ral Week HBV DA suppression rates were lower in HBeAg+ vs HBeAg patients o significant difference between and TDF o resistance was detected through 48 weeks HBV DA suppression was comparable between and TDF treatment up to Week 72

12 Study 110: Phase 3 CHB Study: vs TDF Serologic Results HBeAg+ (=873) n/ (%) n=581 TDF n=292 P-value HBeAg loss 78/565 (14) 34/285 (12) 0.47 HBeAg seroconversion 58/565 (10) 23/285 (8) 0.32 HBsAg loss 4/576 (<1) 1/288 (<1) 0.52 HBsAg seroconversion 3/576 (<1) Similar serologic response between and TDF arms in HBeAg-positive subjects a UL 30 U/L males, 19 U/L females Buti EASL 2016, ral GS06 Chan, EASL 2016, ral GS12 12

13 Patients With ALT ormalization, % Patients With ALT ormalization, % ALT ormalization of and TDF at Week AASLD Criteria 80 TDF * * : 49.1% TDF: 39.0% Central Lab Criteria * * * * * * * : 76.1% TDF: 68.4% Significantly higher ALT normalization rate with vs TDF <19 and <30 U/L for females and males, respectively 34 and 43 U/L for females and males, respectively, aged <69 y, and 32 and 35 U/L, respectively, aged >69 y Fung, AASLD 2016, Poster 1852; Data on File, Gilead Sciences Inc *p<0.05 p<0.005 p 0.001

14 Mean Change From Baseline, ml/min (SD) Mean Change From Baseline, ml/min (SD) Renal Laboratory Parameters in CHB Patients Treated With or TDF 20 egfr CG TDF 10 * * * * * * * * *p<0.001 p<0.01 Agarwal, AASLD 2016, Poster 1844 treatment had statistically significant less effect on egfr compared to TDF at 48 weeks 1 4

15 Mean Change From Baseline, ml/min (SD) Mean Change From Baseline, ml/min (SD) Renal Laboratory Parameters in CHB Patients Treated With or TDF egfr CG TDF * * * * * * * * *p<0.001 p<0.01 Agarwal, AASLD 2016, Poster 1844 treatment had statistically significant less effect on egfr compared to TDF at 72 weeks 1 5

16 Median egfr Change, % Median egfr Change, % Renal Laboratory Parameters in CHB Patients Treated With or TDF Smaller egfr declines with vs TDF in patients with older age and those with comorbid conditions (HT/DM/CVD) Age Comorbid Conditions 0 Age <50 y Age 50 y n=642 n=294 n=185 n= o HT/DM/CVD HT/DM/CVD n=691 n=136 n=337 n= P< P=0.01 n=5 n=8 In patients at greater risk for kidney disease, treatment resulted in smaller declines in egfr CG and fewer patients showed CKD stage worsening compared with TDF treatment P< P=0.003 n=5 n=8 *p-values from Wilcoxon 2-sample test; Hypertension (HT), diabetes mellitus (DM), and cardiovascular disease (CVD) determined by medical history or concomitant medication. Agarwal, AASLD 2016, Poster

17 Mean (SD) % Change From Changes in BMD in CHB Patients Treated With or TDF Hip TDF Spine 4 p <0.001 p < p <0.001 p < Baseline, g/cm Week , TDF, treatment resulted in smaller decline in Hip and Spine BMD compared to TDF p-values from the AVA model including treatment as a fixed effect. CI, Confidence Interval Seto, AASLD 2016, ral

18 Patients, % Change in Diagnosis of steopenia or steoporosis* Through Week 48 ormal steopenia steoporosis 100% Spine Hip % % 40% 20% % Baseline Week 48 n=856 Baseline Week 48 TDF n=426 Baseline Week 48 n=851 Fewer subjects in the group had worsening spine and hip BMD clinical status at Week 48 compared with the TDF group Baseline Week 48 TDF n=426 * ormal, osteopenia and osteoporosis as defined by T-score, where ormal: 1.0; steopenia: -2.5 to -1.0; steoporosis: 2.5 Seto, AASLD 2016, ral 67

19 Resistance Analysis Through 48 Weeks of Treatment With or TDF Sequence Changes bserved by Population Sequencing Through Week 48 n=24 TDF n=14 Sequence Analysis f 38 patients who qualified for sequence analysis, 17 (45%) were found to be nonadherent to study medication Phenotypic Analyses VB in 5 patients on and 4 on TDF while maintained adherence and qualified for phenotypic analysis All isolates remained sensitive to TFV with fold-change values <2 compared with baseline (average 1) 2 patients on TDF qualified with conserved site mutations Isolates remained sensitive to TFV Chan, AASLD 2016, Poster 1843 o resistance to and TDF was detected through Week 48

20 verall Safety Adverse Events Patients, n (%) n=866 TDF n=432 AE 608 (70) 291 (67) Grade 3 4 AE 39 (5) 17 (4) Serious AE 36 (4) 21 (5) D/C due to AE 9 (1) 5 (1) Death 1 * 1 HCC 1 (<1) 5 (1) Grade (31) 126 (29) ALT 70 (8) 40 (9) Laboratory Abnormalities, 1% AST 28 (3) 23 (5) Amylase 23 (3) 10 (2) Fasting LDL cholesterol 37 (4) 1 (<1) Fasting glucose (hyperglycemia) 9 (1) 0 GGT 3 (<1) 6 (1) * 54-year old Asian woman died due to H11 influenza at \week 14 (non-treatment-emergent) 51-year old Asian man with cirrhosis died due to HCC at Week 56 (non-treatment-emergent) Buti, EASL 2016, ral GS06 Chan, EASL 2016, ral GS12 Gilead Sciences, Data on File

21 Future Horizons in HBV Therapy

22 ew Targets for HBV Cure Entry Inhibitors Myrcludex Immunodulators TLR agonists T-cell vaccines PD-1/PD-L1 blockade RT Pol Inhibitors ucleotide analogues on-uc analogues RAseH inhibitrs cccda silencing Fabien Zoulim, and David Durantel Cold Spring Harb Perspect Med 2015;5:a Courtesy of Robert Gish, MD Inhibit protein translation by sira Arrowhead Tekmira Alnylam GSK Core inhibitors ovira Bayer (Aicuris) Assembly Gilead Janssen Roche HBsAg release Inhibitor ucleic acid polymer