Nezam Afdhal, MD Beth Israel Deaconess Medical Center Boston, MA Kim Brown, MD Henry Ford Hospital Detroit, MI Michael Fried, MD University of North Carolina Chapel Hill, NC Jordan Feld, MD Toronto Western Hospital Liver Center Toronto, Canada Ira Jacobson, MD Weill Cornell Medical College New York, NY Supported by: Accredited by: Presented for attendees of the 63rd AASLD Annual Meeting (or The Liver Meeting ). This event/function is sponsored by Chronic Liver Disease Foundation and supported by Vertex Pharmaceuticals. This is not an official function/event of the American Association for the Study of Liver Diseases. Sponsored by:
Welcome Tonight s News Program Field Report Breaking News on New CDC Recommendations Michael Fried, MD Case #1 Treat Now or Wait for Future Therapies Kim Brown, MD; Jordan Feld, MD Field Report Breaking News on Real-World Clinical Data Ira Jacobson, MD Case #2 Optimizing Outcomes with Current Treatments Kim Brown, MD; Jordan Feld, MD Press Conference: Late Breaking Data, Q&A
Glenn: Patient Characteristics 55 year old male Shift worker History/risk factors BMI=34 Hypertension and dyslipidemia Moderate drinker/cigarette smoker Concomitant medications Simvastatin 20 mg/day Lisinopril 10 mg/day
Glenn: Baseline Labs Hemoglobin 15.6 g/dl Neutrophils 1400 cells/mm 3 Platelets 210,000 cells/mm 3 AST/ALT 55/75 IU/L Albumin 4.1 g/dl Bilirubin 0.7 mg/dl
Glenn: Disease Characteristics Treatment naïve Genotype 1a IL28B CC METAVIR F3 BL viral load 1,300,000 IU/mL
ARS #1 How would you manage this patient? 1. Continue to monitor patient but do not start treatment 2. Start patient on first generation protease inhibitor/peg-ifn/rbv
Modeling of Liver Fibrosis in Chronic Hepatitis C n=1157 Patients F Metavir 4 Rapid progressors Intermediate progressors 3 2 Slow progressors 1 0 0 10 20 30 40 50 Poynard et al, Hepatology 1999 Years
Proportion of Patients Cumulative Proportion of Patients Transitioning from Compensated to Decompensated Stage Over Time 1.00 0.75 0.50 0.25 0.00 0 24 48 72 96 120 Pts at risk 806 513 402 302 243 217 months D Amico G et al. J Hepatol. 2006;44:217-231.
% of patients Impact According to Response of 10 Different Treatment Regimens on Evolution of Activity* in 3010 Patients with Paired Biopsies 100% 80% Improved Stabilized Worsened 2% 21% 21% 12% 60% 43% 36% 40% 86% 20% 36% 43% 0% *Necrosis and Inflammation. Non-responders (n=1452) Poynard et al. Gastroenterology, 2002;122:1303-1313. Relapsers (n=464) Sustained responders (n=1094)
ADVANCE: IL28B Genotype Effect on Telaprevir Therapy In Patients Tested for IL28B (%) CC CT TT Total In All ADVANCE Patients T12PR* 90 71 73 78 75 T8PR** 87 58 59 67 69 PR 64 25 23 38 44 *T12PR = T+PR12 weeks, then PR12 or 36 weeks depending on ervr status **T8PR = T+PR8 weeks, then PR16 or 40 weeks depending on ervr status Jacobson et al. EASL 2011
SVR SVR Rates in F1/2 vs F3/4 Naïve Patients 100 90 80 70 67% F1/2 F3/4 76% 67% 60 50 48% 40 30 20 10 0 Boceprevir Telaprevir Jacobson IM et al, NEJM, 2011; 364: 2405-2416 Poordad F et al, NEJM, 2011; 364: 1195-1206
OPTIMIZE Trial: Telaprevir BID vs TID PR + TVR 1125 mg BID versus 750 mg TID Response-guided therapy 740 patients 29% bridging fibrosis or cirrhosis 57% G1a, IL28B CC 29% Buti M et al, Abstract LB-8, AASLD 2012
OPTIMIZE Trial: Results 100 TVR 1125 mg BID 80 69% 67% TVR 750 mg TID 74% 73% (%) 60 40 20 0 Buti M et al, Abstract LB-8, AASLD 2012 RVR SVR
Should Glenn Be Treated Now? F3 disease risk of progression with waiting IL28B CC Potential BID option is attractive I would treat
The Case for Waiting Multiple issues with current therapy Compliance pill burden Co-morbidities Adverse effects
Compliance Pill Burden Food Requirement BOC = 18/d TVR = 12/d RBV 4-7/d RBV 4-7/d
Co-Morbidities Cardiac Risk Factors Hypertension, hyperlipidemia, smoker Pre Treatment DDI Statin with TVR/BOC likely just stop it On Treatment Anemia management consider pre-treatment cardiac testing
Drugs with the Potential to Interact with First Generation Protease Inhibitors are Commonly Used by HCV Patients Mayer et al, Abstract #136, AASLD 2012 Drug Name Percent Drug Name Percent Zolpidem * 17.4 Diazepam 7.9 Codeine 16.0 Bupropion * 7.2 Prednisone 15.4 Trazodone 7.1 Tramadol * 14.3 Fluconazole 6.8 Citalopram 13.5 Sertraline 6.4 Fluticasone 13.1 Clarithromycin 6.1 Methylprednisolone 13 Sildenafil (Viagra) 5.4 Alprazolam * 11.8 Clonazepam 5.3 Amlodipine * 10.2 Simvastatin 5.2 Escitalopram * 8.1 Venlafaxine 5.0 * One of the 20 most frequently filled
New Drug-Drug Interaction Data at AASLD 2012: HCV Protease Inhibitors No clinically significant interactions Boceprevir Prednisone (abstract #1896) Omeprazole (abstract #1808) Ethinyl estrodiol/norethidrone (abstract #1901) Simeprevir (TMC-435) Cyclosporine/tacrolimus (abstract #80) Ethinyl estrodiol/norethidrone (abstract #773)
% of patients Anemia is a Known Side Effect with First Generation Protease Inhibitor Based Therapies % of patients 100 90 80 70 60 50 40 30 20 36% 17% TVR PR 100 90 80 70 60 50 40 30 5/5 11/13 13/14 20 14% 10 5% 10 3% 0 0 < 10 g/dl < 8.5 g/dl < 10 g/dl < 8.5 g/dl Telaprevir (INCIVEK ) Prescribing Information. Vertex Pharmaceuticals Incorporated, Cambridge, MA. October, 2012. Boceprevir (VICTRELIS ) Prescribing Information. Merck Sharp & Dohme Corp., Whitehouse Station, NJ, November 2012. 49% 28% 7% BOC PR
% % Future Options for Waiting? (Short-Term) PILLAR (G1 Naïve) 1 Simeprevir 150 mg OD x 12 wks + PR x 24-48 PR x 48 SILEN C1 (G1 Naïve) 2 Faldaprevir 240 mg OD x 24 wks + PR x 24-48 PR x 48 100 80 81 P=0.013 65 79 93 100 80 83 P=0.001 87 93 60 60 56 40 40 20 n/ 62/ 50/ N = 77 77 0 SVR 1. Fried et al. AASLD 2011 61/ 77 Met RGT 57/ 61 SVR 20 0 n/ N = 118/ 142 SVR 40/ 71 124/ 142 Met RGT 53/ 57 SVR 2. Sulkowski et al. EASL 2011
No Incremental Decline in Hemoglobin or Neutrophils with Simeprevir or Faldaprevir Anemia with Simeprevir + P/R 1 Anemia with Faldaprevir + P/R 2 1. Jacobson et al, IDSA, 2012 2. Sulkowski et al, EASL 2011
Should Glenn Delay Treatment? IL28B CC ~80% chance of shortened therapy - 80-90% chance of SVR F3 disease risk of progression with waiting No clear issues with IFN Seems anxious and willing to be treated now I would suggest treatment
Glenn: On Treatment Response Glenn was started on TVR/PEG/RBV TW4 and TW12 HCV RNA undetectable
ARS #2 Which regimen should Glenn receive? 1. 12 weeks TVR/PEG/RBV 2. 12 weeks TVR/PEG/RBV + 12 weeks PEG/RBV 3. 12 weeks TVR/PEG/RBV + 24 weeks PEG/RBV 4. 12 weeks TVR/PEG/RBV + 36 weeks PEG/RBV 5. 24 weeks TVR/PEG/RBV
Recommended Treatment Duration Treatment-Naïve and Prior Relapse Patients HCV-RNA Triple Therapy TVR/Peg-IFN/RBV Dual Therapy Peg-IFN/RBV Total Treatment Duration Undetectable at TW4 and TW12 Detectable (<1000 IU/mL) at TW4 and/or TW12 First 12 weeks Additional 12 weeks 24 weeks First 12 weeks Additional 36 weeks 48 weeks Telaprevir (INCIVEK ) Prescribing Information. Vertex Pharmaceuticals Incorporated, Cambridge, MA. October, 2012.
HCV-RNA Levels and Lab Assays Undetectable (or target not detected ) result is required for assessing RGT eligibility Below LLOQ but still detectable is not sufficient to shorten therapy ie, patient should continue for full 48 wks LLOQ Values for Various Assays* Assay Name Roche COBAS AmpliPrep/COBAS Taqman HCV Test Roche COBAS Taqman HCV Test, v2.0 LLOQ 43 IU/mL 25 IU/mL Abbott RealTime HCV 4/6 12 IU/mL Assay 13/14 *Package Inserts state the the assay should have a lower limit of HCV-RNA quantification 25 IU/mL and a limit of HCV-RNA detection of approximately 10-15 IU/mL. Usually considered 25 IU/mL, but 23 IU/mL per FDA-approved label. COBAS AmpliPrep/COBAS Taqman HCV Test. Roche Molecular Diagnostics. Accessed July 19, 2011. Harrington PR, et al. Hepatology. 2012;55: 1046-1057. United States Food and Drug and Drug Administration (FDA), FDA Division of Antiviral Products; June 30, 2011.
Jackie: Patient Characteristics 45 year old African American female History/risk factors BMI=32 CHC diagnosed in 2002 Treated with Peg-IFN/RBV in 2007 Tolerability issues: fatigue, anemia, neutropenia, alopecia, anxiety, depression after 6 months (treated with paroxetine)
Jackie: Disease Characteristics Prior relapser (early virologic response) Genotype 1a IL28B CT METAVIR F1 in 2007 BL viral load 18,000,000 IU/mL
Jackie: Baseline Labs Hemoglobin 12.1 g/dl Neutrophils 1300 cells/mm 3 Platelets 200,000 cells/mm 3 Serum creatinine 0.9 mg/dl AST/ALT 73/56 IU/L Albumin 4.1 g/dl Bilirubin 0.8 mg/dl INR 0.9
ARS #3 Would you reassess stage of fibrosis before retreatment and, if so, how? 1. No, I don t believe it is necessary 2. Yes, I would re-biopsy the patient 3. Yes, I would use non-invasive test
ARS #4 Which of the following statements is most accurate? 1. Jackie has a low likelihood of success because she is African American and IL28B CT. 2. Jackie has a very high likelihood of success because she is a prior relapser. 3. If restaging shows cirrhosis, Jackie has a very low chance of success. 4. Treatment is contraindicated for Jackie since she developed depression while on PEG/RBV.
%SVR REALIZE: SVR by Response to Previous Peg-IFN/RBV Therapy 100 80 60 86% All Patients 59% All T12/PR48 Placebo/PR48 40 20 22% 15% 32% 5% 0 Relapsers Partial Responders Null Responders Telaprevir (INCIVEK ) Prescribing Information. Vertex Pharmaceuticals Incorporated, Cambridge, MA. October, 2012.
%SVR RESPOND 2: SVR by Response to Previous Peg-IFN/RBV Therapy 100 80 72% BOC* PR 60 46% 40 20 0 31% 7% 150/208 16/51 53/115 2/29 Prior Relapsers Partial Responders *Response Guided Therapy and 48 Week Arms Combined Boceprevir (VICTRELIS ) Prescribing Information. Merck Sharp & Dohme Corp., Whitehouse Station, NJ, November 2012.
Prior Response Trumps Other Pretreatment Baseline Factors Ethnicity IL28B Genotype Baseline Viral Load Fibrosis Score G1 Subtype
Jackie: On Treatment Labs Hemoglobin (g/dl) Neutrophil Count (cells/mm 3 ) HCV RNA (IU/mL) Baseline 12.1 1300 18,000,000 TW2 11.0 1100 3,300 TW4 9.5 900 Undetectable
ARS #5 How would you manage Jackie s anemia? 1. No change to treatment 2. Add EPO 3. Reduce RBV from 1200 mg to 1000 mg 4. Reduce RBV from 1200 mg to 600 mg 5. Add EPO and reduce RBV (1200 to 600 mg)
Boceprevir: No Difference in SVR Rate in Anemic Patients Undergoing RBV DR vs EPO Use % of Patients 100 90 82 82 RBV DR Arm EPO Arm 80 72 71 70 60 Patients Randomized When Hb <10 g/dl 50 40 30 20 10 10 10 0 203/ 249 205/ 251 178/ 249 178/ 251 19/ 196 EOT Response SVR Relapse Adapted from Poordad F et al. Abstract 1419. Poster presented at the 47th Annual Meeting of the European Association for the Study of the Liver. April 2012, Barcelona, Spain. 19/ 197
SVR (%; 95% CI) SVR Rates Did Not Vary with the Start Time of Anemia Management 100 90 80 70 60 50 40 30 20 10 0 70 38/ 54 RBV DR 71 39/ 55 Poordad F et al, Abstract 154, AASLD 2012 EPO Use 64 58/ 90 68 60/ 88 79 49/ 62 4 Wks >4-8 Wks >8-12 Wks >12-16Wks >16 Wks Timing of the Start of Anemia Management 70 47/ 67 82 18/ 22 88 15/ 17 71 15/ 21 71 17/ 24
SVR, n/n(%) SVR Rates in Treatment Naïve Patients by RBV Dose/Day 90 80 70 60 50 40 30 20 10 0 74% 74% 75% 329/ 446 47% 29/ 62 291/ 395 42% Any Dose reduction Received 600 mg/day Received 800-1000 mg/day 16/ 38 RBV Dose Reductions Never reduced Adapted from Sulkowski MS et al. Abstract 1162. Poster presented at the 47th Annual Meeting of the European Association for the Study of the Liver. April 21, 2012, Barcelona, Spain. 38/ 51 54% 13/ 24 79% 346/ 439 46% 134/ 292 T12PR PR
Jackie: On Treatment Labs Hemoglobin (g/dl) Neutrophil Count (cells/mm 3 ) HCV RNA (IU/mL) Action Baseline 12.1 1300 18,000,000 TW2 11.0 1100 3,300 TW4 9.5 900 Undetectable Decreased RBV (1200 to 600 mg/day) TW6 10.0 850 Undetectable TW8 10.4 900 Undetectable TW12 10.9 900 Undetectable TW16 11.5 1050 Undetectable Increased RBV (600 to 800 mg/day) Increased RBV (800 to 1000 mg/day)
Jackie: Non-hematologic Adverse Events How do you manage? Constitutional symptoms (fatigue, arthralgia) Mouth sores Rash Anorectal burning Depression
LB-2: Daclatasvir (NS5A) + Sofosbuvir (GS-7977, nuc) in GT1a/1b Week 24 SVR 4 SVR 12 SVR 24 SVR 48 n = 15 Group A: SOF 400 mg QD x 7d, then DCV 60 mg QD + SOF 400 mg QD Follow-up n = 14 n = 15 Group C: DCV 60 mg QD + SOF 400 mg QD Group E: DCV 60 mg QD + SOF 400 mg QD + RBV Follow-up Follow-up n = 41 n = 41 Group G: DCV 60 mg QD + SOF 400 mg QD Group H: DCV 60 mg QD + SOF 400 mg QD + RBV Week 12 SVR 4 Follow-Up Follow-Up SVR 48 *12-week groups (G and H) were enrolled after 24-week groups (A, C, and E) RBV: 1000-1200 mg/d, weight-based (GT1) Sulkowski MS et al, Abstract LB-2, AASLD 2012
HCV RNA < LLOQ (% patients) Virologic Response is Maintained at PT Week 24 (GT1a/1b; 24-Week Treatment Groups) 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 93 80 60 40 A: SOF LI + DCV C: DCV + SOF E: DCV + SOF + RBV 20 0 n = 87 93 73 15 14 15 20 100 100 100 100 100 100 100 100 100 93 100 100 15 14 15 15 14 15 15 14 15 15 14 15 % of patients with HCV RNA <LLOQ-TND Week 4 EOT SVR 4 SVR 12 SVR 24 Group A: 1 patient with detectable HCV RNA at PT Week 24: HCV RNA cleared 4 weeks later, sequence not consistent with relapse Sulkowski MS et al, Abstract LB-2, AASLD 2012
Virologic Response During and After Treatment 12 Week Treatment Groups HCV RNA < LLOQ (% patients) 100 80 95 100 100 100 98 95 60 40 20 0 n = 76 78 100 100 98 95 41 41 41 41 41 41 Week 4 EOT SVR 4 G: DCV + SOF (12-wk) H: DCV + SOF + RBV (12-wk) % of patients with HCV RNA <LLOQ-TND Group G: 1 patient with missing HCV RNA at PT Week 4 patient achieved SVR 12 Group H: 1 patient with missing HCV RNA at PT Week 4 patient achieved SVR 12 ; 1 patient with HCV RNA < LLOQ-TND at PT week 2 and HCV RNA = 54 IU/mL at PT week 4 (not confirmed) patient achieved SVR 12 Sulkowski MS et al, Abstract LB-2, AASLD 2012
LB-3: Daclatasvir (NS5A), Asunaprevir (PI), and BMS-791325 (non-nuc) 32 treatment naïve, G1 patients w/o cirrhosis ASV 200 mg BID, DCV 60 mg QD, BMS-791325 75 mg BID (part 2 with 150 mg BID) Patients randomized to 24 vs 12 weeks Majority of patients G1a and non-cc Most common AEs: headache, diarrhea, asthenia Everson G et al, Abstract LB-3, AASLD 2012
SVR(%) Daclatasvir, Asunaprevir, and BMS-791325 (non-nuc) 100 94%* 94%** 80 60 40 20 0 15/16 15/16 Week 12 (24 week group) SVR4 (12 wk group) Everson G et al, Abstract LB-3, AASLD 2012 * One d/c ed early with HCV RNA<LLOQ **One lost to follow up
Abstract LB-1: ABT-450/r, ABT-267, ABT-333 +/- RBV in HCV Genotype 1 Treatment Naïve Patients Randomized to treatment for 8, 12, or 24 weeks with: ABT-450/r (Protease inhibitor + ritonavir boost) combined with ABT- 267(NS5A inhibitor) +/- ABT-333 (Non-nuc polymerase inhibitor) +/- Ribavirin Patient characteristics: Non-cirrhotic Genotype 1a = 66% IL28B non-cc= >90% N=438 naïve N=133 prior null responders Kowdley KV et al, Abstract LB-1, AASLD 2012
% SVR % SVR LB-1: SVR12 Results 100 80 60 40 20 0 97.5% 77/ 79 87.3% 69/ 79 Treatment Naive 96% 52/ 54 83% 43/ 52 Overall G1a G1b 100% 96% 100 93.3% 90 25/ 25 24/ 25 +RBV -RBV 80 70 60 50 40 30 20 10 0 Null Responders +RBV 42/ 45 89% 25/ 28 100% 17/ 17 Overall G1a G1b +RBV Abbott Press Release, Nov. 10, 2012, Kowdley KV et al, Abstract LB-1, AASLD 2012
Abstract 232: Final Results of SOUND-C2 and Predictors of Response Five arm study that evaluated different doses and durations in regimens with faldaprevir (PI) and BI207127 (non-nuc) with or without RBV Durations: 16, 28 or 40 weeks BID vs TID Randomization was stratified by genotype (1a vs 1b) and IL28B 9% of patients had cirrhosis SVR12 ranged between 52% to 69% in RBV-containing arms and 39% without RBV SVR in cirrhotics is 54% IL28B CC, genotype 1b and female gender were favorably associated with SVR12 Zeuzem S et al, Abstract 232, AASLD 2012; Soriano V et al, Abstract 84, AASLD 2012
Abstract 229: Once Daily Sofosbuvir (GS-7977) Plus RBV in Patients with HCV G1, 2, and 3: The ELECTRON Trial Evaluate sofosbuvir +RBV as single agent treatment for HCV Small phase IIb exploratory study Non-cirrhotic patients Well-tolerated regimen Prior Null GT 1 Naive GT 1 Experienced GT 2/3 Naive GT 2/3 Naive GT 2/3 Sofosbuvir +RBV Sofosbuvir + RBV Sofosbuvir +RBV Sofosbuvir + RBV Sofosbuvir + RBV (800mg/d) SVR12 1/10 (10%) 21/25 (84%) 17/25 (68%) 16/25 (64%) 6/10 (60%) SVR8 Gilead Press Release, Nov. 10, 2012 0 8 12 Weeks
Press Conference Q&A
Conclusions More patients will be screened, diagnosed and referred into HCV specialty practices as a result of new recommendations Many of these patients are good candidates for treatment today Treatment outcomes with current treatments can be optimized with appropriate management/interventions The HCV pipeline is promising with potential new treatment modalities in the near future
We thank Vertex Pharmaceuticals for the educational grant to support this activity Supported by: Accredited by: Presented for attendees of the 63rd AASLD Annual Meeting (or The Liver Meeting ). This event/function is sponsored by Chronic Liver Disease Foundation and supported by Vertex Pharmaceuticals. This is not an official function/event of the American Association for the Study of Liver Diseases. Sponsored by: