Simply Speaking Hepatitis February 7 2014

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Simply Speaking Hepatitis February 7 2014

  1. 1. New and Emerging Strategies to Simplify the Cure of Chronic Hepatitis C Infection Sponsored for CME credit by Rush University Medical Center Supported by an independent educational grant from Gilead Sciences Medical Affairs
  2. 2. 2 New Sign-In ProcessNew Sign-In Process We Are Eliminating Hard Copy Evaluations!• Please clearly print all information on the sign-in sheet • You must indicate your NAME, DEGREE, MAILINGNAME, DEGREE, MAILING ADDRESS, EMAIL and SIGNATUREADDRESS, EMAIL and SIGNATURE (NAPB # pharmacists only) in order to attend this lecture • Completion is required for all healthcare providers • Failure to provide complete information will result in removal from attending future lectures
  3. 3. 3 CME Disclosure and Slide HandoutsCME Disclosure and Slide Handouts We Are Eliminating Hard Copy Evaluations!● CME DisclosureCME Disclosure - These slides may not be videotaped, published, posted online, and/or presented for Continuing Medical Education credit without written permission from Rush University Medical Center and Practice Point Communications ● Disclosure InformationDisclosure Information - It is the policy of the Rush University Office of Interprofessional Continuing Education to ensure that its CME activities are independent, free of commercial bias and beyond the control of persons or organizations with an economic interest in influencing the content of CME - Everyone who is in a position to control the content of an educational activity must disclose all relevant financial relationships with any commercial interest (including but not limited to pharmaceutical companies, biomedical device manufacturers, or other corporations whose products or services are related to the subject matter of the presentation topic) within the preceding 12 months - If there are relationships that create a conflict of interest, these must be resolved by the CME Course Director in consultation with the Office of Interprofessional Continuing Education prior to the participation of the faculty member in the development or presentation of course content ● Slide HandoutsSlide Handouts - The enclosed slide handouts are provided for reference purposes only - The faculty presenter may have customized the slides through reordering or deleting and thus the handouts may not exactly match the presentation
  4. 4. 4 EducatorEducator We Are Eliminating Hard Copy Evaluations! ● Disclosures - Grants/Research Support: list here - Consultant: list here - Speakers’ Bureau: list here - Stock Shareholder: list here - Other Financial or Material Support: list here Educator Title, Degree Affiliation City, State EDUCATOR TO COMPLETE
  5. 5. 5 Accreditation and DesignationAccreditation and Designation Supported by an independent educational grant from Gilead Sciences Medical Affairs. Rush University (OH-390, 8/25/2014) is an approved provider of continuing education by the Ohio Nurses Association (OBN-001-91), an accredited approver by the American Nurses Credentialing Center’s Commission on Accreditation. Rush University designates this live activity for one (1) Continuing Nursing Education credit. Rush University Medical Center is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians. Rush University Medical Center designates this live activity for a maximum of 1 AMA PRA Category 1 Credit™. Physicians should claim only credit commensurate with the extent of their participation in the activity. The University of Florida College of Pharmacy is accredited by the Accreditation Council for Pharmacy Education as a provider of continuing pharmacy education (UAN #0012-9999-13-013-L01-P). This activity is accredited for 1 hour of continuing pharmacy education (CPE) credit. The University of Florida College of Pharmacy will report all credit to CPE Monitor within 30 working days after receiving evidence of successful completion of the course. Successful completion means that you must attend the entire program and complete an evaluation form.
  6. 6. 6 FacultyFaculty CME Course DirectorCME Course Director Harold A. Kessler, MD rofessor of Medicine and Immunology/Microbiology Associate Director, Section of Infectious Diseases Rush University Medical Center Chicago, Illinois Content Development and TrainingContent Development and Training Mark S. Sulkowski, MD Professor of Medicine Medical Director, Viral Hepatitis Center Johns Hopkins Medical Institution Baltimore, Maryland Program ChairProgram Chair S. Martin Cohen, MD Medical Director, Hepatology Professor of Medicine University Hospitals/Case Medical Center Cleveland, Ohio CME ReviewerCME Reviewer David M. Simon, MD, PhD Associate Professor of Medicine Section of Infectious Diseases Rush University Medical Center Chicago, Illinois
  7. 7. 7 Faculty DisclosuresFaculty Disclosures CME Course Director: Harold A. Kessler, MD Program Chair: S. Martin Cohen, MD Content Development and Training: Mark S. Sulkowski, MD Grants/research support None None Anadys, BIPI, Genentech, Gilead Sciences, Merck, Tibotec, Vertex Consultant None Bristol-Myers Squibb, Gilead Sciences, Vertex AbbVie, Anadys, BIPI, Genentech, Gilead Sciences, Merck, Tibotec, Vertex Speakers’ bureau None Bristol-Myers Squibb, Genentech, Gilead Sciences, Vertex None Stock shareholder AbbVie, GlaxoSmithKline, Merck None None Other financial or material support None None None
  8. 8. 8 Faculty DisclosuresFaculty Disclosures CME Reviewer: David M. Simon, MD, PhD Medical Editor: Peter Pinkowish Grants/research support None None Consultant None None Speakers’ bureau None None Stock shareholder None None Other financial or material support None None
  9. 9. 9 Opinions and Off-Label DiscussionsOpinions and Off-Label Discussions The opinions or views expressed in this educational program are those of the participants and do not necessarily reflect the opinions or recommendations of Gilead Sciences Medical Affairs, Rush University Medical Center, Rush University College of Nursing, or the University of Florida College of Pharmacy The faculty may have included discussion on unlabeled uses of a commercial product or an investigational use of a product not yet approved for this purpose Please consult the full prescribing information before usingPlease consult the full prescribing information before using any medication mentioned in this programany medication mentioned in this program
  10. 10. 10 New Electronic Evaluation ProcessNew Electronic Evaluation Process We Are Eliminating Hard Copy Evaluations!• You will receive an electronic evaluation to the email address provided within 1 business day • Reminder email communications will be sent up to 5 days post lecture until the evaluation is completed • Completion Is Required for CME/CNE/CPE credit and future attendance • Incomplete evaluations will preclude attendees from receiving their CME/CNE/CPE certificate & future communications about lectures in your area
  11. 11. 11 Learning ObjectivesLearning Objectives (CME/CNE and CPE)(CME/CNE and CPE) We Are Eliminating Hard Copy Evaluations! ● Upon completion of this activity, the participant intends to incorporate the following objectives into their practice of medicine: - Assess my hepatitis C (HCV)-infected patients on their chances of achieving a successful outcome after failing to respond to either PI-based therapy of a peginterferon-based initial regimen - Appropriately select specifically targeted antiviral HCV therapies agents for my HCV-infected patients who are not responding to current standard of care, as they become available - Appropriately select targeted antiviral HCV therapies agents for my HCV- infected patients who are not candidates for initial therapy with PI- based therapy of peginterferon + ribavirin, as they become available CME/CNECME/CNE ● Upon completion of this activity, the pharmacist should be able to: - Assess my hepatitis C (HCV)-infected patients on their chances of achieving a successful outcome after failing to respond to either PI-based therapy of a peginterferon-based initial regimen - Review and discuss specifically targeted antiviral HCV therapies agents for my HCV-infected patients who are not responding to current standard of care, as they become available - Review and discuss targeted antiviral HCV therapies agents for my HCV- infected patients who are not candidates for initial therapy with PI- based therapy of peginterferon + ribavirin, as they become available CPECPE
  12. 12. 12 Chronic HCV Therapy (Genotype 1): Advances in Raising Cure Rates SVR(%) 16% 44% ~70% 35%1991 1998 2001 2011 IFN IFN/RBV PegIFN/RBV Telaprevir or Boceprevir + PegIFN/RBV >90% >2013 2nd Generation DAAs PegIFN-Free Regimens Schaefer EA, et al. Gastroenterology. 2012;142:1340-1350. Ghany MG, et al. Hepatology. 2009;49:1335-1374. Ghany MG, et al. Hepatology. 2011;54:1433-1444.
  13. 13. 13 SVR Rates in Treatment-Naïve, Genotype 1 HCV: Telaprevir and Boceprevir Patients(%) T12/PR (n=363) 75%* 69%* 44% T8/PR (n=364) PR48 (n=361) Patients(%) 68%* 67%* 40% LI/B24/PR (n=350) LI/B44/PR (n=354) PR48 (n=344) ADVANCE (Telaprevir + PR) SPRINT-2 (LI-PR, Boceprevir + PR) *P<0.001 versus PR48. Jacobson IM, et al. N Engl J Med. 2011;364:2405-2416. Poordad F, et al. N Engl J Med. 2011;364:1195-1206. *P<0.0001 versus PR48. T:telaprevir 750 mg tid; B:boceprevir 800 mg tid; PR: pegIFN + RBV.
  14. 14. 14 Toxicities Impacting Completion of Telaprevir and Boceprevir Based Therapy Patients(%) Discontinuations 10% 7% 36% Hemoglobin (g/dL) ADVANCE (Telaprevir + PR) SPRINT-2 (LI-PR, Boceprevir + PR) Jacobson IM, et al. N Engl J Med. 2011;364:2405-2416. Poordad F, et al. N Engl J Med. 2011;364:1195-1206. Telaprevir 12/PR (n=363) PR48 (n=361) LI:lead-in; PR: pegIFN + RBV. AEs Rash <10 <8.5 Patients(%) Discontinuations Hemoglobin (g/dL) AEs Rash <10 <8.5 Pooled boceprevir (n=804) PR48 (n=344) 7% 1% 14% 9% 2% 12% N/A 16% 29% 6% 3% 49%
  15. 15. 15 Variation in SVR Rates: Previously Treated, HCV Genotype 1 Patients (REALIZE Study) Zeuzem S, et al. N Engl J Med. 2011;364:2417-2428. Patients(%) Prior Relapsers 32% 86% 85% F2-3 (n=62/15) F0-1 (n=167/38) F4 (n=57/15) T:telaprevir 750 mg q8h; PR: pegIFN + RBV. METAVIR: F0-1 (no, minimal, or portal fibrosis); F2-3 (bridging fibrosis); F4 (cirrhosis). Patients(%) Prior Partial Responders Null Responders 13% 13% 84% Pooled T12/PR PR48 Pooled T12/PR PR48 Pooled T12/PR PR48 72% 56% 34% 18% 0% 20% F2-3 (n=18/5) F0-1 (n=47/17) F4 (n=32/5) F2-3 (n=38/9) F0-1 (n=59/18) F4 (n=50/10) 41% 39% 14% 6% 0% 10% Patients(%)
  16. 16. 16 Treatment of Chronic HCV: Recent Successes ● Telaprevir or boceprevir + PR - Offer patients an improved chance of cure and the opportunity for a shorter duration of therapy - SVR rates • Treatment-naïve patients: 68%-75% • Prior relapsers, partial responders: 59%-88% • Null responders: 40%-41% ● Potential for yet another quantum leap in the field - Recent proof of concept studies demonstrating the capacity to eradicate HCV without interferon - PegIFN-free regimens for genotypes 1-6 Fox AN, et al. Clin Infect Dis. 2012;55(suppl 1):S16-S24. Lawitz E, et al. J Hepatol. 2013;58(suppl 1):S567. Abstract 1411. Lawitz E, et al. N Engl J Med. 2013;368:1878-1887. Updated Slide
  17. 17. 17 Telaprevir or Boceprevir + PR: Shortcomings of the Current Standard of Care ● Only effective in HCV genotype 1 patients ● Require PR therapy ● Thrice-daily dosing ● Cirrhotics not eligible for response-guided therapy ● Side effects - Both agents: hemoglobin decline (1.0-1.5 g/dL >PR) - Telaprevir: rash, anorectal discomfort - Boceprevir: dysgeusia, neutropenia ● Low barrier to resistance, emergence of resistant variants - >50% who fail to achieve an SVR have detectable variants (wane in frequency over time off-therapy) - Stopping rules designed to minimize resistance ● Potential for drug-drug interactions - CYP3A4 inhibition Fox AN, et al. Clin Infect Dis. 2012;55(suppl 1):S16-S24. Updated Slide
  18. 18. 18 Chronic HCV Infection: Targets for Direct-Acting Antiviral Agents ● Prevent viral entry - Polyclonal and monoclonal antibodies ● Prevent translation of viral RNA - NS3/4 protease inhibitors ● Inhibit HCV-RNA polymerase - Nucleoside analogue NS5B polymerase inhibitors - Non-nucleoside analogue NS5B polymerase inhibitors - Replication complex inhibitor - Cyclophilin B inhibitors ● Viral assembly/release - Glucosidase inhibitor Pereira AA, et al. Nat Rev Gastroenterol Hepatol. 2009;6:403-411.
  19. 19. 19 Selected Characteristics of Direct-Acting Antiviral Agents for Chronic HCV Infection Protease Inhibitors Nucleos(t)ide Polymerase Inhibitors Non-Nucleoside Polymerase Inhibitors NS5A Inhibitors Potency High (varies by HCV genotype) Moderate-to-high (consistent across HCV genotypes, subtype) Variable (HCV genotypes) High (multiple HCV genotypes) Barrier to resistance Low (1a<1b) High (1a=1b) Very low (1a<1b) Low (1a<1b) Potential for drug interactions High Low Variable Low-to- moderate Toxicity Rash, anemia, ↑ Bilirubin Mitochondrial, NRTI interactions (ART, RBV) Variable Variable Dosing qd to tid qd to bid qd to tid qd Comments 2nd generation PIs (higher barrier to resistance, pan-genotype) Single target Active site Allosteric Many targets Multiple antiviral MOA Schaefer EA, et al. Gastroenterology. 2012;142:1340-1350.
  20. 20. 20 Combination Therapy: Potential for Preventing the Emergence of Resistant Variants Variant NS3 Linear NS3 Macrocytic NS5A Inhibitor NS5B Nuc NS5B Palm NS5B Thumb NS5B Finger IFN RBV NS3 PI V36M R S S S S S S S S T54A R S S S S S S S S R155K R R S S S S S S S A156T R R S S S S S S S D168V S R S S S S S S S NS5A L28V S S R S S S S S S Y93H S S R S S S S S S NS5B S282T S S S R S S S S S C316Y S S S S R S S S S M414T S S S S R S S S S R422K S S S S S R S S S M423T S S S S S R S S S P495S S S S S S S R S S HCV DrAG ResisSS. 2012;1.2. Available at http://www.hivforum.org. S: susceptible and R: resistant based on arbitrary <4 and >4 fold shift in HCV replicon EC50, respectively.
  21. 21. 21 Program Overview ● DAA + pegIFN + ribavirin ● Multiple DAAs + pegIFN + ribavirin ● Interferon-free regimens
  22. 22. 22 DAA + PegIFN + Ribavirin in Late Stage Clinical Development NS3/4A Protease Inhibitors Nucleotide NS5B Polymerase Inhibitors Non- Nucleoside NS5B Polymerase Inhibitors NS5A Replication Complex Inhibitors PegIFN RBV Sofosbuvir (genotypes 1-6) PegIFN RBV Daclatasvir (genotypes 1-3) PegIFN RBV Danoprevir* PegIFN RBV Simeprevir* PegIFN RBV Faldaprevir* PegIFN RBV *Genotype 1. Updated Slide
  23. 23. 23 ATOMIC Trial: Sofosbuvir + PR HCV RNA >50,000 IU/mL, no cirrhosis. BMI: >18 kg/m2 . Non-CC IL28B: 72.4%; genotype 1a: 71.4%. Week 0 12 24 48 PR: pegIFN + RBV (weight-based dosing: 1000 or 1200 mg). Follow-Up Sofosbuvir (400 mg) + PR Stratified by IL28B (CC versus non-CC) and by HCV RNA (<800K and >800K IU/mL). Kowdley KV, et al. Lancet. 2013;Mar 14. [Epub ahead of print]. G1 (n=52) G1,4,6 (n=125) GT 1 (n=155) Sofosbuvir (400 mg) + PegIFN + RBV Sofosbuvir (400 mg) + PR Sofosbuvir (n=75) Sofosbuvir + RBV (n=75) Follow-Up Follow-Up Phase 2b Treatment-naïve Updated Slide
  24. 24. 24 ATOMIC Trial: Treatment Outcomes ● SVR12 and SVR24 - Similar among sofosbuvir regimens (12 and 24 weeks) - Genotype 4 (n=11) • SVR12/SVR24: 82%/82% - Genotype 6 (n=5) • SVR12/SVR24: 100%/100% ● Sequence data from 4 patients who relapsed showed no S282T mutation (population sequencing) - Deep sequencing for all patients with relapse is ongoing SVR12 and SVR24 (ITT) Patients(%) 90%89% 93% 12 Sofosbuvir + PR (weeks) SVR12 SVR24 91% 24 12 + 12 89% 87% PR: pegIFN + RBV (weight-based dosing: 1000 or 1200 mg). Kowdley KV, et al. Lancet. 2013;Mar 14. [Epub ahead of print]. Updated Slide
  25. 25. 25 ATOMIC Trial: Relapse and Safety and Tolerability ● Relapse: 3% - No S282T mutation detected (phenotypic data generated in 10/11 relapse patients) - No change in susceptibility to sofosbuvir ● Safety and tolerability - Well tolerated up to 24 weeks, with no serious adverse events • Discontinuation due to adverse events: <5% ● Most common adverse events - Consistent with those associated with PR • Constitutional symptoms, influenza-like symptoms, rash, anemia Updated Slide Kowdley KV, et al. Lancet. 2013;Mar 14. [Epub ahead of print].
  26. 26. 26 NEUTRINO Study: Sofosbuvir + PR in Treatment-Naïve, HCV Genotype 1, 4, 5, and 6 Lawitz E, et al. J Hepatol. 2013;58(suppl 1):S567. Abstract 1411. Lawitz E, et al. N Engl J Med. 2013;368:1878-1887. Phase 3 Open-label Treatment-Naïve Genotype 1, 4, 5, and 6 Week 0 12 24 36 Sofosbuvir (nucleotide NS5B polymerase Inhibitor). No upper limit to age or BMI. Opioid substitution permitted. Platelets >90,000/mm3 , neutrophils >1500/mm3 or 1000/mm3 (blacks). Cirrhosis permitted (17% enrolled). Primary efficacy endpoint: SVR12. Prespecified comparison to historical SVR control rate of 60%. Follow-UpSofosbuvir 400 mg qd + PR (n=327) New Slide
  27. 27. 27 NEUTRINO Study: SVR12 Rates by Prespecified Subgroups Lawitz E, et al. J Hepatol. 2013;58(suppl 1):S567. Abstract 1411. Lawitz E, et al. N Engl J Med. 2013;368:1878-1887. Patients(%) 82% 90%* 96% 92% Overall (n=327) 100% 96% 89% 92% 80% 98% 1a (n=255) 1b (n=66) <6 (n=71) >6 (n=256) No (n=273) Yes (n=54) Genotype Baseline HCV RNA (log) Cirrhosis CC (n=98) Non-CC (n=232) IL28B 87% 4 (n=28) 5/6 (n=7) *P<0.001 versus historical SVR rate of 60%. Sofosbuvir 400 mg qd + PR (12 weeks) New Slide
  28. 28. 28 NEUTRINO Study: Resistance and Safety ● No resistance detected in sofosbuvir + PR virologic failures and 1 relapse patient who discontinued therapy (HCV RNA >1000 IU/mL) ● Safety of sofosbuvir + PR - Well tolerated and no additive effects of the addition of sofosbuvir to PR • Discontinuations due to adverse events: 2% - Most common adverse events • Fatigue (59%), headache (36%), nausea (34%), insomnia (25%), anemia (21%), rash (18%) - Safety profile consistent with ribavirin • Hemoglobin <10 g/dL: 23% • Hemoglobin <8.5 g/dL: 2% Lawitz E, et al. J Hepatol. 2013;58(suppl 1):S567. Abstract 1411. Lawitz E, et al. N Engl J Med. 2013;368:1878-1887. New Slide
  29. 29. 29 COMMAND-1 Study: Daclatasvir + PR PR: pegIFN + RBV. All daclatasvir patients not achieving a protocol-defined response at week 12 (HCV RNA <LLOQ at week 4 and undetectable [<10 IU/mL] at week 10) received PR for 24 weeks. HCV RNA: 6.5 log10 IU/mL. Compensated cirrhosis: 7.3%. BMI: >18 kg/m2 . Non-CC IL28B: 69%; genotype 1a: 70%; genotype 4: 8%. Week 0 12 24 48 Follow-UpDaclatasvir (20 mg) + PR (n=159) PR (n=78) Daclatasvir 60 mg + PR (n=158) Daclatasvir + PR Follow-Up Phase 2b Treatment-naïve Genotype 1 or 4 Hezode C, et al. Hepatology. 2012;56(suppl 4):553A. Abstract 755. PR Daclatasvir + PR PR PR (n=78)
  30. 30. 30 COMMAND-1 Study (ITT): SVR12 Rates (All PDR) Patients(%) Genotype 67%65% 36% 100% Genotype 1 (n=147/146/72) 64% 50% DCV 20 mg + PR DCV 60 mg + PR PR Genotype 4 (n=12/12/6) Hezode C, et al. Hepatology. 2012;56(suppl 4):553A. Abstract 755. Patients(%) Genotype 1 Subgroup 78% 59% 38% 87% Genotype 1a (n=106/113/56) 58% 31% DCV 20 mg + PR DCV 60 mg + PR PR Genotype 1b (n=41/31/16) PDR: week-12 protocol-defined response (HCV RNA <LLOQ at week 4 and undetectable [<10 IU/mL] at week 10) received PR for 24 weeks). PR: pegIFN + RBV.
  31. 31. 31 COMMAND-1 Study: SVR12 Rates by IL28B (All PDR) Patients(%) Genotype 1a 51% 85% 45% 31% CC (n=41/36/18) 61% 36% CT (n=51/61/26) Hezode C, et al. Hepatology. 2012;56(suppl 4):553A. Abstract 755. Patients(%) Genotype 1b DCV 20 mg + PR PR DCV 60 mg + PR PDR: week-12 protocol-defined response (HCV RNA <LLOQ at week 4 and undetectable [<10 IU/mL] at week 10) received PR for 24 weeks). PR: pegIFN + RBV. TT (n=11/14/9) 78% 22% CC (n=11/7/4) CT (n=24/20/10) TT (n=6/4/2) 71% 40% 85% 67% 0% 75% 100% 25% DCV 20 mg + PR PR DCV 60 mg + PR
  32. 32. 32 COMMAND-1 Study: Treatment Failure and Safety and Tolerability ● Treatment failure - Overall (daclatasvir versus PR): 35% versus 64% • Treatment failure rates were lower in daclatasvir-treated patients who achieved PDR (11%-24%) ● Safety and tolerability - Similar adverse event profile between the daclatasvir + PR and PR treatment arms • Discontinuation due to adverse events: <5% - Changes in laboratory parameters were consistent across all treatment arms ● Future clinical trials will be with genotype 1b patients only Hezode C, et al. Hepatology. 2012;56(suppl 4):553A. Abstract 755. PR: pegIFN + RBV. PDR: week-12 protocol-defined response.
  33. 33. 33 COMMAND-2 Study: Daclatasvir + PR PR: pegIFN + RBV. All daclatasvir patients not achieving a protocol-defined response at week 12 (HCV RNA <LLOQ at week 4 and undetectable [<10 IU/mL] at week 10) received PR for 24 weeks. HCV RNA: 6.5 log10 IU/mL. Compensated cirrhosis: 7.3%. BMI: >18 kg/m2 . Non-CC IL28B: 69%; genotype 1a: 70%; genotype 4: 8%. Week 0 12 16 24 48 Follow-Up Daclatasvir 60 mg qd + PR (n=50) Daclatasvir 60 mg qd + PR (n=50) Follow-Up Follow-Up Phase 2b Treatment-naïve Genotype 2, 3 Dore GJ, et al. J Hepatol. 2013;58(suppl 1):S570-S571. Abstract 1418. PR Daclatasvir + PR PR PR (n=51) Follow-Up Follow-Up (36 weeks) New Slide
  34. 34. 34 COMMAND-2 Study (ITT): SVR24 Rates (ITT) Patients(%) Genotype 69% 83% 63% 67% Genotype 2 (n=24/23/24) 83% 59% DCV + PR (12 weeks) DCV + PR (16 weeks) PR Genotype 3 (n=26/27/27) Patients(%) IL28B Genotypes 50% 80% 85% 75% CC 83% 64% Dore GJ, et al. J Hepatol. 2013;58(suppl 1):S570-S571. Abstract 1418. 100% Non-CC Genotype 2 CC Non-CC Genotype 3 75% 56% 81% 64% 56% DCV + PR (12 weeks) DCV + PR (16 weeks) PR New Slide
  35. 35. 35 COMMAND-2 Study: Treatment Failure and Safety in Genotype 2/3 ● Treatment failure (daclatasvir versus PR) - Genotype 2: 5% versus 5% - Genotype 3: 25% verus 14% • With versus without baseline NS5A Y93 and/or A30 polymorphisms (50% versus 19%) • Cirrhotics versus non-cirrhotics (36% versus 21%) • No apparent effect of IL28B genotype or baseline HCV RNA on relapse ● Safety and tolerability - Similar adverse event profile across all arms • Discontinuation due to adverse events (daclatasvir versus PR): 7% versus 4%) - Changes in laboratory parameters were consistent across all treatment arms ● Further evaluation of daclatasvir + PR in HCV genotype 2/3 patients is planned PR: pegIFN + RBV. New Slide Dore GJ, et al. J Hepatol. 2013;58(suppl 1):S570-S571. Abstract 1418.
  36. 36. 36 DAUPHINE Study: Danoprevir/r + PR *RGT (response-guided therapy): week 12 all drugs stopped if eRVR [HCV RNA <15 IU/L achieved during weeks 2-10, if not then continue to week 24. PR: pegIFN + RBV. HCV RNA: >50,000 IU/Ml; fibrosis score: F0-F2; non-CC IL28B: 70%; genotype 1a: 60%; genotype 4: 8%. Week 0 12 24 48 Follow-UpDanoprevir/r 200/100 mg + PR (n=94) PR (n=46) Follow-Up Phase 2b Treatment-naïve Genotype 1 or 4 Danoprevir/r 100/100 mg + PR (n=94)* Follow-Up Danoprevir + PR Danoprevir/r 100/100 mg + PR (n=93) Danoprevir/r 50/100 mg + PR (n=94) Follow-Up eRVR: Follow-Up Everson GT, et al. Hepatology. 2012;56(suppl 4):552A. Abstract 754.
  37. 37. 37 DAUPHINE Study: SVR24 Rates ● Dose-dependent increases in SVR24 - Highest SRV24 rates achieved in the danoprevir/r 200/100 mg treatment arm ● Dose-response relationship seen in a harder-to-treat subgroup (genotype 1a, IL28B non-CC) - 200/100 mg: 88% - 100/100 mg: 70% - 50/100 mg: 58% ● Genotype 1b/IL28B CC and genotype 4 patients - All achieved SVR24 in <12 weeks Everson GT, et al. Hepatology. 2012;56(suppl 4):552A. Abstract 754. SVR24 (ITT) Patients(%) 1a (n=56/56/58/49) 4 (n=8/8/7/7) 1b (n=29/29/26/37) 84% 60% 70% 97% 93% 100% 88% 73% 100% 200/100 mg 50/100 mg 100/100 mg 100/100 mg RGT Genotype RGT: response-guided therapy. Danoprevir/r was administered with PR (pegIFN + RBV). 59% 78%
  38. 38. 38 DAUPHINE Study: Treatment Failure and Safety and Tolerability ● Treatment failure: 17.5% - Relapse: 11% • Predominately genotype 1a and non-CC IL28G genotype - Resistance uniquely associated with the NS3 R155K substitution ● Safety and tolerability - Similar adverse event profile between the danoprevir/r + PR and PR treatment arms • Discontinuation of danoprevir/r due to adverse events: 5% - Laboratory abnormalities were not dose related - Anemia (hemoglobin <8.9 g/dL or any decrease >4.5 g/dL): 7% Le Pogam, et al. Hepatology. 2012;56(suppl 4):571A-572A. Abstract 782. Everson GT, et al. Hepatology. 2012;56(suppl 4):552A. Abstract 754.
  39. 39. 39 QUEST-1 and -2 Trials: Simeprevir + PR in Treatment-Naïve, HCV Genotype 1 Jacobson I, et al. J Hepatol. 2013;58(suppl 1):S574. Abstract 1425. Manns M, et al. J Hepatol. 2013;58(suppl 1):S568. Abstract 1413. Week 0 12 24 48 72 Simeprevir (NS3/4A protease inhibitor). HCV RNA >10,000 IU/mL. PR: pegIFN (alpha 2a or 2b) + RBV (weight-based dosing: 1000-1200 mg). Patients stratified by HCV subtype and IL28B genotype. Response-guided therapy criteria: HCV RNA <25 IU/mL at week 4 and undetectable at week 12. METAVIR score: F0-F1 (~50%); >F2 (~50%). Primary efficacy endpoint: SVR12. Simeprevir 150 mg qd + PR Follow-Up Follow-Up Phase 3 Treatment-naïve Genotype 1 PR PR PR (n=134) Follow-Up New Slide
  40. 40. 40 QUEST-1 and -2 Trials: Overall SVR12 Rates by Genotype 1 Subgroup Patients(%) 49% 80%* 71%* 90%* 50% Overall (n=264/130) 52% Simeprevir + PR PR 1a (n=147/74) 1b (n=117/56) Genotype *P<0.01 versus PR. New Slide Jacobson I, et al. J Hepatol. 2013;58(suppl 1):S574. Abstract 1425. Manns M, et al. J Hepatol. 2013;58(suppl 1):S568. Abstract 1413. QUEST 1 Patients(%) 46% 81%* 80%* 82%* 50% Overall (n=257/134) 53% Simeprevir + PR PR 1a (n=107/57) 1b (n=150/77) Genotype QUEST 2 *P<0.01 versus PR.
  41. 41. 41 QUEST-1 and -2 Trials: SVR12 Rates by Prespecified Subgroups Patients(%) 42% 94%* 76%* 65%* 78% 24% Simeprevir + PR PR 83%* 60% CC (n=77/37) CT (n=150/76) TT (n=37/17) F0-F2 (n=183/90) IL28B Genotype METAVIR Score F3 (n=46/23) F4 (n=37/17) 58%* 29% 78%* 26% *P<0.01 versus PR. New Slide Patients(%) 41% 96%* 80%* 58%* 81% 19% Simeprevir + PR PR 85%* 51% CC (n=75/42) CT (n=142/71) TT (n=40/21) F0-F2 (n=195/102) IL28B Genotype METAVIR Score F3 (n=37/17) F4 (n=17/15) 65%* 40% 67%* 53% *P<0.01 versus PR. QUEST 1 QUEST 2 Jacobson I, et al. J Hepatol. 2013;58(suppl 1):S574. Abstract 1425. Manns M, et al. J Hepatol. 2013;58(suppl 1):S568. Abstract 1413.
  42. 42. 42 QUEST-1 and -2 Trials: Resistance and Safety ● NS3 PI mutations were detected in the time of failure for the majority (>90%) of simeprevir-treated patients not achieving an SVR - Genotype 1: mainly R155 alone - Genotype 1b: mainly D168V or Q80R + D168E ● Simeprevir + PR was well tolerated - Simeprevir treatment discontinuations due to adverse events • QUEST-1: 3% • QUEST-2: 1.6% ● Adverse event profile of simeprevir + PR was similar to the PR arm - Headache, pyrexia, fatigue, influenza-like illness, rash, anemia, pruritus New Slide Jacobson I, et al. J Hepatol. 2013;58(suppl 1):S574. Abstract 1425. Manns M, et al. J Hepatol. 2013;58(suppl 1):S568. Abstract 1413.
  43. 43. 43 ASPIRE Study: Simeprevir + PR Week 0 12 24 48 72 SMV 100 mg 12/PR (n=66) HCV RNA >10,000 IU/mL. PR: pegIFN + RBV (weight-based dosing: 1000-1200 mg). Follow-Up Phase 2b Previously failed Genotype 1 PR SMV (150 mg qd) + PR Follow-Up PRSMV 150 mg 12/PR (n=66) SMV 100 mg 24/PR (n=65) SMV (100 mg qd) + PR Follow-Up PR SMV (150 mg qd) + PR Follow-Up PRSMV 150 mg 24/PR (n=66) Follow-Up SMV (100 mg qd) + PR PR SMV (100 mg qd) + PR SMV (150 mg qd) + PR Follow-Up Follow-Up Zeuzem S, et al. J Hepatol. 2012;54(suppl 2):S1. Abstract 2. PR48 (n=66) SMV 100 mg 48/PR (n=66) SMV 150 mg 48/PR (n=65)
  44. 44. 44 ASPIRE Trial: SVR24 Rates With Simeprevir + PR Patients(%) Prior Relapsers 85% 85% 100 mg (n=79) 150 mg (n=79) PR48 (n=27) *Duration pooled. PR: pegIFN + RBV (weight-based dosing: 1000-1200 mg). Patients(%) Prior Partial Responders Null Responders 37% 75% 57% 9% 51% 46% 19% Patients(%) Zeuzem S, et al. J Hepatol. 2012;54(suppl 2):S1. Abstract 2. Simeprevir + PR48 100 mg (n=68) 150 mg (n=69) PR48 (n=23) Simeprevir + PR48 100 mg (n=68) 150 mg (n=69) PR48 (n=23) Simeprevir + PR48
  45. 45. 45 ASPIRE Trial: Resistance and Safety and Tolerability ● Viral breakthrough/relapse was usually associated with emerging mutations to simeprevir - Q80K at baseline did not alter SVR24 rates in the simeprevir 150 mg treatment arms ● Safety and tolerability - Well tolerated, treatment discontinuations due to adverse events: 7%) - Hematologic abnormalities were similar across all treatment arms - Mild and reversible increases in bilirubin were seen in the simeprevir arms • No other liver changes Lenz O, et al. J Hepatol. 2012;54(suppl 2):S5. Abstract 9. Zeuzem S, et al. J Hepatol. 2012;54(suppl 2):S1. Abstract 2.
  46. 46. 46 STARTVerso1 Trial: Faldaprevir + PR in Treatment-Naïve, Genotype 1 Ferenci P, et al. J Hepatol. 2013;58(suppl 1):S569-S570. Abstract 1416. Week 0 12 24 48 72 ETS, Follow-Up Follow-Up Faldaprevir 120 mg qd + PR (n=261) PR Faldaprevir 240 mg qd + PR (n=262) PR ETS, Follow-Up PR Follow-Up Faldaprevir (NS3/4A protease inhibitor). Platelets >90,000 cells/mm3 . No HBV or HIV coinfection. Fibrosis stage >F3: 17% ETS: early treatment success (HCV RNA <25 IU/mL at week 4 and undetectable at week 8. Primary efficacy endpoint: SVR12 Phase 3 Treatment-Naïve Genotype 1 PR Follow-Up PRFaldaprevir + PR No ETS No ETS New Slide
  47. 47. 47 STARTVerso1 Trial: SVR12 Rates by Prespecified Subgroups Ferenci P, et al. J Hepatol. 2013;58(suppl 1):S569-S570. Abstract 1416. Patients(%) 36% 69% 84%83% 76% Overall (n=259/261/132) 60% 70% 90% 63% 69% 95% 51% Faldaprevir 120 mg qd + PR Faldaprevir 240 mg qd + PR PR 76% 1a (n=87/90/45) 1b (171/171/86) CC (n=75/42) CT (n=142/71) TT (n=40/21) Genotype IL28B Genotype ETS Patients (n=225/232) 86% 89% 79% 28% *P<0.0001 versus PR. 79%*80%* 52% New Slide
  48. 48. 48 STARTVerso1 Trial: Resistance and Safety ● No significant effect of Q80K on SVR12 in genotype 1a patients ● Faldaprevir + PR was well tolerated - Discontinuations due to adverse events: 4% ● Adverse event profile of faldaprevir + PR was similar to the PR arm - Most common adverse events of at least moderate severity • Rash (8%), anemia (12%) ● Total bilirubin elevations >2.6 x ULN with faldaprevir + PR were benign and transient - 120 mg qd: 12% - 240 mg qd: 53% Ferenci P, et al. J Hepatol. 2013;58(suppl 1):S569-S570. Abstract 1416. The Q80K mutation is associated with a decreased susceptibility to some NS3/4A protease inhibitors. New Slide
  49. 49. 49 SILEN-C2 Study: Faldaprevir + PR (Non-Responders) Sulkowski MS, et al. J Hepatol. 2011;54(suppl 1):S30. Abstract 66. Week 0 24 48 72 LI/240 mg qd/PR (n=142) 240 mg qd/PR (n=76) eRVR, Follow-Up Follow-Up LI/120 mg qd/PR (n=70) Faldaprevir 240 mg qd + PR LI* PR Faldaprevir 240 mg qd + PR PR Follow-Up Faldaprevir 120 mg qd + PR LI* PR Follow-Up *LI: 3-day lead-in with PR. Relapsers excluded. HCV RNA >100,000 IU/mL, no cirrhosis. PR: pegIFN + RBV (weight-based ribavirin: 1000-1200 mg). Phase 2b Non-responders Genotype 1
  50. 50. 50 SILEN-C2 Study: SVR and Overall Relapse With Faldaprevir Patients(%) LI/240 mg qd/PR (n=142) Sustained Virologic Response 27% 41% 31% Relapse: rebound from undetectable at end of all treatment. 240 mg qd/PR (n=76) LI/240 mg bid/PR (n=70) Patients(%) Overall Relapse 25% 9% 19% LI/240 mg qd/PR (n=142) 240 mg qd/PR (n=76) LI/240 mg bid/PR (n=70) Sulkowski MS, et al. J Hepatol. 2011;54(suppl 1):S30. Abstract 66.
  51. 51. 51 SILEN-C2 Study: Virologic Failure, Discontinuations, and Adverse Events LI/240 mg qd/PR (n=142) 240 mg qd/PR (n=76) LI/240 mg bid/PR (n=70) Virologic failure (%) During faldaprevir During PR phase 25 5 28 7 17 6 Discontinuation (%) Adverse events 6 4 23 Adverse events (%) Rash Jaundice Nausea Diarrhea Vomiting 34 19 48 32 17 28 21 53 32 22 42 41 64 39 32 Sulkowski MS, et al. J Hepatol. 2011;54(suppl 1):S30. Abstract 66.
  52. 52. 52 Program Overview ● DAA + pegIFN + ribavirin ● Multiple DAAs + pegIFN + ribavirin ● Interferon-free regimens
  53. 53. 53 Multiple DAA + PegIFN + Ribavirin in Late Stage Clinical Development NS3/4A Protease Inhibitors Nucleotide NS5B Polymerase Inhibitors Non- Nucleoside NS5B Polymerase Inhibitors NS5A Replication Complex Inhibitors PegIFN RBV Danoprevir Mericitabine PegIFN RBV Asunaprevir Daclatasvir PegIFN RBV
  54. 54. 54 Phase 2a Genotype 1 Prior Partial Responders Prior Null Responders MATTERHORN Study: Danoprevir/r + Mericitabine + PR Week 0 24 48 72 Danoprevir/r + Mericitabine + PR (n=50) Danoprevir/r + PR (n=49) QUAD Danoprevir/r + Mericitabine + RBV (n=52) IFN Free Feld JJ, et al. Hepatology. 2012;56(suppl 4):231A-232A. Abstract 81. Triple Danoprevir/r + Mericitabine + PR (n=77) Danoprevir/r + PR (n=77) Danoprevir/r + Mericitabine + RBV (n=74) QUADPR HCV RNA >50,000 IU/mL. Absence of cirrhosis. Mericitabine dosed bid. PR: pegIFN + RBV (weight-based dosing: 1000-1200 mg). QUAD IFN Free
  55. 55. 55 MATTERHORN Study: Treatment Outcomes ● QUAD regimen produced the highest overall SVR12 rates - Genotype 1b patients (91% to 100%) - Genotype 1a • Adding mericitabine increased SVR12 from 30% to 75% ● Virologic breakthrough was associated with resistance to danoprevir (R155K, D168E/T) ● QUAD, triple, and IFN-free regimens were safe and well tolerated - Addition of mericitabine did not change the safety profile of danoprevir/r + pegIFN + RBV Patients(%) SVR12 84%86% 39% N/A Prior Partial Responders (n=50/48/23) 56% 55% QUAD IFN free Triple Prior Null Responders (n=74/31) Feld JJ, et al. Hepatology. 2012;56(suppl 4):231A-232A. Abstract 81.
  56. 56. 56 Study 011 (Expansion Cohort): Daclatasvir + Asunaprevir + PR Week 0 24 36 48 Dual-1 (n=18) Daclatasvir 60 mg qd + Asunaprevir 200 mg bid (Genotype 1b only) Follow-Up Lok AS, et al. Hepatology. 2012;56(suppl 4):230A. Abstract 79. SVR12 Primary Endpoint Dual-2 (n=20) QUAD-1 (n=20) QUAD-2 (n=21) Triple (n=22) Phase 2a Genotype 1 Prior null responders Daclatasvir 60 mg qd + Asunaprevir 200 mg qd (Genotype 1b only) Daclatasvir 60 mg qd + Asunaprevir 200 mg bid + PR (Genotype 1a/1b) Daclatasvir 60 mg qd + Asunaprevir 200 mg qd + PR (Genotype 1a/1b) Daclatasvir 60 mg qd + Asunaprevir 200 mg bid + RBV (Genotype 1a/1b) Follow-Up Follow-Up Follow-Up Follow-Up Non-cirrhotic PR: pegIFN + RBV (weight-based dosing: 1000-1200 mg).
  57. 57. 57 Study 011: Treatment Outcomes ● SVR12 rates higher in the QUAD arm compared with the dual arm ● Virologic breakthrough - IFN-free arm: 56% ● QUAD, triple, and IFN-free regimens were well tolerated - Discontinuations due to adverse events: 0% ● Most common adverse events - Headache, diarrhea, fatigue, and insomnia SVR12 Rate Patients(%) Dual-1 (n=78) Dual-2 (n=65) 78% 97% 90% 65% QUAD-1 (n=20) QUAD-2 (n=21) Lok AS, et al. Hepatology. 2012;56(suppl 4):230A. Abstract 79.
  58. 58. 58 Program Overview ● DAA + pegIFN + ribavirin ● Multiple DAAs + pegIFN + ribavirin ● Interferon-free regimens
  59. 59. 59 Interferon-Free Regimens in Late Stage Clinical Development NS3/4A Protease Inhibitors Nucleotide NS5B Polymerase Inhibitors Non-Nucleoside NS5B Polymerase Inhibitors NS5A Replication Complex Inhibitors PegIFN RBV Sofosbuvir Sofosbuvir RBV Sofosbuvir Daclatasvir Sofosbuvir Daclatasvir RBV Faldaprevir BI 207127 Faldaprevir BI 207127 RBV Faldaprevir PegIFN RBV ABT-450/r ABT-333 ABT-267 RBV ABT-450/r ABT-333 RBV ABT-450/r ABT-267 RBV ABT-450/r ABT-333 ABT-267
  60. 60. 60 FISSION Trial: Sofosbuvir + RBV in Treatment-Naïve, HCV Genotype 2 or 3 Gane E, et al. J Hepatol. 2013;58(suppl 1):S3. Abstract 5. Lawitz E, et al. N Engl J Med. 2013;368:1878-1887. Phase 3 Open-label Treatment-Naïve Genotype 2 or 3 Week 0 12 24 36 Sofosbuvir (nucleotide NS5B polymerase inhibitor). No upper limit to age or BMI. Opioid substitution permitted. Platelet >75,000/mm3 (cirrhotic: 20% maximum). Stratified by genotype, HCV RNA, and cirrhosis. Primary efficacy endpoint: SVR12 (non-inferiority margin: 15%). Follow-UpSofosbuvir 400 mg qd + RBV 1000-1200 mg/day (n=256) PegIFN + RBV (800 mg/day) (n=243) Follow-Up New Slide
  61. 61. 61 FISSION Trial: SVR12 Rates by Prespecified Subgroups Gane E, et al. J Hepatol. 2013;58(suppl 1):S3. Abstract 5. Lawitz E, et al. N Engl J Med. 2013;368:1878-1887. Patients(%) 78% 67% 97% 56% 67% Overall* (n=253/243) 63% 66% 75% 62% 72% 67% 74% Sofosbuvir + RBV PR 47% 38% 2 (n=70/67) 3 (n=183/176) <6 (n=107/106) >6 (n=146/137) No (n=204/193) Yes (n=49/50) Genotype Baseline HCV RNA (log) Cirrhosis Male (n=168/156) Female (n=85/87) Gender 79%76% 61% 62% *Non-inferiority criteria met. New Slide
  62. 62. 62 FISSION Trial: SVR12 Rates by Genotype and Cirrhosis Gane E, et al. J Hepatol. 2013;58(suppl 1):S3. Abstract 5. Lawitz E, et al. N Engl J Med. 2013;368:1878-1887. Patients(%) Genotype 2 98% 91% 82% 62% No Cirrhosis (n=59/54) Cirrhosis (n=11/13) Patients(%) Genotype 3 61% 71% 34% 30% No Cirrhosis (n=145/139) Cirrhosis (n=38/37) Sofosbuvir + RBV PR Sofosbuvir + RBV PR New Slide
  63. 63. 63 FISSION Trial: Resistance and Safety ● No resistance detected in sofosbuvir + RBV virologic failures - Relapse accounted for all but 1 virologic failure (nonadherence) ● Safety of sofosbuvir + RBV - Well tolerated and few adverse events - Most common adverse events • Fatigue (36%), headache (25%), nausea (18%), insomnia (12%) - Safety profile consistent with ribavirin Gane E, et al. J Hepatol. 2013;58(suppl 1):S3. Abstract 5. Lawitz E, et al. N Engl J Med. 2013;368:1878-1887. New Slide
  64. 64. 64 FUSION Trial: Sofosbuvir + RBV for 12 Versus 16 Weeks in HCV Genotype 2/3, Previously Failed PR Therapy Nelson DR, et al. J Hepatol. 2013;58(suppl 1):S3-S4. Abstract 6. Jacobson IM, et al. N Engl J Med. 2013;368:1867-1877. Phase 3 Double-blind Failed Prior PegIFN-Based Therapy Genotype 2 or 3 Sofosbuvir (nucleotide NS5B polymerase inhibitor). No upper limit to age or BMI. Opioid substitution permitted. Platelet >50,000/mm3 , no neutrophil minimum. Cirrhosis at baseline (34%). Prior relapsers (76%). Stratified by genotype and cirrhosis. Primary efficacy endpoint: SVR12. Follow-UpSofosbuvir 400 mg qd + RBV 1000-1200 mg/day (n=103) Week 0 12 16 24 Placebo Sofosbuvir 400 mg qd + RBV 1000-1200 mg/day (n=98) Follow-Up New Slide
  65. 65. 65 FUSION Trial: SVR12 Rates by Prespecified Subgroups Nelson DR, et al. J Hepatol. 2013;58(suppl 1):S3-S4. Abstract 6. Jacobson IM, et al. N Engl J Med. 2013;368:1867-1877. Patients(%) 94% 50% 86% 30% 73%* Overall (n=100/95) 62%* 77% 50% 50% 61%62% 76% Sofosbuvir + RBV 12 weeks 16 weeks 31% 66% 2 (n=36/32) 3 (n=64/63) <6 (n=26/29) >6 (n=74/66) No (n=64/63) Yes (n=36/32) Genotype Baseline HCV RNA (log) Cirrhosis Male (n=71/64) Female (n=29/31) Gender 69% 87% 42% 66% *P<0.001 versus 12 weeks of active therapy. New Slide
  66. 66. 66 FUSION Trial: SVR12 Rates by Genotype and Cirrhosis Nelson DR, et al. J Hepatol. 2013;58(suppl 1):S3-S4. Abstract 6. Jacobson IM, et al. N Engl J Med. 2013;368:1867-1877. Patients(%) Genotype 2 96% 60% 100% 78% No Cirrhosis (n=26/23) Cirrhosis (n=10/9) Patients(%) Genotype 3 37% 63% 19% 61% No Cirrhosis (n=38/40) Cirrhosis (n=26/23) Sofosbuvir + RBV 12 weeks 16 weeks Sofosbuvir + RBV 12 weeks 16 weeks New Slide
  67. 67. 67 FUSION Trial: Resistance and Safety ● No resistance detected in sofosbuvir + RBV virologic failures ● Safety of sofosbuvir + RBV - Well tolerated and few adverse events • No discontinuations due to adverse events - Most common adverse events • Fatigue (46%), headache (27%), nausea (21%), insomnia (24%) - Safety profile consistent with ribavirin • Hemoglobin <10 g/dL: 7.5% • Hemoglobin <8.5 g/dL: 1% Nelson DR, et al. J Hepatol. 2013;58(suppl 1):S3-S4. Abstract 6. Jacobson IM, et al. N Engl J Med. 2013;368:1867-1877. New Slide
  68. 68. 68 POSITRON Trial: Sofosbuvir + RBV in HCV Genotype 2 or 3 With Limited Options Jacobson IM, et al. J Hepatol. 2013;58(suppl 1):S28. Abstract 61. Jacobson IM, et al. N Engl J Med. 2013;368:1867-1877. Phase 3 Double-blind, placebo-controlled Interferon-Ineligible, Intolerant, or unwilling Genotype 2 or 3 Sofosbuvir (nucleotide NS5B polymerase inhibitor). No upper limit to age or BMI. Opioid substitution permitted. No lower limit to platelet or neutrophil count. Cirrhosis at baseline (16%). Prior relapsers (76%). Stratified by presence or absence of cirrhosis. Primary efficacy endpoint: SVR12. Follow-UpSofosbuvir 400 mg qd + RBV 1000-1200 mg/day (n=207) Week 0 12 24 Placebo (n=71) Follow-Up New Slide
  69. 69. 69 POSITRON Trial: SVR12 Rates With Sofosbuvir + RBV by Prespecified Subgroups Patients(%) 93% 78% Overall (n=207) 61% 79%76% 81% 61% 2 (n=109) 3 (n=98) <6 (n=67) >6 (n=140) No (n=176) Yes (n=31) Genotype Baseline HCV RNA (log) Cirrhosis Male (n=117) Female (n=90) Gender 84% 73% SVR12 rate was 0% in the placebo arm. Jacobson IM, et al. J Hepatol. 2013;58(suppl 1):S28. Abstract 61. Jacobson IM, et al. N Engl J Med. 2013;368:1867-1877. New Slide
  70. 70. 70 POSITRON Trial: SVR12 Rates With Sofosbuvir + RBV by Genotype and Cirrhosis Patients(%) Genotype 2 92% 94% No Cirrhosis (n=92) Cirrhosis (n=17) Patients(%) Genotype 3 68% 21% No Cirrhosis (n=84) Cirrhosis (n=14) SVR12 rate was 0% in the placebo arm. Jacobson IM, et al. J Hepatol. 2013;58(suppl 1):S28. Abstract 61. Jacobson IM, et al. N Engl J Med. 2013;368:1867-1877. New Slide
  71. 71. 71 POSITRON Trial: Resistance and Safety ● No resistance detected in sofosbuvir + RBV virologic failures ● Safety of sofosbuvir + RBV - Well tolerated and few adverse events • Treatment discontinuations due to adverse events: 2% - Most common adverse events • Fatigue (44%), headache (21%), nausea (22%), insomnia (19%) - Safety profile consistent with ribavirin • Hemoglobin <10 g/dL: 7% • Hemoglobin <8.5 g/dL: 1% Jacobson IM, et al. J Hepatol. 2013;58(suppl 1):S28. Abstract 61. Jacobson IM, et al. N Engl J Med. 2013;368:1867-1877. New Slide
  72. 72. 72 ELECTRON Study: Sofosbuvir + Ribavirin Week 0 4 8 12 24 Follow-Up Treatment-Naïve Genotype 2, 3 (n=10) Sofosbuvir (nucleotide NS5B polymerase Inhibitor). PR: pegIFN + RBV. HCV RNA >50,000 IU/mL. No cirrhosis. Weight-based ribavirin dosing (800-1200 mg). Sofosbuvir 400 mg qd + PR Follow-Up Sofosbuvir 400 mg qd + RBV Null Responders Genotype 1 (n=10) Sofosbuvir 400 mg qd + RBV Follow-Up Treatment-Naïve Genotype 1 (n=25) Sofosbuvir 400 mg qd + RBV Follow-Up Treatment-Experienced Genotype 2, 3 (n=25) Gane EJ, et al. N Engl J Med. 2013;368:34-44. Phase 2b
  73. 73. 73 ELECTRON Study: SVR Rates in HCV Genotype 2/3 and 1 Patients(%) Genotype 2/3 SVR12 SVR24 100% 68% 100% NR PR: pegIFN + RBV; NR: not reported. Treatment-Naïve Sofosbuvir + PR 8 weeks (n=10) Treatment-Experienced Sofosbuvir + RBV 12 weeks (n=25) Patients(%) Genotype 1 SVR12 SVR24 84% 10% NR NR Null Responders Sofosbuvir + RBV 12 weeks (n=10) Treatment-Naïve Sofosbuvir + RBV 12 weeks (n=25) Gane EJ, et al. N Engl J Med. 2013;368:34-44.
  74. 74. 74 ELECTRON Study: Sofosbuvir + RBV + Either Ledipasvir (NS5A Inhibitor) or GS-9669 (NS5B Non-Nucleoside Inhibitor) Week 0 4 8 12 24 Follow-Up Treatment-Naïve (n=25) Sofosbuvir (nucleotide NS5B polymerase Inhibitor). No cirrhosis. Weight-based ribavirin dosing (1000-1200 mg). Sofosbuvir 400 mg qd + RBV Sofosbuvir 400 mg qd + RBV Null Responders (n=10) Sofosbuvir 400 mg qd + Ledipasvir + RBV Follow-Up Treatment-Naïve (n=25) Sofosbuvir 400 mg qd + Ledipasvir + RBV Follow-Up Null Responders (n=9) Gane EJ, et al. J Hepatol. 2013;58(suppl 1):S6-S7. Abstract 14. Phase 2b Genotype 1 Follow-Up Sofosbuvir 400 mg qd + GS-9669 + RBV Follow-Up Treatment-Naïve (n=25) Sofosbuvir 400 mg qd + GS-9669 + RBV Follow-Up Null Responders (n=9) New Slide
  75. 75. 75 ELECTRON Study (Genotype 1 Cohort): Interim Analysis of SVR12 Rates Gane EJ, et al. J Hepatol. 2013;58(suppl 1):S6-S7. Abstract 14. Patients(%) Treatment-Naive 84% 92% Sofosbuvir + RBV (n=25) Null Responders 100% Sofosbuvir + Ledipasvir + RBV (n=25) Sofosbuvir + GS-9669 + RBV (n=25) Patients(%) 10% 100% Sofosbuvir + RBV (n=10) 100% Sofosbuvir + Ledipasvir + RBV (n=9) Sofosbuvir + GS-9669 + RBV (n=3) New Slide
  76. 76. 76 ELECTRON Study (Genotype 1 Cohort): Safety ● Adding ledipasvir to sofosbuvir + RBV - No additional safety or tolerability issues ● Adding GS-9669 to sofosbuvir + RBV - No additional safety or tolerability issues ● Fix-dose combination of sofosbuvir/ledipasvir - Undergoing phase 3 trial in patients with and without cirrhosis - Additional studies exploring shorter duration of therapy Gane EJ, et al. J Hepatol. 2013;58(suppl 1):S6-S7. Abstract 14. New Slide
  77. 77. 77 Phase 2a Treatment-naïve Genotype 2/3 Genotype 1 Study 040: Sofosbuvir + Daclatasvir + Ribavirin Week 0 12 24 48 Sofosbuvir 400 mg qd + Daclatasvir 60 mg qd (n=16) Sulkowski MS, et al. Hepatology. 2012;56:1516A-1517A. Abstract LB-2. Sofosbuvir 400 mg qd + Daclatasvir 60 mg qd (n=14) Follow-Up Sofosbuvir 400 mg qd + Daclatasvir 60 mg qd + RBV (n=14) *LI: 7-day lead-in with sofosbuvir 400 mg qd. HCV RNA >50K IU/mL, no cirrhosis. Primary outcome: SVR12. LI* Follow-Up Sofosbuvir 400 mg qd + Daclatasvir 60 mg qd (n=15) Sofosbuvir 400 mg qd + Daclatasvir 60 mg qd (n=14) Follow-Up Sofosbuvir 400 mg qd + Daclatasvir 60 mg qd + RBV (n=15) LI* Follow-Up Sofosbuvir 400 mg qd + Daclatasvir 60 mg qd (n=14) Follow-Up Sofosbuvir 400 mg qd + Daclatasvir 60 mg qd + RBV (n=15) Follow-Up
  78. 78. 78 Study 040 (24-Week Treatment): SVR12 and SVR24 Rates Patients(%) Genotype 2/3 SVR12 SVR24 88% 86% 93% 93% LI/SOF/ DCV (n=16) Sulkowski MS, et al. Hepatology. 2012;56:1516A-1517A. Abstract LB-2. 100% SOF/DCV (n=14) SOF/DCV + RBV (n=14) LI: 7-day lead-in with sofosbuvir 400 mg qd. Patients(%) Genotype 1 SVR12 SVR24 100% 93% 100% LI/SOF/ DCV (n=15) 100% SOF/DCV (n=14) SOF/DCV + RBV (n=15)
  79. 79. 79 Study 040 (24-Week Treatment): Safety and Tolerability ● Sofosbuvir + daclatasvir + RBV was well tolerated - Discontinuations due to adverse events: 3% ● Most common adverse events - Fatigue (36%) - Headache (27%) - Nausea (26%) ● No grade 3/4 elevations in ALT, AST, or total bilirubin ● Anemia (hemoglobin <9 g/dL): 7% • All in the RBV-containing arms Sulkowski MS, et al. Hepatology. 2012;56:1516A-1517A. Abstract LB-2.
  80. 80. 80 Study 040 (12-Week Treatment): SVR4 Rate and Safety Sulkowski MS, et al. Hepatology. 2012;56:1516A-1517A. Abstract LB-2. Patients(%) Genotype 1: SVR4 98% 95% SOF/DCV (n=41) SOF/DCV + RBV (n=41) ● No virologic failure reported ● SVR12 evaluable for 68 of 82 patients: 100% ● Safety - No discontinuations due to adverse events - Hemoglobin <9 g/dL • Without ribavirin: 0% • With ribavirin: 12%
  81. 81. 81 Phase 2a Prior Nonresponse, Relapse, or Breakthrough with Telaprevir or Boceprevir With PR Genotype 1 Study 040: Sofosbuvir + Daclatasvir + RBV in Previous Telaprevir or Boceprevir Failures Week 0 12 24 48 Sofosbuvir 400 mg qd + Daclatasvir 60 mg qd (n=21) Sofosbuvir 400 mg qd + Daclatasvir 60 mg qd + RBV (n=20) Follow-Up Follow-Up Sulkowski MS, et al. J Hepatol. 2013;58(suppl 1):S570. Abstract 1417. Sofosbuvir (nucleotide NS5B polymerase inhibitor). Daclatasvir (NS5A replication complex inhibitor). HCV RNA >105 IU/mL. No upper limit to age or BMI. METAVIR score: F0-F1 (12%), >F2 (88%). NS3 polymorphisms conferring resistance to boceprevir or telaprevir as baseline: 46% NS5A polymorphisms conferring resistance to daclatasvir: 7% Excluded: patients who discontinued telaprevir or boceprevir due to an adverse event. Primary efficacy endpoint: SVR12. New Slide
  82. 82. 82 Study 040 (24-Week Treatment): SVR4 and SVR12 Rates ● No virologic failures ● Neither baseline NS3 PI resistance nor use of RBV influenced response ● Sofosbuvir + daclatasvir + RBV was well tolerated - No discontinuations due to adverse events ● Most common adverse events (without RBV) - Fatigue (29%), headache (33%), arthralgia (14%) ● No grade 3/4 elevations in ALT, AST, or total bilirubin ● Anemia (hemoglobin <9 g/dL): 0% Sulkowski MS, et al. J Hepatol. 2013;58(suppl 1):S570. Abstract 1417. Patients(%) Genotype 1 SVR4 SVR12 100% 100% 95%* Sofosbuvir + Daclatasvir (n=21) 100% Sofosbuvir + Daclatasvir + RBV (n=20) *1 patient missing at post-treatment 12 weeks, HCV RNA undetectable at post-treatment week 24 (preliminary). New Slide
  83. 83. 83 Study 014: Asunaprevir + Daclatasvir + BMS-791325 ● Phase 2a, open-label study in treatment-naïve, HCV genotype 1 patients (n=32) - Non-cirrhotic - HCV RNA 6.3 log10 IU/mL - Genotype 1b (75%) - IL28B CC genotype: 28% ● Asunaprevir + daclatasvir + BMS- 791325 75 mg - 24 or 12 weeks of therapy ● Primary outcome: SVR12 - Interim analysis • SVR4: 24 and 12-week arms • SVR12: 12-week arm only) 24-Week Treatment (n=16) 12-Week Treatment (n=16) SVR4 (%) Overall Genotype 1a 94 92 94 100 SVR12 (%) N/A 94 Safety (%) Discontinuations due to adverse events Grade 3/4 laboratory abnormalities Headache Diarrhea Asthenia 0 0 25 13 13 0 6 38 38 19 Interim Outcomes Everson GT, et al. Hepatology. 2012;56:1517A-1518A. Abstract LB-3.
  84. 84. 84 SOUND-C2 Study: Faldaprevir + BI 207127 + Ribavirin Week 0 16 28 40 TID16W (n=81) Follow-Up TID28W No RBV (n=46) TID28W (n=80) Follow-Up Faldaprevir + BI 207127 TID + RBV Follow-UpTID40W (n=77) BID28W (n=78) Zeuzem S, et al. Hepatology. 2012;54(suppl 4):308A-309A. Abstract 232. Faldaprevir + BI 207127 TID + RBV Faldaprevir + BI 207127 BID + RBV Follow-Up Follow-Up Faldaprevir + BI 207127 TID HCV RNA >100K IU/mL, cirrhotic patients permitted. Faldaprevir (NS3/4A inhibitor), BI 207127 (non-nucleoside NS5B inhibitor). Phase 2b Treatment-naïve Genotype 1 Faldaprevir + BI 207127 TID + RBV
  85. 85. 85 SOUND-C2 Study: Final SVR12 Results Patients(%) Overall 69% 59% 52% 39% 59% Patients(%) Genotype 1 Subtypes Genotype 1a Genotype 1b TID16W (n=81) TID28W No RBV (n=46) TID28W (n=80) TID40W (n=77) BID28W (n=78) TID16W (n=34/47) TID28W No RBV (n=18/28) TID28W (n=32/48) TID40W (n=34/43) BID28W (n=30/48) Zeuzem S, et al. Hepatology. 2012;54(suppl 4):308A-309A. Abstract 232. 38% 75% 44% 68% 47% 56% 43% 85% 11% 57%
  86. 86. 86 SOUND-C2 Study: SVR12 by Genotype Subtype and METAVIR Score Patients(%) Genotype 1a METAVIR Score F0-F2 F3-F4 TID16W (n=27/7) TID28W No RBV (n=16/2) TID28W (n=26/6) TID40W (n=29/5) BID28W (n=25/5) Zeuzem S, et al. J Hepatol. 2013;58(suppl 1):S498. Abstract 1227. 44% 14% 40% 67% 45% 60% 44% 40% 13% 0% Patients(%) Genotype 1b METAVIR Score F0-F2 F3-F4 TID16W (n=36/10) TID28W No RBV (n=19/9) TID28W (n=33/15) TID40W (n=33/10) BID28W (n=32/16) 78% 70% 64% 80% 52% 70% 91% 75% 63% 44% New Slide
  87. 87. 87 SOUND-C2 Study: Virologic Failure and Baseline Predictors of SVR12 ● Virologic failure (twice daily, 28-week treatment arm) - Genotype 1a versus 1b: 47% versus 8% - Genotype-1a patients had a higher rate of resistance compared with genotype-1b patients ● Baseline predictors of SVR12 (multivariate odds ratio) - Gender (female:male): 3.99 (P<0001) - HCV subtype (1b:1a): 7.11 (P<0.0001) - IL28B genotype (CC:non-CC): 4.94 (P<0.0001) - GGT (normal:>ULN): 2.08 (P=016) Zeuzem S, et al. Hepatology. 2012;54(suppl 4):308A-309A. Abstract 232.
  88. 88. 88 SOUND-C2 Study: Safety and Tolerability ● Twice daily, 28-week treatment arm - Most favorable safety and tolerability profile • Grade 3/4 bilirubin increase: 39% • Grade 3/4 hemoglobin decrease: 2% • No adverse hematologic effects ● The inclusion of ribavirin remains necessary component of treatment ● Future phase 3 studies (genotype 1b only) - Faldaprevir 120 mg bid + BI 207600 600 mg bid + RBV Zeuzem S, et al. Hepatology. 2012;54(suppl 4):308A-309A. Abstract 232.
  89. 89. 89 Phase 2 Treatment-naïve Genotype 1 AVIATOR Study: ABT-450/r-Based Therapy (Treatment-Naïve Cohort) Week 0 8 12 24 ABT-450/r 150/100 mg qd + ABT-267 + ABT-333 + RBV (n=80) Follow-Up ABT-450/r 150/100 mg qd + ABT-333 + RBV (n=41) Follow-Up ABT-450/r 100/100 or 200/100 mg qd + ABT-267 + RBV (n=79) ABT-450 (NS3/4A protease inhibitor); ABT-267 (NS5A replication complex inhibitor); ABT-333 (non-nucleoside NS5B polymerase inhibitor). HCV RNA >50K IU/mL, absence of cirrhosis, no HIV or HBV. ABT-267 25 mg qd; ABT-333 400 mg bid. Ribavirin 1000-1200 mg divided bid. Primary outcome: SVR24. Follow-Up ABT-450/r 150/100 mg qd + ABT-267 + ABT-333 (n=79) Follow-Up ABT-450/r 100/100 or 150/100 mg qd + ABT-267 + ABT-333 + RBV (n=79) Follow-Up ABT-450/r 100/100 or 150/100 mg qd + ABT-267 + ABT-333 + RBV (n=80) Kowdley KV, et al. J Hepatol. 2013;58(suppl 1):S2. Abstract 3. New Slide
  90. 90. 90 AVIATOR Study (ITT): Overall SVR Rates (Treatment-Naïve Cohort) Patients(%) 83% 89% 85% 91%88% ABT-450/r ABT-267 ABT-333 RBV (n=80) 8 Weeks 12 Weeks ABT-450/r -- ABT-333 RBV (n=41) ABT-450/r ABT-267 -- RBV (n=79) ABT-450/r ABT-267 ABT-333 -- (n=79) ABT-450/r ABT-267 ABT-333 RBV (n=79) Kowdley KV, et al. J Hepatol. 2013;58(suppl 1):S2. Abstract 3. 89% 96% 90% 99% 93% 87% 90% ABT-450/r ABT-267 ABT-333 RBV (n=80) 24 Weeks SVR12 SVR24 New Slide
  91. 91. 91 AVIATOR Study: SVR24 by Baseline Subgroups (Treatment-Naïve Cohort) Patients(%) 98% 92% 91% 94% Male (n=78) Kowdley KV, et al. J Hepatol. 2013;58(suppl 1):S2. Abstract 3. 89% 91% 94% 94% 95% 89% ABT-450r + ABT-267 + ABT-333 + RBV (12- and 24-Week Arms Combined) Female (n=81) 1a (n=108) 1b (n=50) >7 (n=35) <7 (n=124) F0-F1 (n=113) F2-F3 (n=42) Non-CC (n=115) CC (n=44) Genotype HCV RNA (log) Fibrosis Stage IL28B Genotype New Slide
  92. 92. 92 Phase 2 Null Responders Genotype 1 AVIATOR Study: ABT-450/r-Based Therapy (Null Responders Cohort) Week 0 8 12 24 Received at least 12 weeks of pegIFN + RBV and failed to achieve >2 log10 IU/mL HCV RNA decrease. HCV RNA >50K IU/mL, absence of cirrhosis, no HIV or HBV. IL28B CC genotype (~3%). ABT-267 25 mg qd; ABT-333 400 mg bid. Ribavirin 1000-1200 mg divided bid. Primary outcome: SVR24. Follow-Up Follow-Up ABT-450/r 100/100 or 150/100 mg qd + ABT-267 + ABT-333 + RBV (n=43) Kowdley KV, et al. J Hepatol. 2013;58(suppl 1):S2. Abstract 3. ABT-450/r 100/100 or 200/100 mg qd + ABT-267 + RBV (n=45) ABT-450/r 100/100 or 150/100 mg qd + ABT-267 + ABT-333 + RBV (n=45) New Slide
  93. 93. 93 AVIATOR Study (ITT): Overall SVR Rates (Null Responders Cohort) Patients(%) 89% 89% 12 Weeks ABT-450/r ABT-267 -- RBV (n=45) ABT-450/r ABT-267 ABT-333 RBV (n=45) Kowdley KV, et al. J Hepatol. 2013;58(suppl 1):S2. Abstract 3. ABT-450/r ABT-267 ABT-333 RBV (n=43) 24 Weeks SVR12 SVR24 93% 93% 98% 95% New Slide
  94. 94. 94 AVIATOR Study: SVR24 by Baseline Subgroups (Null Responders Cohort) Patients(%) 97% 93% 93% 97% Male (n=55) Kowdley KV, et al. J Hepatol. 2013;58(suppl 1):S2. Abstract 3. 91% 93% 96% 95% 94% 100% ABT-450r + ABT-267 + ABT-333 + RBV (12- and 24-Week Arms Combined) Female (n=53) 1a (n=55) 1b (n=33) >7 (n=22) <7 (n=66) F0-F1 (n=41) F2-F3 (n=45) Non-CC (n=85) CC (n=3) Genotype HCV RNA (log) Fibrosis Stage IL28B Genotype New Slide
  95. 95. 95 AVIATOR Study: Virologic Relapse and Safety ● Virologic relapse in prior null responders - 8-, 12-, and 24-week arms: 12.5%, 6.3%, 2.5% ● Discontinuations due to adverse events in the 12- and 24-week arms: 2.4% - Considered related to treatment (n=4/6): hepatitis cholestatic, feeling jittery, homicidal ideation, decreased creatinine clearance ● Most common adverse events - Headache (31%), fatigue (30%), nausea (23%), insomnia (20%), diarrhea (15%) - Bilirubin increase: 2.4% - Anemia (hemoglobin 6.5 to <8 g/dL): 2.4% Kowdley KV, et al. J Hepatol. 2013;58(suppl 1):S2. Abstract 3. New Slide
  96. 96. 96 New and Emerging Strategies: Clinical Considerations ● Recent recommendations from the CDC emphasize the importance to screen and early diagnosis of HCV infection ● Newly diagnosed patients with chronic HCV infection still require comprehensive counseling ● For patients who are candidates for therapy - Initiate treatment with currently available therapy - Defer treatment until availability of new antiviral agents with the potential for increased efficacy, decreased adverse events, and shorter duration of therapy over existing regimens
  97. 97. 97 New and Emerging Strategies: Conclusions ● Results from phase 2 trials for all oral agents are excellent, with well tolerated regimens and high SVR rates ● High SVR rates with interferon-free regimens are possible in a variety of patient populations, including difficult-to-treat patient populations (prior null responders and cirrhotics) - Ribavirin and IL28B status remain important for some regimens ● Non-CC and genotype 1a status remain important for DAA + peginterferon + ribavirin regimens ● Further study is needed for DAAs in special patient populations - Cirrhosis - HIV coinfection - Liver transplant recipients
  98. 98. 98 New Electronic Evaluation ProcessNew Electronic Evaluation Process We Are Eliminating Hard Copy Evaluations!• You will receive an electronic evaluation to the email address provided within 1 business day • Reminder email communications will be sent up to 5 days post lecture until the evaluation is completed • Completion Is Required for CME/CNE/CPE credit and future attendance • Incomplete evaluations will preclude attendees from receiving their CME/CNE/CPE certificate & future communications about lectures in your area
  99. 99. 99 Outcomes Measurement ReminderOutcomes Measurement Reminder • We are required to assess “changes in learners’ competence, performance or patient outcomes achieved as a result of their participation in a CME/CNE/CPE sponsored educational activity” • As a result of this requirement you will receive a short survey via email 8 to 12 weeks after completing this course • We consider the survey to be an additional component of your overall participation in this educational activity and would urge you to reflect on what you learned in the activity and then complete this survey

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