Learning Objectives. HCV Treatment Evolution. Evolution of HCV Therapy 4/7/2014. Hepatitis C: A health problem of global importance!

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1 Therapy New HCV In Frontiers We have no conflict of interest to declare. How the Magic Pill Cured Hep C Spring Therapeutics Update Trana Hussaini, Pharm D Nilu Partovi, Pharm D Google Images; collage by T. Hussaini Learning Objectives Understand Hepatitis C epidemiology and its natural history Review prior standard of care Hepatitis C treatment including their side effects and cure rates Describe the common targets for direct acting antiviral therapy for HCV Discuss all oral direct acting antiviral combinations that will be used in the near future Non-A Non-B HCV Treatment Evolution INF Dr. Alter HCV Virus Identified HCV Testing RBV PEG-INF Boceprevir Telaprevir Simeprevir Sofosbuvir ++DAA Faldaprevir Ledipasvir Daclatasvir Asunaprevir Dr. Houghton & scientists at Chiron & CDC Google Images, collage by T. Hussaini Evolution of HCV Therapy Standard INF 6% 16% RBV 34% Adapted from US Food and Drug Administration by T. Hussaini 39% PEG-INF 55% 1 st PI 70+%?100% New DAA 6-12M 6-12wk Hepatitis C: A health problem of global importance! 160 Million people infected worldwide Most infected years ago before virus identification and screening 350,000 deaths per year 22% of new cases of liver cancer every year are attributed to HCV Lim TR, et al. J Antimicrob Agents (2013) In Press 1

2 20 to 30 Years 4/7/2014 Global Distribution of HCV Genotypes Clin Microbiol Rev April; 13(2): HCV in Canada & British Columbia BCCDC 2012 BCCDC HCV Transmission: Blood to Blood Contact Natural history of HCV Infection Percutaneous Injection drug use Highly efficient mode of transmission Prevalence 50-90% after 5 years Transfusion, transplant from infected donor Prior to 1992 Nosocomial (contaminated equipment, unsafe injection practices, occupational (needle-stick) HIV HBV ETOH Age > 35 NASH Cirrhosis 20% Acute Infection Chronic Resolved 85% 15% Stable 80% Permucosal Perinatal Sexual Adapted from CDC by T. Hussaini HCC, Transplant Death 25% Slowly Progressive 75% 2

3 Metavir Stages of Fibrosis No Fibrosis Mild Fibrosis Moderate Fibrosis Severe Fibrosis Cirrhosis F0 F1 F2 F3 F4 No Fibrosis Fibrous Portal Expansion Few Bridges or Septa Numerous Bridges or Septa Cirrhosis RESPONSE TO HCV THERAPY SURVIVAL OF THE FITTEST... Adapted from Goodman Z et al. J Hepatol 2007;47: Predictors of Response to Therapy Viral Kinetics on Treatment Viral Factors Genotype 2,3 > 1,4 GT 1b > 1a Viral Load > 800,000 IU /ml Host Factors Stage of Fibrosis IL28B polymorphism CC > CT & TT Co-infection Age BMI DM Race Previous response to therapy Limit of detection Rapid virologic response (RVR): undetectable HCV RNA at week 4 Extended RVR (ervr): undetectable HCV RNA at weeks 4 and 12 Early virologic response (EVR): undetectable or 2 log 10 reduction from baseline HCV RNA by week 12. Sustained Virological Response (SVR 24): HCV RNA undetectable 24 weeks after cessation of treatment Adapted from Am J Gastroenterol 2012; 107: Pegylated Interferon & Ribavirin GT 1,4 Ribavirin mg divided BID Interferon SC weekly SVR 24 HCV Therapy THE PAST. THE BAD, THE UGLY 0 24 Weeks Ribavirin 400mg BID GT 2,3 SVR 24 Interferon SC weekly Image by T. Hussaini 3

4 SVR (%) 4/7/2014 Response Rate with PEG/R PEG/R ADRs 38-44% 24-29% 7-15% High Viral Load F3-4 Fibrosis GT 1a African Americans IL28 TT or CT 5% 65-84% Interferon Ribavirin Flu like symptoms Anemia (~34%) Muscle aches, Bacterial Headaches, infections Dizziness Nausea, vomiting, loss of appetite, Fever, Autoimmune chills disease Fatigue flare Itching/dry skin Injection site tenderness Severe depression, psychosis, Respiratory problems: mild Diarrhea, Weight disorientation, loss suicidal shortness ideation of breath, nasal or Insomnia, Depression Cardiac event sinus congestion, cough Personality changes, forgetfulness, Nausea irritability, anxiety, Thyroid emotional abnormalities lability Severe pancytopenia Mild bone marrow suppression decreased platelets, white blood cells Dry, itchy skin, Hair loss Genotype 1 PEG/R Summary Nonspecific Poor cure rates average 40% (20-80%) Depends on multiple factors Genotype, IL28B status, race, viral load, etc. Significant Toxicities Many contraindications Prolonged therapy 48 wks for GT 1 and 24 wks for GT 2,3 The promise of a better therapy... DIRECT ACTING ANTIVIRALS (DAA) 1 ST GENERATION HCV Life Cycle Targets for Direct-Acting Antivirals (DAAs) 1 st Gen Protease Inhibitors Receptor binding and endocytosis Fusion and uncoating Transport and release (+) RNA Virion assembly Translation NS3/4 and polyprotein protease processing inhibitors Membranous web NS5A inhibitors replication and assembly NS5B polymerase RNA inhibitors replication Nucleos(t)ide Non-nucleoside Nat Rev Drug Discov. 2007;6: Class Agents Potency Barrier to Resistance NS3/4 Protease Inhibitors 1 st Gen: Telaprevir Boceprevi Genotypic coverage High Low GT 1 4

5 SVR (%) 4/7/ st Gen NS3/4A Protease Inhibitors Telaprevir & Boceprevir FDA approved in 2011 SOC for GT1 Added to PEG/RBV -> Triple Therapy Improved efficacy Response Guided Therapy Shorten therapy in individuals with favorable viral kinetics Stopping rules Limit ADRs and cost Comparison of BOC & TVR BOC Genotype GT 1 GT 1 Dosage 800mg q8h X wks Take with food TVR 1125mg q12h X 12 wks Take with high fat food T/2 T1/2 = 3.4hrs T1/2 = 9-11h Metabolism Renal dosage adjustment Drug Interactions aldoketoreductase (AKR) CYP 3/4 pathway (major) and CYP3A4/5 (minor) none Strong inhibitor of CYP3A4/5 P-gp substrate and potential inhibitor none Inhibitor of CYP3A, P-gp, OATP1B1 & 1B2 Substrate of P-gp What does the regimen look like? Boceprevir Weekly PEG INF Injections Up to 18 pills per day Triple Therapy SVR TN TE PR PR + BOC PR + BOC PR Week SVR 24 SVR 12 Telaprevir Weekly PEG INF Injections Up to 12 pills per day PR + TVP PR Cirrhotic or non-ervr: continue PR SVR 24 Week SVR 12 TVR NEJM 2011; 364:2405 NEJM 2011; 364;1195 REALIZE study; NEJM 2011; 364:2417 Toxicity of Triple Therapy CUPIC Trial: Safety and efficacy of TVR&BCP in Real Life Experience ADVANCE (TVR) SPRINT-2 (BOC) TVR12/PR PR BOC-RGT PR Discontinuation 10% 7% 12% 16% Rash (D/C) 56% (7%) 34% (1%) - - Anemia (Hgb<100/<85) 36% / 9% 14% / 2% 45% / 5% 26% / 4% Advance Trial, Jacobson I et al, Poordad F et al, NEJM 2011 H. Fontaine et al, Abstract 60. EASL, April 2013 H. Fontaine et al, Abstract 60. EASL, April

6 Drug Interactions - Contraindicated Medication/Class Contraindicated with BOC Alpha blockers Alfluzosin Alfluzosin Anticonvulsants CBZ, Phenobarb, Phenytoin N/A Antimycobacterials Rifampin Rifampin Ergot derivatives Dihydroergotamine, ergonovine, ergotamine GI motilities Cisapride Cisapride Contraindicated with TVR Dihydroergotamine, ergonovine, ergotamine Herbal products St John s Wort St John s Wort HMG CoA reductase Inhibitors Lovastatin, simvastatin Oral contraceptives Drospirenone N/A Neuroleptics Pimozide Pimozide Atorvastatin, lovastatin, Simvastatin PD- 5 Inhibitors pulmonary hypertension pulmonary hypertension Sedatives Triazolam and orally administered midazolam Triazolam and orally administered midazolam Product Monographs 1st Gen PI Summary Genotype 1 only Potential for viral resistance Cannot be given alone combination with P/R Modest improvement in SVR in real life experience In difficult to treat population Significant toxicity compared to PEG/R +++ Drug Interactions +++ Pill burden (compliance) Prolonged treatment course New Gen DAA Class Agents Potency Barrier to Resistance 2 nd Gen NS3/4 Protease Inhibitors Simeprevir Asunaprevir Genotypic coverage High Low Multigenotypic Evolution of DAA.... NEW GENERATION DAA NS5B Nuc- Polymerase Inhibitors NS5B Non-nuc Polymerase Inhibitors NS5A Inhibitors Sofosbuvir Mericitabine Tegobuvir Deleobuvir Daclatasvir Ledipasvir Mod-High High Pangenotypic Low- Moderate Very low Genotype 1 high low Pangenotypic Google Images DAA Combinations in Clinical Trials Simeprevir: 2 nd waive NS3/4A PI Gut 2014; 63(2):207 Now Future Multigenotypic -GT 1, 2, 4, 5 and 6 GT 1a Q80K One capsule, once per day 150mg daily with food X 12wks PK: T1/2 ~ 41 hrs (200mg daily in HCV pts) No dosage adjustment for renal dycfunction Less drug Interactions Substrate of CYP 3A4 and P-gp Inhibits CYP1A2 and intestinal CYP3A4 and P-gp and OATP1B1 6

7 Naïve Relapsers NR SMV 150mg/PEG/R BV SMV 150mg/PEG/R BV PEG/RBV RGT Post-Therapy Follow-Up PEG/RBV Simeprevir Phase III RCTs Post-Therapy Follow-Up Weeks QUEST-1: SVR by Subgroup 80% 81% 79% 50% 50% 37% 54/ 90 11/ 40 36/ 74 29/ 56 29/ 37 32/ 76 4/ 17 Fibrosis Genotype IL28B genotype TN TN TE Jacobson I, et al. EASL Abstract Manns M, et al. EASL Abstract Lawitz E, et al. DDW Abstract 869b. Jacobson et al, Abstract EASL, April 2013 QUEST: No Benefit of SMV if Q80K+ Simeprevir ADRs SIM Placebo Serious AE 3% 4% Bilirubin > 2.5 ULN 4% 2% Rash 28% 20% Pruritis 22% 15% Anemia 16% 11% Antiviral Drug Advisory Committee Meeting Briefing Document Simeprevir Product Monograph Manns M, et al. EASL Abstract Concomitant Drug Simeprevir Drug Interactions Effect on SIM or Co-med Comment Digoxin Digoxin P-gp inhibition; AUC by 39% Anticonvulsants SIM Contraindicated; CYP3A4 induction Clarithromycin & Erythromycin SIM Erythromycin Contraindicated CYP3A4 inhibition +/_ P-gp inhibition Azoles SIM Contraindicated; CYP3A4 inhibition Rifampin SIM Contraindicated; 48% SIM AUC CCB CCB CYP3A4 and P-gp inhibition. Monitor HMG CO-A RI (Stains) Statins Inhibition of OATP1B1 and/or CYP3A4 Use lowest possible dose & monitor Cyclosporine CSA AUC by 19%, monitor Tacrolimus TAC AUC by 17% PDE-5 Inhibitors PDE-5I Use lowest possible dose & monitor Triazolam (oral) Midazolam (oral) BDZ 45% midazolam AUC Use lowest possible dose & monitor Summary of Simeprevir Pros One pill once daily regimen Better tolerated with less rash and anemia vs 1 st Gen PI 85% of patients shorten treatment duration to 6 months Improved SVR Cons Q80K pretreatment testing required in all GT1a patients Drug interactions still an issue Must be combined with PEG/R Product monograph 7

8 Sofosbuvir: The first Nuc NS5B Breakthrough Therapy Designation Pangenotypic High barrier to resistance Favorable PK Once daily dosing, 400mg tablet No effect of food Prodrug: active metabolite GS Minimal Drug interactions (P-gp substrate) Excellent safety profile Renally eliminated Dose modification in pts with mod-severe renal impairment CrCl < 30ml/min Sofosbuvir: NEUTRINO GT1/4/5/6, TN, Open label SOF(400mg/day)+PEG (180 mcg/wk) +RBV ( mg/day)for 12 weeks Week N=327 Sofosbuvir/PEG/RBV, n= / /292 27/28 7/7 Lawitz et al., NEJM 2013, 368: 1878 Sofosbuvir: Difficult to Treat 206/225 54/66 248/273 47/54 252/273 43/54 GT 1, F3-4, IL28B non-cc, RNA > 800,00 SVR = 71% Lawitz et al., NEJM 2013, 368: 1878 Event NEUTRINO Trial ADR SOF + PEG + RBV (n=327) Discontinuation due to adverse event 5 (2%) Fatigue 192 (59%) Headache 118 (36%) Nausea 112 (34%) Rash 59 (18%) Hemoglobin < 10 g/dl 74 (23%) Neutropenia 54 (17%) Influenza-like illness 51 (16%) Depression 31 (9.5%) Insomnia 81 (41%) Rates of adverse events shown in triple therapy did not exceed rates seen in dual therapy (Peg + RBV) arm of FISSION. Lawitz E, et al. N Engl J Med. 2013;368: SOF Drug Interactions Effect of Other Drugs on Sofosbuvir All Oral Regimens INTERFERON FREEDOM Drug Monograph 8

9 COSMOS: SOF+SMV±RBV Phase II, R, Open label in GT1 COSMOS: GT 1 (12wks) Week N =24 N=30 SOF + SMV + RBV 36 Null Naïve SVR4 Null N =15 N=16 SOF + SMV N =27 N=27 SOF + SMV + RBV N =14 N=14 SOF + SMV Cohort 1: N= 80, Prior Null Responders; F0-F2 77% GT1a (50%Q80K), 94% IL28B non-cc, 59% F2 Cohort 2: N=87 Treatment Naïve & Prior Null Responders; F3-F4 78% GT1a (40%Q80K), 79% IL28B non-cc, 47% F4 SMV 150 mg QD + SOF 400 mg QD with/without RBV 1000 or 1200 mg/day (BID) Jacobson IM, et al. AASLD. Nov, Abstract LB-3. 26/27 13/14 12/12 7/7 14/15 7/7 F0-2 F3-4 Jacobson IM, et al. COSMOS, AASLD 2013, #LB3 Cosmos Safety COSMOS in AASLD CPG Most common ADRs: fatigue headache Nausea insomnia. RBV arms: Rash, itching, anemia, bilirubin no patients (12 week arms) discontinued treatment due to ADR LDV/SOF FDC Phase II Trials Shorter Treatment Duration Fixed Dose Combos? no RBV Ledipasvir-Sofosbuvir (90 mg/400 mg) PO once daily for 8-12 weeks for GT1 Study Genotype Regimen ELECTRON +++ arms LONESTAR ION 1, 2, 3 Phase 3 SYNERGY TN & TE GT1 TN & TE GT1 TN & TE GT1 Treatmentnaïve GT1 LDV: Ledipasvir (NS5A) SOF: Sofosbuvir (NS5B) FDC: Fixed Dose Combo LDV/SOF FDC with or without RBV X 6 or 12 weeks LDV/SOF FDC with or without RBV X 8 or 12 weeks LDV/SOF with or without RBV for 12 or 24 weeks LDV/SOF FDC X 12 weeks SOF/LDV with GS-9669 (Non-Nuc NS5B) X 6 weeks SOF/LDV with GS-9451 (PI) X 6 weeks 9

10 Non-Cirrhotics Patients with SVR 12 (%) SVR 12 4/7/2014 Electron Trial (Arms &22) Sofosbuvir + (Ledipasvir or GS-9669 NNI) +/- Ribavirin in GT1 n = 25 LDV + SOF + RBV Noncirrhotic n = 25 Treatment Naive SOF + GS RBV n = 25 LDV-SOF + RBV Noncirrhotic Null responder Cirrhotic Null responder Week n = 9 LDV + SOF + RBV n = 10 SOF + GS RBV n = 10 LDV-SOF n = 9 LDV-SOF + RBV /25 23/25 17/25 9/10 10/10 7/10 9/9 0 LDV LDV LDV-SOF LDV LDV LDV-SOF LDV-SOF SOF GS-9669 RBV SOF GS-9669 RBV RBV RBV (6 wks) RBV RBV Noncirrhotic TN Noncirrhotic TE Null Cirrhotic TE Null Gane EJ, et al. Gastroenterogy. 2014:146: Included PI Failures 1 person lost to F/U 2 virological failures Relapses in groups without RBV Had NS5A resistance at baseline Lawitz E, et al. Lancet. 2014:383: Graphics from AASLD 2013 LONESTAR Trial Sofosbuvir/Ledipasvir +/- Ribavirin in GT1 19/20 21/21 18*/1 9 18/19 21/21 Adverse Event LONESTAR Trial ADR SOF-LDV 8 wk (n=20) SOF-LDV + RBV 8 wk (n=21) SOF-LDV 12 wk (n=19) Grade 3-4 Adverse Events 0 (0%) 4 (19%) 0 (0%) Serious Adverse Events (AE) 0 (0%) 1 (5%) 1 (5%) Treatment discontinuation due to AE 0 (0%) 0 (0%) 0 (0%) Anemia Overall Hemoglobin <10 g/dl 0 (0%) 0 (0%) 2 (10%) 2 (10%) 0 (0%) 0 (0%) Headache 2 (10%) 3 (14%) 0 (0%) Nausea 2 (10%) 2 (10%) 1 (5%) Fatigue 0 (0%) 1 (5%) 1 (5%) Insomnia 0 (0%) 2 (10%) 0 (0%) Upper respiratory tract infection 2 (10%) 0 (0%) 1 (5%) Lawitz E, et al. Lancet. 2014:383: ION-1,2,3: SOF/LDV FDC +/- RBV Phase III Studies, R, Open Label once-daily fixed-dose combination of SOF/LDV for 8, 12 or 24 weeks, +/- RBV N=1,952 GT 1 (TN, TE including failed 1 st gen PI) N=865 N=440 N=647 GILEAD Communications SYNERGY Trial: STR/FDC for 6 or 12 wks Open label Phase 2 study; treatment-naïve GT 1 patients Arm A (n=20) F0 4 LDV 90 mg/sof 400 mg STR QD \\ Arm B (n=20) LDV 90 mg/sof 400 mg FDC F0 3 + GS-9669 (NNI) 500 mg QD \\ Arm C (n=20) LDV 90 mg/sof 400 mg FDC + GS-9451 (PI) 80 mg QD F0 3 Weeks \\ \\ \\ N= 60 IL28B non-cc 80% 70% Fibrosis 0-2 BEYOND SOF/LDV... 20/20 19/20 20/20 STR, single tablet regimen; FDC, fixed-dose combination; NNI, non-nucleoside polymerase inhibitor; PI, protease inhibitor Kohli, A et al. CROI Boston, MA #27 10

11 20 to 30 Years 4/7/2014 N=25 N=27 N=13 C-WORTHY MK-5172 (PI) + MK-8742(NS5AI) TN, non-cirrhotic (F0-F2) GT1 wk 0 Wk 12 GT1 - MK MK-8742 (20mg) + RBV GT1 -MK MK-8742 (50mg) + RBV GT1b - MK MK-8742 (50mg) MK-5172 (PI) 100mg once daily MK-8724 (NS5AI) 20 or 50mg once daily N= 65 ADR: H/A, Fatigue, Nausea, hyperbilirubinemia In clinical trials for ESRD pts SVR 12 = 96% SVR 12 = 89% SVR 12 = 100% Lawitz E, et al. C-WORTHY, AASLD 2013, #76 AI (3DAA): Daclatasvir (NS5AI)+ Asunaprevir (PI)+ BMS (NN-NS5BI) TN, GT1 N=166 Regimen: DCV 30mg BID ASV 200mg BID BMS or 150 mg BID Duration: 12 weeks Low ADR Phase III trials initiated with FDC: DCV/ASV/BMS at 75mg Everson GT, et al AASLD 2013, #LB1 Abbvie Regimen RCTs (3DAA): FDC: ABT-450/ritonavir (150/100mg) PI + ABT-267 (25mg) NS5A daily ABT- 333 (250mg) NN-NS5B BID STUDY PATIENTS REGIMEN PEARL-II (12 wks), Open label PEARL-III (12 wks), Double blind PEARL-IV (12 wks), Double blind TURQUOISE-II (12 & 24 wks) Open label Phase III SAPPHIRE-I (12 wks) SAPPHIRE-II (12 wks) GT1b, TE N=179 GT1b, TN N=419 GT1a, TN N=305 GT1, TN & TE Compensated Cirrhosis N=380 GT1, TN N=631 GT1, TE N=394 AbbVie + RBV 97% (85/88) AbbVie 100% (91/91) AbbVie + RBV 99% (209/210) AbbVie 99% (207/209) AbbVie + RBV 97% (97/100) AbbVie 90% (185/205) AbbVie + RBV 12 wks AbbVie + RBV 24wks 92% (191/208) 96% (165/172) AbbVie + RBV 96% (455/473) AbbVie + RBV 96% (286/297) $$$ Matters PEG/RBV for 12 weeks = $5,000 48wk = $20,000 TVP for 12 weeks = $35,000 Simeprevir 12 week course = $38,000 Sofosbuvir 12 week course = $55,000 Cosmos trial for 12 weeks = $93,000 Liver Transplant = $60,000 IMS = $3,000 ESLD = $$$$$$ Natural history of HCV Infection HCC, Transplant Death 25% Cirrhosis Cirrhosis 20% Acute Infection Chronic Resolved 85% 15% Stop the Progression of HCV HCC Liver Transplant Death Slowly Progressive 75% Stable 80% Summary HCV therapy is becoming more effective, better tolerated, shorter and exorbitantly expensive! Plethora of evidence is emerging Constantly increasing DAA in development Fine tuning of treatment regimens.. Patient selection Regimen selection Treatment duration price 11

12 Thank You! 12