EASL 2013 Interferon Free, All Oral Regimens for Hepatitis C Maria Buti Hospital Universitario Valle Hebron Barcelona Spain
The first Results with Oral therapy: a Protease Inhibitor and NS5A inhibitor All oral dual combination: daclatasvir + asunaprevir Combined data published for HCV GT1b N=33 N=22 Chayama et al, Hepatology 2012; Lok et al, NEJM 2012; Suzuki et al, J Hepatol 2013
HCV Drug in Development Viral targets C E1 E2 p7 NS2 NS3 NS4A NS4B NS5A NS5B Host targets NS3 NS5A NS5B Cyclophilin A LAUNCHED Boceprevir Telaprevir PHASE III ABT-450/r Asunaprevir Simeprevir FAldaprevir Daclatasvir Ledipasvir (GS-5885) ABT-267 PPI-668 * *On clinical hold, Idenix press release; **On clinical hold, Novartis press release Nucleos(t)ide analogue Sofosbuvir Non-nucleoside analogue BI-207127, ABT-333 ABT-072, BMS-791325 Alisporivir**
All Oral Therapies How They Differentiate? 1. Genotype dependency 2. Efficacy Standard population/special populations 3. Treatment duration Standard population/special populations 4. Resistance 5. Drug Drug Interactions 6. Safety and Tolerability 7. Compliance, Pill Burden 4
Formula 1 Race
HCV Drug in Development Viral targets C E1 E2 p7 NS2 NS3 NS4A NS4B NS5A NS5B Host targets NS3 NS5A NS5B Cyclophilin A PHASE III ABT-450/r ABT-267 Non-nucleoside analogue ABT-333 * *On clinical hold, Idenix press release; **On clinical hold, Novartis press release
AVIATOR Study: ABT 450/r, ABT 267, ABT 333 +/ RBV in Non Cirrhotic, Naïve and Null Responders N Regimen/Duration SVR 12 % SVR 24 * % Breakthrough/Rel apse 80 ABT-450 ABT-267 ABT-333 RBV 89 88 0 / 10 Treatment naïve 41 79 79 79 ABT-450 ABT-333 RBV ABT-450 ABT-267 RBV ABT-450 ABT-267 ABT-333 ABT-450 ABT-267 ABT-333 RBV 85 83 1 / 4 91 89 1 / 8 90 87 1 / 5 99 96 0 / 1 Null Responder 80 Wk 0 45 45 ABT-450 ABT-267 ABT-333 RBV ABT-450 ABT-267 Wk 8 Wk 12 Wk 24 RBV ABT-450 ABT-267 ABT-333 RBV 43 ABT-450 ABT-267 ABT-333 RBV 93 90 0 / 2 89 89 0 / 5 93 93 3 / 0 98 95 1 / 0 N = 571 * 8 patients with SVR12 have not returned for >24 weeks and are counted as virologic failures for SVR24; 3 patients relapsed between SVR12 and SVR24. Kowdley K, et al. 48th EASL; Amsterdam, Netherlands; April 24 28, 2013. Abst. 3.
AVIATOR: Most Common Adverse Events The majority of adverse events were mild 3 DAAs + RBV Event, % Total (N =247) Treatment Naïve (N =159) Null Responders (N = 88) Headache 31.2 31.4 30.7 Fatigue 29.6 32.7 23.9 Nausea 22.7 24.5 19.3 Insomnia 19.8 22.6 14.8 Diarrhea 15.0 13.2 18.2 Kowdley K, et al. 48th EASL; Amsterdam, Netherlands; April 24 28, 2013. Abst. 3.
AVIATOR: Safety Grade 3 event, n Pooled (N =247) 3 DAAs + RBV Treatment Naïve (N =159) Null Responders (N = 88) ALT >5x 20x ULN 1 1 0 AST >5x 20x ULN 0 0 0 Alkaline Phosphatase >3x 20x ULN 0 0 0 Total bilirubin > 3x 10xULN 6 4 2 Hemoglobin < 8.0 6.5 g/dl 0 0 0 Grade 4 event, n ALT > 20x ULN 0 0 0 AST > 20x ULN 0 0 0 Alkaline Phosphatase > 20x ULN 0 0 0 Total bilirubin > 10x ULN 0 0 0 Hemoglobin < 6.5 g/dl 0 0 0 Note: Value must also be more extreme than the baseline value Kowdley K, et al. 48th EASL; Amsterdam, Netherlands; April 24 28, 2013. Abst. 3.
HCV Drug in Development Viral targets C E1 E2 p7 NS2 NS3 NS4A NS4B NS5A NS5B Host targets NS3 NS5A NS5B Cyclophilin A FAldaprevir non-nucleoside analogue BI-207127, * *On clinical hold, Idenix press release; **On clinical hold, Novartis press release
SOUND C2: Faldaprevir+ BI207127+ RBV 16/28 weeks in naive G1 Zeuzem et al EASL 2012 Abstract #101
Adverse Events and discontinuations TID16W (n=81) TID28W (n=80) Number (%) of patients TID40W (n=77) BID28W (n=78) TID28W, no RBV (n=46) D/C due to AEs 4 ( 4.9) 10 ( 12.5) 19 ( 24.7) 6 ( 7.7) 5 ( 10.9) Photosensitivity AEs Moderate 4 (5) 3 (4) 6 (8) 0 0 Severe 0 1 (1) 2 (3) 0 0 Jaundice AEs Moderate 2 (3) 6 (8) 3 (4) 2 (3) 0 Severe 0 0 0 0 0 Rash AEs Moderate 2 (3) 2 (3) 2 (3) 0 4 (9) Severe 1 (1) 0 1 (1) 0 0 Vomiting AEs Moderate 4 (5) 10 (13) 3 (4) 3 (4) 2 (4) ALT/GPT Grade 3 1 (1) 0 0 2 (3) 0 Bilirubin Grade 3 33 (41) 15 (19) 20 (26) 20 (26) 6 (13) Grade 4 4 (5) 10 (13) 5 (6) 10 (13) 0
HCV Drug in Development Viral targets C E1 E2 p7 NS2 NS3 NS4A NS4B NS5A NS5B Host targets NS3 NS5A NS5B Cyclophilin A Nucleos(t)ide Analogue Ledipasvir (GS-5885) Sofosbuvir Non-Nucs GS 9669 * *On clinical hold, Idenix press release; **On clinical hold, Novartis press release
ELECTRON Study: Sofosbuvir + Ledipasvir (NS5A )or GS 9669 (NonN NS5B) + RBV: 12 week Regimens in GT1 non cirrhotic Patients with HCV RNA <LOD* over time, n/n (%) SOF + RBV SOF + LDV + RBV SOF + GS 9669 + RBV Naïve (n=25) Null (n=10) Naïve (n=25) Null (n=9) Naïve (n=25) Null (n=10) Week 1 8/25 (32) 1/10 (10) 11/25 (44) 0/9 (0) 3/25 (12) 0/10 (0) Week 2 17/25 (68) 7/10 (70) 22/25 (88) 4/9 (44) 15/25 (60) 2/10 (20) Week 4 25/25 (100) 10/10 (100) 25/25 (100) 8/9 (89) 23/25 (92) 10/10 (100) EOT 25/25 (100) 10/10 (100) 25/25 (100) 9/9 (100) 25/25 (100) 10/10 (100) SVR4 22/25 (88) 1/10 (10) 25/25 (100) 9/9 (100) 23/25 (92) 10/10 (100) SVR12 21/25 (84) 1/10 (10) 25/25 (100) 9/9 (100) 23/25 (92) 3/3 * Analyzed by TaqMan HCV Test 2.0 with limit of detection (LOD) of 15 IU/mL. Includes 1 pa ent who stopped all treatment due to a serious adverse event (AE) at Week 8; this pa ent subsequently achieved SVR12. EOT, end of treatment; SVR4, sustained virologic response 4 weeks after EOT. Gane E, et al. 48th EASL; Amsterdam, Netherlands; April 24 28, 2013. Abst. 14.
Lonestar study. Sofosbuvir + Ledipasvir Genotype 1 naive non cirrhosis Press Release May 3 2013
Phase 3 All Oral Treatment With Sofosbuvir+Ribavirin For 12 Weeks Compared To 24 Weeks Of PEG+Ribavirin In Treatment Naïve GT2/3 HCV Infected Patients 100 97 FISSION study SVR12 results 80 78 SVR12 (%) 60 40 56 63 SOF + RBV PEG + RBV 20 0 68 70 52 67 102 183 110 176 Genotype 2 Genotype 3 E. Gane et al, Abstract 5. EASL, April 2013; Lawitz et al., N Engl J Med 2013. DOI: 10.1056/NEJMoa1214853
FISSION study SOF+RBV 12 wks SVR12 results by Genotype and Fibrosis 100 98 91 80 82 71 SVR12 (%) 60 40 62 61 34 30 SOF + RBV PEG + RBV 20 0 58 59 44 54 10 11 8 13 89 145 99 139 No cirrhosis Cirrhosis No cirrhosis Cirrhosis Genotype 2 Genotype 3 E. Gane et al, Abstract 5. EASL, April 2013; Lawitz et al., N Engl J Med 2013. DOI: 10.1056/NEJMoa1214853 13 38 11 37
FUSION Study: Treatment experienced, Genotype 2 or 3 Patients SVR12 by HCV Genotype/Cirrhosis SOF + RBV 12 weeks SOF + RBV 16 weeks 100 80 96 100 60 78 100 80 63 61 SVR12 (Percentage) 60 40 20 60 40 20 37 19 0 25/2623/23 6/10 7/9 0 14/38 25/40 5/26 14/23 No cirrhosis Cirrhosis No cirrhosis Cirrhosis GT3= 62%, Relapse 75% GT 2 GT 3 Nelson D, et al. 48th EASL; Amsterdam, Netherlands; April 24 28, 2013. Abst. 6.
POSITRON Study: Interferon Ineligible/Intolerant Genotype 2 or 3 Patients SVR12 by Cirrhosis Status No cirrhosis Cirrhosis 100 92 94 SVR12 (Percentage) 80 60 40 20 68 21 0 85/92 16/17 57/84 3/14 GT 2 GT 3 Jacobson I, et al. 48th EASL; Amsterdam, Netherlands; April 24 28, 2013. Abst. 61.
POSITRON: Adverse Events SOF + RBV Placebo Preferred term, n (%) n=207 n=71 P value* Fatigue 91 (44) 17 (24) 0.003 Nausea 46 (22) 13 (18) 0.614 Headache 43 (21) 14 (20) 1.00 Insomnia 39 (19) 3 (4) 0.002 Pruritus 23 (11) 6 (9) 0.655 Anemia 27 (13) 0 <0.001 Decreased appetite 7 (3) 7 (10) 0.053 AEs consistent with those expected with RBV Most AEs mild or moderate in severity Health related quality of life minimally impacted by SOF + RBV treatment 1 1 Younossi Z, et al. International Liver Congress 2013, poster LB 1431. * 2 sided p value using Fisher exact test to assess difference between treatment arms. Jacobson I, et al. 48th EASL; Amsterdam, Netherlands; April 24 28, 2013. Abst. 61.
HCV Drug in Development Viral targets C E1 E2 p7 NS2 NS3 NS4A NS4B NS5A NS5B Host targets NS3 NS5A NS5B Cyclophilin A Nucleos(t)ide Analogue Simeprevir Sofosbuvir * *On clinical hold, Idenix press release; **On clinical hold, Novartis press release
Simeprevir plus sofosbuvir with or without ribavirin in HCV genotype 1 null responders. COSMOS: efficacy results Patients SMV + SOF + RBV 24 weeks 12 weeks SMV + SOF SMV + SOF + RBV SMV + SOF RVR 1, n/n (%) 18/22 (81.8) 10/15 (66.7) 23/27 (85.2) 8/14 (57.1) Undetectable end of treatment, n/n (%) 10/12 (83.3) 8/9 (88.9) 27/27 (100.0) 14/14 (100.0) Relapse, n 0 0 1 1 SVR4, n/n (%) 4/6 (66.7) 5/5 (100.0) 26/27 (96.3) 13/14 (92.9) SVR8, n/n (%) 4/6 (66.7) 5/5 (100.0) 26/27 (96.3) 13/14 (92.9) Of the patients in the 12 week arms who achieved SVR8 24/24 who reached post-treatment Week 12 had undetectable HCV RNA (SVR12) 8/8 who reached post-treatment Week 24 had undetectable HCV RNA (SVR24) 1 RVR is based on patients with available data at Week 4 (2 patients discontinued before Week 4) EOT, end of treatment; RVR, rapid virologic response; SMV, simeprevir; SOF, sofosbuvir; SVR, sustained virologic response
COSMOS: safety & tolerability Adverse events, treatment discontinuation and RBV dose reduction 24 weeks 12 weeks Patients SMV + SOF SMV + SOF SMV + SOF SMV + SOF Total + RBV + RBV (n=24) (n=15) (n=27) (n=14) (n=80) Grade 3/4 AEs 1, % 4.2 13.3 18.5 0 10.0 Serious AEs, % 0 0 0 0 0 Most common AEs ( 10% of total patients) Fatigue, % 25.0 26.7 18.5 21.4 22.5 Headache, % 16.7 26.7 14.8 28.6 20.0 Insomnia, % 16.7 13.3 18.5 21.4 17.5 Nausea, % 4.2 6.7 18.5 28.6 13.8 Anemia, % 25.0 0 11.1 0 11.3 Cough, % 20.8 6.7 3.7 7.1 10.0 Rash, % 12.5 13.3 11.1 0 10.0 Treatment discontinuation Due to AEs, n 1 1 0 0 2 Non-safety reason, n 2 1 0 0 3 RBV dose reduction, % 16.7 NA 3.7 NA 9.8 AE, adverse event; NA, not applicable; RBV, ribavirin; SMV, simeprevir; SOF, sofosbuvir 1 WHO Toxicity Grading Scale, 2003
HCV Drug in Development Viral targets C E1 E2 p7 NS2 NS3 NS4A NS4B NS5A NS5B Host targets NS3 NS5A NS5B Cyclophilin A Nucleos(t)ide Analogue Daclatasvir Sofosbuvir * *On clinical hold, Idenix press release; **On clinical hold, Novartis press release
Daclatasvir Plus Sofosbuvir ± RBV in GT1 who Previously Failed Telaprevir or Boceprevir HCV RNA < LLOQ (%) 100 80 60 40 20 100 100 100 100 100 95 DCV+SOF DCV+SOF+RBV 0 EOT SVR4 SVR12 1 patient missing at post-treatmentweek 12: HCV RNA was undetectable at PT Week 4 and at PT Week 24 21/41 patients have reached PT Week 24; all have achieved SVR 24 No patients discontinued due to adverse events. Most common AEs ( 30% total) were fatigue and headache No Grade 3/4 hematologic or hepatic laboratory abnormalities M.S. Sulkowski et al, Abstract 1417. EASL, April 2013
All-oral combination regimen Antiviral activity in all HCV genotypes QD (or BID) dosing No selection of resistance Short treatment duration Excellent safety and tolerability Applicable in difficult-to-treat populations Affordable