IFN-free for Genotype 1 HCV: the current landscape Prof. Graham R Foster
Wonderful new drugs are coming Poordad F, et al. New Engl J Med 2014; online DOI: 10.1056/NEJMoa1402869. 2
The New Drugs Two treatment strategies are emerging Protease inhibitor based Nucleotide based (At present these are restricted to Genotype 1 but G3 trials with both combinations are under way) 3
TREATMENT-NAIVE PATIENTS
SAPPHIRE-I: GT1 treatment-naive patients ABT-450/r/ABT-267 (ombitasvir) + ABT-333 (dasabuvir) + RBV HCV GT1, treatment-naive, non-cirrhotic (N=631) n=473 n=158 ABT-450/r/ombitasvir + dasabuvir + RBV Placebo ABT-450/r/ombitasvir + dasabuvir + RBV 0 12 24 Study weeks ABT-450/r/ombitasvir = 150/100/25 mg QD co-formulated; dasabuvir = 250 mg BID; RBV = 1000 1200 mg weight-based BID. Feld JJ, et al. EASL 2014. Abstract 60 [oral presentation]. 5
SAPPHIRE-I: GT1 treatment-naive patients SVR12 rates by HCV GT1 subtype SVR12 (%) Treatment-naive n N 455 473 307 322 148 151 Error bars: 95% CI. Feld JJ, et al. EASL 2014. Abstract 60 [oral presentation]. 6
SAPPHIRE-I: GT1 treatment-naive patients adverse events occurring in 10% subjects Event, n (%) 3D + RBV (N=473) Placebo (N=158) D P Value Any AE 414 (87.5) 116 (73.4) 14.1 <0.05 Fatigue 164 (34.7) 45 (28.5) 6.2 NS Headache 156 (33.0) 42 (26.6) 6.4 NS Nausea 112 (23.7) 21 (13.3) 10.4 <0.05 Pruritus 80 (16.9) 6 (3.8) 13.1 <0.05 Insomnia 66 (14.0) 12 (7.6) 6.4 <0.05 Diarrhea 65 (13.7) 11 (7.0) 6.7 <0.05 Asthenia 57 (12.1) 6 (3.8) 8.3 <0.05 Rash 51 (10.8) 9 (5.7) 5.1 NS AEs were generally mild Low (0.6%) rate of discontinuation due to AEs in each treatment group Serious AEs occurred in 2.1% of 3D + RBV recipients. Feld JJ, et al. EASL 2014. Abstract 60 [oral presentation]. 7
PEARL-III: GT1b treatment-naive patients ABT-450/r/ABT-267 (ombitasvir) + ABT-333 (dasabuvir) +/- RBV HCV GT1, treatment-naive, non-cirrhotic (N=419) n=210 n=209 ABT-450/r/ABT-267 (ombitasvir) + ABT-333 (dasabuvir) + RBV ABT-450/r/ABT-267 (ombitasvir) + ABT-333 (dasabuvir) + Placebo for RBV 0 12 24 Study weeks ABT-450/r/ombitasvir = 150/100/25 mg QD co-formulated; dasabuvir = 250 mg BID; RBV = 1000 1200 mg weight-based BID. Ferenci P, et al. EASL 2014. Abstract 1299 [Latebreaker poster]. 8
PEARL-III: SVR rates with 3D ± RBV in GT1b treatmentnaive patients SVR12 (% patients) n N 209 210 307 322 207 209 Error bars: 95% CI. Ferenci P, et al. EASL 2014. Abstract 1299 [Latebreaker poster]. 9
Laboratory Abnormalities of Note 3-DAA + RBV (N = 210) Decreased hemoglobin levels were infrequent in the absence of RBV 3-DAA (N = 209) P value Hemoglobin below LLN a 106 (51.2) 7 (3.4) <0.001 Hemoglobin 10 g/dl 19 (9.0) 0 (0) <0.001 Total bilirubin >3 x ULN 12 (5.7) 1 (0.5) 0.003 Alanine aminotransferase >5 x ULN 2 (1.0) 0 (0) Aspartate aminotransferase >5 x ULN 0 (0) 0 (0) a Sample sizes were 207 and 205 for 3-DAA + RBV and 3-DAA, respectively, excluding patients below LLN at baseline. LLN, lower limit of normal; ULN, upper limit of normal. No patient discontinued study drug due to laboratory abnormalities RBV dose was reduced because of decreased hemoglobin in 19/210 (9%) patients All of these patients achieved SVR 12 10
CHC GT1 patients (N=865) ION-1: SOF/LDV ± RBV in GT1 treatment-naive patients SOF/LDV (n=214) SOF/LDV + RBV (n=217) SOF/LDV (n=217) SOF/LDV + RBV (n=217) 0 6 12 18 24 30 36 Weeks Including 136 (15.7%) of patients with cirrhosis SOF = 400 mg/day; LDV = 90 mg/day; RBV = 1000 or 1200 mg/day. Afdhal N, et al. New Engl J Med 2014; online DOI: 10.1056/NEJMoa1402454. 11
SVR12 (%) ION-1: SOF/LDV ± RBV in GT1 treatment-naive patients SVR12 rates in the ITT population (N=875) n N 211 214 211 217 212 217 215 217 Afdhal N, et al. New Engl J Med 2014; online DOI: 10.1056/NEJMoa1402454. 12
ION-1: SOF/LDV ± RBV in GT1 treatment-naive patients safety data Patients, n (%) SOF/LDV 12 weeks (N=214) SOF/LDV + RBV 12 weeks (N=217) LDV/SOF 24 weeks (N=217) LDV/SOF + RBV 24 weeks (N=217) Treatment discontinuations 0 0 4 (2) 6 (3) Serious AEs 1 (<1) 7 (3) 18 (8) 7 (3) Any AE 169 (79) 185 (85) 178 (82) 200 (92) AEs in >15% of patients Fatigue 44 (21) 79 (36) 53 (24) 82 (38) Headache 53 (25) 49 (23) 54 (25) 65 (30) Insomnia 17 (8) 45 (21) 26 (12) 47 (22) Nausea 24 (11) 37 (17) 29 (13) 32 (15) Hemoglobin level <10 g/dl 0 20 (9) 0 16 (7) Afdhal N, et al. New Engl J Med 2014; online DOI: 10.1056/NEJMoa1402454. 13
ION-3: Phase III SOF/LDV ± RBV in GT1 treatment-naive patients CHC GT1 patients (N=647) SOF/LDV (n=215) SOF/LDV + RBV (n=216) SOF/LDV (n=216) 0 4 8 12 16 20 24 Weeks SOF = 400 mg/day; LDV = 90 mg/day; RBV = 1000 or 1200 mg/day. Kowdley, KV, et al. New Engl J Med 2014; online DOI: 10.1056/NEJMoa1402355. 14
ION-3: Phase III SOF/LDV ± RBV in GT1 treatment-naive patients SVR12 data SVR12 (%) Overall GT1a GT1b n N 202 215 159 171 42 43 201 216 159 172 42 44 206 216 163 172 43 44 * One patient achieved SVR12, but was not sub-genotyped; Error bars: 95% CI. Kowdley, KV, et al. New Engl J Med 2014; online DOI: 10.1056/NEJMoa1402355. 15
Summary For treatment naïve patients with Genotype 1 we have fabulous treatment options:- We can use Protease + regimes OR Sofosbuvir + regimes Both regimes are very well tolerated and require no more than 3 months of therapy 16
TREATMENT- EXPERIENCED PATIENTS
SAPPHIRE-II: 3D + RBV in GT1 treatment-experienced patients ABT-450/r/ABT-267 (ombitasvir) + ABT-333 (dasabuvir) + RBV HCV GT1, treatmentexperienced, non-cirrhotic (N=394) n=297 n=97 ABT-450/r/ombitasvir + dasabuvir + RBV Placebo ABT-450/r/ombitasvir + dasabuvir + RBV 0 12 24 Study weeks ABT-450/r/ombitasvir = 150/100/25 mg QD co-formulated; dasabuvir = 250 mg BID; RBV = 1000 1200 mg weight-based BID. Zeuzem S, et al. EASL 2014. Abstract 1 [oral presentation]. 18
SAPPHIRE-II: GT1 treatment-experienced patients SVR12 rates by HCV GT1 subtype SVR12 (%) Treatment-experienced n N 286 297 166 173 119 123 * One patient achieved SVR12, but was unable to be subgenotyped. Error bars: 95% CI. Zeuzem S, et al. EASL 2014. Abstract 1 [oral presentation]. 19
SAPPHIRE-II: GT1 treatment-experienced patients SVR12 rates by prior P/R response SVR12 (%) Treatment-experienced n N 82 86 65 65 139 146 Error bars: 95% CI. Zeuzem S, et al. EASL 2014. Abstract 1 [oral presentation]. 20
SVR12 (%) PEARL-II: HCV GT1b treatment-experienced patients ABT-450/r/ABT-267 (ombitasvir) + ABT-333 (dasabuvir) ± RBV for 12 weeks GT1b Treatment-experienced n N 91 91 85 88 ABT-450/r/ombitasvir = 150/100/25 mg QD co-formulated; dasabuvir = 250 mg BID; RBV = 1000 1200 mg weight-based BID. AbbVie press release 2014 [Accessed 21-03-14]. 21
CHC GT1 patients (N=440) ION-2: SOF/LDV ± RBV in GT1 treatment-experienced patients SOF/LDV (n=109) SOF/LDV + RBV (n=111) SOF/LDV (n=109) SOF/LDV + RBV (n=111) 0 6 12 18 24 30 36 Study weeks Including 88 (20.0%) of patients with cirrhosis SOF = 400 mg/day; LDV = 90 mg/day; RBV = 1000 or 1200 mg/day. Afdhal N, et al. New Engl J Med 2014; online DOI: 10.1056/NEJMoa1316366. 22
ION-2: SOF/LDV ± RBV in GT1 treatment-experienced patients SVR12 (%) Overall GT1a GT1b n N 102 109 82 86 20 23 107 111 84 88 23 23 108 109 84 85 24 24 110 111 87 88 23 23 Error bars: 95% CI. Afdhal N, et al. New Engl J Med 2014; online DOI: 10.1056/NEJMoa1316366. 23
Summary: data in non-cirrhotic patients SVR rates achieved in around 95% of GT1 patients with emerging IFN-free all-oral Phase III programmes Very low treatment discontinuation rates reflecting good safety and tolerability profile 24
CIRRHOTIC PATIENTS
TURQUOISE-II: GT1 treatment-naive and experienced cirrhotic patients ABT-450/r/ABT-267 (ombitasvir) + ABT-333 (dasabuvir) + RBV for 12 or 24 weeks HCV GT1, treatment-naive or -experienced, cirrhotic (N=380) n=208 n=172 ABT-450/r /ombitasvir + dasabuvir + RBV ABT-450/r /ombitasvir + dasabuvir + RBV 0 12 24 Study weeks ABT-450/r/ombitasvir = 150/100 mg/25 mg QD co-formulated; dasabuvir = 250 mg BID; RBV = weight-based BID. Poordad F, et al. N Engl J Med 2014. Online DOI:10.1056/NEJMoa1402869. 26
SVR12, % Patients TURQUOISE-II: SVR12 rates in GT1 treatment-naive and experienced cirrhotic patients 91.8 P=0.089 95.9 191 208 12 Weeks 3D + RBV 165 172 24 Weeks 3D + RBV Poordad F, et al. N Engl J Med 2014. Online DOI:10.1056/NEJMoa1402869. 27
SVR12, % Patients TURQUOISE-II: SVR12 rates in GT1 treatment-naive and experienced cirrhotic patients by HCV genotype 88.6 94.2 98.5 100 3D + RBV 12-week arm 24-week arm 124 140 114 121 67 68 51 51 GT1a GT1b Poordad F, et al. N Engl J Med 2014. Online DOI:10.1056/NEJMoa1402869. 28
SVR12, % Patients TURQUOISE-II: SVR12 rates in GT1b treatment-naive and experienced cirrhotic patients by prior treatment response 100 100 100 100 85.7 100 100 100 3D + RBV 12-week arm 24-week arm 22 22 18 18 Naive 25 25 20 20 Prior Relapse Response 6 7 3 3 Prior Partial Response HCV Subtype 1b 14 14 10 10 Prior Null Response Poordad F, et al. N Engl J Med 2014. Online DOI:10.1056/NEJMoa1402869. 29
SVR12, % Patients TURQUOISE-II: SVR12 rates in GT1a treatment-naive and experienced cirrhotic patients by prior treatment response 92.2 92.9 93.3 100 100 100 80.0 92.9 3D + RBV 12-week arm 24-week arm 59 64 52 56 Naive 14 15 13 13 Prior Relapse Response 11 11 10 10 Prior Partial Response HCV Subtype 1a 40 50 39 42 Prior Null Response Poordad F, et al. N Engl J Med 2014. Online DOI:10.1056/NEJMoa1402869. 30
TURQUOISE-II: safety summary in GT1 treatment-naive and experienced cirrhotic patients Event, % 12-Week Arm (N=208) Hepatic decompensation events were rare (4 patients, 1.1%) None were considered related to study drug 3D + RBV 24-Week Arm (N=172) Any AE 91.8 90.7 Severe AE 6.7 7.6 Serious AE 6.3 4.7 AE leading to drug discontinuation 1.9 2.3 Death* 0 0 *1 patient with a non-treatment emergent death (occurring 80 days after last dose of study treatment), not attributed to 3D or RBV. Poordad F, et al. N Engl J Med 2014. Online DOI:10.1056/NEJMoa1402869. 31
TURQUOISE-II: safety summary in GT1 treatment-naive and experienced cirrhotic patients Event, % 12-Week Arm (N=208) 3D + RBV 24-Week Arm (N=172) P Value Fatigue 32.7 46.5 <0.05 Headache 27.9 30.8 NS Nausea 17.8 20.3 NS Pruritus 18.3 19.2 NS Insomnia 15.4 18.0 NS Diarrhea 14.4 16.9 NS Asthenia 13.9 12.8 NS Rash 11.1 14.5 NS Cough 11.5 11.0 NS Irritability 7.2 12.2 NS Anemia 7.7 10.5 NS Dyspnea 5.8 12.2 <0.05 Poordad F, et al. N Engl J Med 2014. Online DOI:10.1056/NEJMoa1402869. 32
TURQUOISE-II: laboratory assessments in GT1 treatment-naive and experienced cirrhotic patients 3D + RBV 12-Week Arm (N=208) 24-Week Arm (N=172) ALT >5x ULN (%) 2.9 0 Total bilirubin >3x ULN (%) 13.5 5.2 Hemoglobin (%) <10 g/dl 7.2 11.0 <8.0 g/dl 1.4 0.6 ALT elevation Asymptomatic, transient, and improved or resolved with ongoing study drug dosing Bilirubin elevation Transient, predominantly indirect, no discontinuations due to hyperbilirubinemia Hemoglobin decrease Managed with reduction of ribavirin dose in 34 patients (8.9%) Poordad F, et al. N Engl J Med 2014. Online DOI:10.1056/NEJMoa1402869. 33
ION-1: SOF + LDV ± RBV in GT1 treatment-naive cirrhotic patients (subgroup analysis) CHC GT1 patients (N=136) SOF/LDV (n=34) SOF/LDV + RBV (n=33) Overall study (N=865) 15.7% of patients were cirrhotic SOF/LDV (n=33) SOF/LDV + RBV (n=36) Weeks 0 6 12 18 24 30 36 SOF = 400 mg/day; LDV = 90 mg/day; RBV = 1000 or 1200 mg/day. Afdhal N, et al. New Engl J Med 2014; online DOI: 10.1056/NEJMoa1402454. 34
SVR12 (%) ION-1: SVR rates* in GT1 treatment-naive cirrhotic patients (subgroup analysis) SVR12 rates in the mitt population (N=852): subgroup results do not include patients who withdrew consent or who were lost to No cirrhosis Cirrhosis n N 179 179 32 33 178 178 33 33 181 182 31 32 179 179 36 36 Afdhal N, et al. New Engl J Med 2014; online DOI: 10.1056/NEJMoa1402454. 35
CHC GT1 patients (N=88) ION-2: SOF + LDV ± RBV in GT1 treatment-experienced cirrhotic patients (subgroup analysis) Overall study (N=440) 20.0% of patients were cirrhotic SOF/LDV (n=22) SOF/LDV + RBV (n=22) SOF/LDV (n=22) SOF/LDV + RBV (n=22) Study weeks 0 6 12 18 24 30 36 SOF = 400 mg/day; LDV = 90 mg/day; RBV = 1000 or 1200 mg/day. Afdhal N, et al. New Engl J Med 2014; online DOI: 10.1056/NEJMoa1316366. 36
ION-2: SVR rates in GT1 treatment-experienced cirrhotic patients (subgroup analysis) No cirrhosis Cirrhosis n N 83 87 19 22 89 89 18 22 86 87 22 22 88 89 22 22 Afdhal N, et al. New Engl J Med 2014; online DOI: 10.1056/NEJMoa1316366. 37
Summary slide In patients with cirrhosis across multiple regimens response rates of 84 97% are seen Therapy was well tolerated with very low treatment discontinuation rates Virologic characteristics may still play a role in selecting the optimal treatment regimen and duration 38
In summary Prof. Graham Foster
HCV Therapy today and tomorrow We have solved the HCV problem we now know how to kill this virus For Genotype 1 we have fabulous drugs today! 40