Moderiba
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Moderiba - Scientific Information

Manufacture: Abbvie
Country: Canada
Condition: Hepatitis C
Class: Purine nucleosides
Form: Tablets
Ingredients: ribavirin, carnauba wax, croscarmellose sodium, indigo carmine aluminum lake lactose monohydrate, magnesium stearate, microcrystalline cellulose, polyethylene glycol, polyvinyl alcohol, povidone, talc, titanium dioxide

Pharmaceutical information

Proper name: ribavirin
Chemical name: 1-β-D-ribofuranosyl-1H-1,2,4-triazole-3-carboxamide
Molecular formula and molecular mass: C8H12N4O5 244.21
Structural formula:


Physicochemical properties: Ribavirin is a white to off-white powder. It is freely soluble in water and slightly soluble in anhydrous alcohol.

Clinical Trials

Consult the respective Product Monograph(s) of products used in combination with MODERIBA (ribavirin) for information on the relevant clinical studies.

Clinical Trials: Ribavirin in Combination Therapy with HOLKIRA PAK

Trial Design

The efficacy and safety of ribavirin in combination with HOLKIRA PAK was evaluated in six randomized Phase 3 clinical trials, including one trial exclusively in subjects with cirrhosis (Child-Pugh A), in over 2300 subjects with genotype 1 chronic hepatitis C infection, as summarized in Table 1.

Table 1. Summary of Clinical Trial Designs in Treatment of Genotype 1 Chronic Hepatitis C Infection
Study # Number of
Subjects
Treateda
HCV
Genotype
(GT)
Trial Design Dosage, Route of
Administration and Durationb
Treatment-Naïvec, without Cirrhosis
SAPPHIRE-I
(M11-646)
631 GT1 Double-blind, randomized, placebo controlled ombitasvir/paritaprevir /ritonavir tablet: 25/150/100 mg or placebo QD;
dasabuvir tablet: 250 mg or placebo BID;
RBV tablet: 1000 or 1200 mg or placebo QD (divided BID);

Oral
12 weeks
PEARL-III
(M13-961)
419 GT1b Double-blind, randomized
(RBV or RBV placebo)
ombitasvir/ paritaprevir /ritonavir tablet: 25/150/100 mg QD;
dasabuvir tablet: 250 mg BID;
RBV tablet: 1000 to 1200 mg or placebo QD (divided BID);

Oral
12 weeks
PEARL-IV
(M14-002)
305 GT1a Double-blind, randomized
(RBV or RBV placebo)
ombitasvir/ paritaprevir /ritonavir tablet: 25/150/100 mg QD;
dasabuvir tablet: 250 mg BID;
RBV tablet: 1000 to 1200 mg or placebo QD (divided BID)

Oral
12 weeks
Treatment-Experiencedd, without Cirrhosis
SAPPHIRE-II
(M13-098)
394 GT1 Double-blind, randomized, placebo controlled ombitasvir/ paritaprevir /ritonavir tablet: 25/150/100 mg or placebo QD;
dasabuvir tablet: 250 mg or placebo BID;
RBV tablet: 1000 or 1200 mg or placebo QD (divided BID)

Oral
12 weeks
PEARL-II
(M13-389)
179 GT1b Open-label, randomized
(with or without RBV)
ombitasvir/ paritaprevir /ritonavir tablet: 25/150/100 mg QD;
dasabuvir tablet: 250 mg BID;
RBV tablet: 1000 or 1200 mg QD (divided BID)

Oral
12 weeks
Treatment-Naïve and Treatment-Experienced, with Cirrhosis
TURQUOISE-II
(M13-099)
380 GT1 Open-label, randomized to 12 or 24 weeks ombitasvir/ paritaprevir /ritonavir tablet: 25/150/100 mg QD;
dasabuvir tablet: 250 mg BID;
RBV tablet: 1000 to 1200 mg or placebo QD (divided BID)

Oral
12 or 24 weeks

BID = twice daily, QD = daily, pegIFN = pegylated interferon, RBV = ribavirin

a. Treated is defined as subjects who were randomized and received at least one dose of HOLKIRA PAK.

b. For subjects who received ribavirin, the ribavirin dose was 1000 mg per day for subjects weighing less than 75 kg or 1200 mg per day for subjects weighing greater than or equal to 75 kg.

c. Treatment naïve was defined as not having received any prior therapy for HCV infection.

d. Treatment-experienced subjects were defined as either: prior relapsers (subjects with HCV RNA undetectable at or after the end of at least 36 weeks of pegIFN/RBV treatment, but HCV RNA was detectable within 52 weeks of treatment follow-up) or prior partial responders (received at least 20 weeks of pegIFN/RBV and achieved a greater than or equal to 2 log10 IU/mL reduction in HCV RNA at Week 12, but not achieving HCV RNA undetectable at end of treatment) or prior null-responders (received at least 12 weeks of pegIFN/RBV treatment and failed to achieve a 2 log10 IU/mL reduction in HCV RNA at Week 12 or, for PEARL-III and PEARL-IV, received at least 4 weeks of pegIFN/RBV treatment and achieved a < 1 log10 IU/mL reduction in HCV RNA at week 4).

Sustained virologic response (SVR) (virologic cure) was defined as unquantifiable or undetectable HCV RNA 12 weeks after the end of treatment (SVR12) in the Phase 3 trials. Treatment duration was fixed in each trial and was not guided by subjects’ HCV RNA levels (no response guided algorithm). Plasma HCV RNA values were measured during the clinical trials using the COBAS TaqMan HCV test (version 2.0), for use with the High Pure System. The assay had a lower limit of quantification (LLOQ) of 25 IU per Ml.

Clinical Trials in Treatment-Naïve Adults

SAPPHIRE-I was a randomized, global multicenter, double-blind, placebo-controlled trial conducted in 631 treatment-naïve adults with genotype 1 chronic hepatitis C virus infection without cirrhosis. HOLKIRA PAK was given for 12 weeks of treatment in combination with ribavirin (RBV). Subjects randomized to the placebo arm received placebo for 12 weeks, after which they received open-label HOLKIRA PAK in combination with ribavirin for 12 weeks.

PEARL-III and PEARL-IV were randomized, global, multicenter, double-blind, controlled trials conducted in 419 treatment-naïve adults with genotype 1b chronic hepatitis C virus infection without cirrhosis (PEARL-III) and 305 treatment-naïve adults with genotype 1a chronic hepatitis C virus infection without cirrhosis (PEARL-IV). Subjects were randomized, in a 1:1 ratio (PEARL-III) or a 1:2 ratio (PEARL-IV), to receive HOLKIRA PAK with or without ribavirin for 12 weeks of treatment.

Demographic and baseline characteristics for treatment-naïve subjects in SAPPHIRE-I, PEARL-III and PEARL-IV are provided in Table 2.

Table 2. Demographic and Baseline Characteristics of Treatment-Naïve Subjects without Cirrhosis in SAPPHIRE-I, PEARL-III and PEARL-IV
Characteristics SAPPHIRE-I
N=631
PEARL-III
N=419
PEARL-IV
N=305
Age (years)
Median (range) 52 (18 – 70) 50 (19 – 70) 54 (19 – 70)
Gender, n (%)
Male 344 (54.5) 192 (45.8) 199 (65.2)
Female 287 (45.5) 227 (54.2) 106 (34.8)
Race, n (%)
White 572 (90.6) 394 (94.3) 257 (84.3)
Black or African American 34 (5.4) 20 (4.8) 36 (11.8)
Asian 14 (2.2) 2 (0.5) 4 (1.3)
Other 11 (1.7) 2 (0.5) 8 (2.6)
Ethnicity, n (%)
Hispanic or Latino 32 (5.1) 7 (1.7) 28 (9.2)
None of the above 599 (94.9) 412 (98.3) 277 (90.8)
Body mass index, n (%)
< 30 kg/m2 529 (83.8) 350 (83.5) 245 (80.3)
≥ 30 kg/m2 102 (16.2) 69 (16.5) 60 (19.7)
HCV genotype, n (%)
1a 427 (67.7) N/A 304 (99.7)
1b 204 (32.3) 419 (100) 1 (0.3)
Baseline HCV RNA
Mean ± SD (log10 IU/mL) 6.42 ± 0.63 6.31 ± 0.72 6.57 ± 0.63
< 800000 IU/mL, n (%) 132 (20.9) 112 (26.7) 41 (13.4)
≥ 800000 IU/mL, n (%) 499 (79.1) 307 (73.3) 264 (86.6)
IL28B, n (%)
CC 194 (30.7) 88 (21.0) 94 (30.8)
Non-CC 437 (69.3) 331 (79.0) 211 (69.2)
Baseline fibrosis stage, n (%)
F0-F1 479 (75.9) 291 (69.6) 195 (63.9)
F2 97 (15.4) 85 (20.3) 56 (18.4)
≥ F3 55 (8.7) 42 (10.0) 54 (17.7)
History of depression or bipolar disorder, n (%)
No 535 (84.8) 380 (90.7) 242 (79.3)
Yes 96 (15.2) 39 (9.3) 63 (20.7)

N/A = Not Applicable.

Study Results

Table 3 shows the SVR12 rates for genotype 1-infected, treatment-naïve subjects receiving HOLKIRA PAK with or without ribavirin for 12 weeks in SAPPHIRE-I, PEARL-III and PEARL-IV. All treatment groups met the primary efficacy endpoint. In study PEARL-III, HOLKIRA PAK without ribavirin had similar SVR12 rates (99.0%) compared to HOLKIRA PAK with ribavirin (99.5%). In study PEARL-IV, HOLKIRA PAK without ribavirin did not meet the pre-specified criteria for non-inferiority to HOLKIRA PAK with ribavirin.

Table 3. SVR12 for Genotype 1-Infected Treatment-Naïve Subjects without Cirrhosis in SAPPHIRE-I, PEARL-III and PEARL-IV
Treatment Outcome SAPPHIRE-I
Genotype 1
PEARL-III
Genotype 1b
PEARL-IV
Genotype 1a
HOLKIRA
PAK + RBV
N=473
% (n/N)
HOLKIRA
PAK + RBV
N=210
% (n/N)
HOLKIRA
PAK
N=209
% (n/N)
HOLKIRA
PAK + RBV
N=100
% (n/N)
HOLKIRA
PAK
N=205
% (n/N)
Overall SVR12 96 (455/473) 99 (209/210) 99 (207/209) 97 (97/100) 90 (185/205)
95% CI 94.5 to 97.9 98.6 to 100 97.7 to 100 93.7 to 100 86.2 to 94.3
HCV genotype 1a 95 (307/322) N/A N/A 97 (97/100) 90 (184/204)
HCV genotype 1b 98 (148/151) 99 (209/210) 99 (207/209) N/A
Outcome for subjects without SVR12
On-treatment VFa <1 (1/473)d <1 (1/210) 0 1 (1/100) 3 (6/205)
Relapseb 2 (7/463)d 0 0 1 (1/98) 5 (10/194)
Otherc 2 (10/473) 0 1 (2/209) 1 (1/100) 2 (4/205)

CI = confidence interval, VF = virologic failure, N/A = Not Applicable

a. On-treatment VF was defined as confirmed HCV ≥ 25 IU/mL after HCV RNA < 25 IU/mL during treatment, confirmed 1 log10 IU/mL increase in HCV RNA from nadir, or HCV RNA persistently ≥ 25 IU/mL with at least 6 weeks of treatment.

b. Relapse was defined as confirmed HCV RNA ≥ 25 IU/mL post-treatment before or during SVR12 window among subjects with HCV RNA < 25 IU/mL at last observation during at least 11 weeks of treatment.

c. Other includes subjects not achieving SVR12 but not experiencing on-treatment VF or relapse (e.g. missing HCV RNA values in the SVR12 window).

d. No subjects with HCV genotype 1b infection experienced on-treatment virologic failure and one subject with HCV genotype 1b infection experienced relapse.

Table 4 presents the SVR12 rates by selected subgroups for genotype 1-infected, treatment-naïve subjects in studies SAPPHIRE-I, PEARL-III and PEARL-IV.

Table 4. SVR12 rates for Selected Subgroups of Genotype 1-infected, Treatment-Naïve Subjects without Cirrhosis in SAPPHIRE-I, PEARL-III and PEARL-IV
Treatment Outcome SAPPHIRE-I
Genotype 1
PEARL-III
Genotype 1b
PEARL-IV
Genotype 1a
HOLKIRA
PAK + RBV
N=473
% (n/N)
HOLKIRA
PAK + RBV
N=210
% (n/N)
HOLKIRA
PAK
N=209*
% (n/N)
HOLKIRA
PAK + RBV
N=100**
% (n/N)
HOLKIRA
PAK
N=205
% (n/N)
IL28B
CC 97 (139/144) 100 (44/44) 98 (43/44) 100 (31/31) 97 (61/63)
Non-CC 96 (316/329) 99 (165/166) 99 (164/165) 96 (66/69) 87 (124/142)
Sex
Female 98 (197/202) 99 (103/104) 100 (123/123) 100 (30/30) 95 (72/76)
Male 95 (258/271) 100 (106/106) 98 (84/86) 96 (67/70) 88 (113/129)
Age
< 65 years 96 (437/454) 99 (195/196) 99 (188/190) 97 (87/90) 90 (172/192)
≥ 65 years 95 (18/19) 100 (14/14) 100 (19/19) 100 (10/10) 100 (13/13)
Race
Black 96 (27/28) 100 (11/11) 100 (11/11) 100 (10/10) 85 (23/27)
Non-black 96 (428/445) 99 (198/199) 99 (196/197) 97 (87/90) 91 (162/178)
Ethnicity
Hispanic or Latino 93 (25/27) 100 (2/2) 80 (4/5) 90 (9/10) 89 (16/18)
None of the above 430/446 (96.4) 99 (207/208) 99 (203/204) 98 (88/90) 90 (169/187)
Body mass index
< 30 kg/m2 97 (390/402) 100 (182/182) 100 (168/168) 99 (78/79) 92 (153/166)
≥ 30 kg/m2 92 (65/71) 96 (27/28) 95 (39/41) 90 (19/21) 82 (32/39)
Baseline HCV RNA
< 800000 IU/mL 98 (102/104) 100 (51/51) 100 (61/61) 100 (8/8) 91 (30/33)
≥ 800000 IU/mL 96 (353/369) 99 (158/159) 99 (146/148) 97 (89/92) 90 (155/172)
Baseline fibrosis stage
F0-F1 97 (352/363) 99 (149/150) 100 (141/141) 97 (61/63) 92 (122/132)
F2 94 (66/70) 100 (38/38) 100 (47/47) 95 (20/21) 83 (29/35)
≥ F3 93 (37/40) 100 (22/22) 90 (18/20) 100 (16/16) 89 (34/38)
History of depression
or bipolar disorder
No 97 (389/403) 99 (189/190) 99 (189/190) 96 (80/83) 89 (142/159)
Yes 94 (66/70) 100 (20/20) 95 (18/19) 100 (17/17) 93 (43/46)

* For subjects with GT1b infection without cirrhosis, HOLKIRA PAK alone for 12 weeks is the recommended regimen.

** For subjects with GT1a infection without cirrhosis, HOLKIRA PAK with RBV for 12 weeks is the recommended regimen.

These baseline viral (genotype 1 subtype, baseline viral load) and host factors (gender, race, ethnicity, age, IL28B allele, baseline body mass index, history of depression or bipolar disorder, fibrosis stage) were not associated with lower SVR12 rates across subgroups.

In addition, subjects who underwent ribavirin dose modifications did not have lower SVR12 rates.

Clinical Trials in Treatment-Experienced Adults

SAPPHIRE-II was a randomized, global multicenter, double-blind, placebo-controlled trial conducted in 394 subjects with genotype 1 chronic hepatitis C virus infection without cirrhosis who did not achieve SVR with prior treatment with peginterferon and ribavirin (pegIFN/RBV). HOLKIRA PAK in combination with ribavirin was given for 12 weeks of treatment. Subjects randomized to the placebo arm received placebo for 12 weeks, after which they received HOLKIRA PAK in combination with ribavirin for 12 weeks.

PEARL-II was a randomized, global, multicenter, open-label trial conducted in 179 adults with chronic genotype 1b hepatitis C virus infection without cirrhosis who did not achieve SVR with prior treatment with pegIFN/RBV. Subjects were randomized, in a 1:1 ratio, to receive HOLKIRA™ PAK with or without ribavirin for 12 weeks of treatment.

Demographic and baseline characteristics for treatment-experienced subjects in SAPPHIRE-II and PEARL-II are provided in Table 5.

Table 5. Demographic and Baseline Characteristics of Treatment-Experienced Subjects without Cirrhosis in SAPPHIRE-II and PEARL-II
Characteristics SAPPHIRE-II
N=394
PEARL-II
N=179
Age (years)
Median (range) 54 (19 – 71) 57 (26 – 70)
Gender, n (%)
Male 227 (57.6) 97 (54.2)
Female 167 (42.4) 82 (45.8)
Race, n (%)
White 355 (90.1) 165 (92.2)
Black or African American 32 (8.1) 7 (3.9)
Asian 6 (1.5) 3 (1.7)
Other 1 (0.3) 4 (2.3)
Ethnicity, n (%)
Hispanic or Latino 25 (6.3) 3 (1.7)
None of the above 369 (93.7) 176 (98.3)
Body mass index, n (%)
< 30 kg/m2 316 (80.2) 140 (78.2)
≥ 30 kg/m2 78 (19.8) 39 (21.8)
HCV genotype, n (%)
1a 230 (58.4) N/A
1b 163 (41.4) 179 (100)
Baseline HCV RNA
Mean ± SD (log10 IU/mL) 6.55 ± 0.52 6.51 ± 0.55
< 800000 IU/mL, n (%) 51 (12.9) 22 (12.3)
≥ 800000 IU/mL, n (%) 343 (87.1) 157 (87.7)
IL28B, n (%)
CC 41 (10.4) 17 (9.5)
Non-CC 353 (89.6) 162 (90.5)
Type of response to previous pegIFN/RBV
treatment, n (%)
Null responder 193 (49.0) 63 (35.2)
Nonresponder/partial responder 86 (21,8) 51 (28.5)
Relapser 115 (29.2) 65 (36.3)
Baseline fibrosis stage, n (%)
F0-F1 267 (67.8) 122 (68.2)
F2 70 (17.8) 32 (17.9)
≥ F3 57 (14.5) 25 (14.0)
History of depression or bipolar disorder, n (%)
No 313 (79.4) 156 (87.2)
Yes 81 (20.6) 23 (12.8)

N/A = Not Applicable

Study Results

Table 6 shows the SVR12 rates for treatment-experienced subjects with genotype 1-infection receiving HOLKIRA PAK in combination with ribavirin for 12 weeks in SAPPHIRE-II and PEARL-II and HOLKIRA PAK alone in PEARL-II. All the treatment groups met the primary efficacy endpoint.

Table 6. SVR12 for Genotype 1-Infected Treatment-Experienced Subjects without Cirrhosis in SAPPHIRE-II and PEARL-II
Treatment Outcome SAPPHIRE-II
Genotype 1
PEARL-II
Genotype 1b
HOLKIRA PAK +
RBV
N=297
% (n/N)
HOLKIRA PAK +
RBV
N=88
% (n/N)
HOLKIRA PAK*
N=91
% (n/N)
Overall SVR12 96 (286/297) 97 (85/88) 100 (91/91)
95% CI 94.1 to 98.4 92.8 to 100 95.9 to 100
HCV genotype 1a 96 (166/173) N/A N/A
Prior pegIFN/RBV null
responder
95 (83/87) N/A N/A
Prior pegIFN/RBV partial
responder
100 (36/36) N/A N/A
Prior pegIFN/RBV relapser 94 (47/50) N/A N/A
HCV genotype 1b 97 (119/123) 97 (85/88) 100 (91/91)
Prior pegIFN/RBV null
responder
95 (56/59) 94 (29/31) 100 (32/32)
Prior pegIFN/RBV partial
responder
100 (28/28) 96 (24/25) 100 (26/26)
Prior pegIFN/RBV relapser 97 (35/36) 100 (32/32) 100 (33/33)
Outcome for subjects without SVR12
On-treatment VFa 0 0 0
Relapseb 2 (7/293) 0 0
Otherc 1 (4/297) 3 (3/88) 0

CI = confidence interval, VF = virologic failure, N/A = Not Applicable

* For subjects with GT1b infection without cirrhosis, HOLKIRA PAK alone for 12 weeks is the recommended regimen.

a. On-treatment VF was defined as confirmed HCV ≥ 25 IU/mL after HCV RNA < 25 IU/mL during treatment, confirmed 1 log10 IU/mL increase in HCV RNA from nadir, or HCV RNA persistently ≥ 25 IU/mL with at least 6 weeks of treatment.

b. Relapse was defined as confirmed HCV RNA ≥ 25 IU/mL post-treatment before or during SVR12 window among subjects with HCV RNA < 25 IU/mL at last observation during at least 11 weeks of treatment.

c. Other includes subjects not achieving SVR12 but not experiencing on-treatment VF or relapse (e.g. missing HCV RNA values in the SVR12 window).

Table 7 presents the SVR12 rates by selected subgroups for genotype 1-infected, treatment-experienced subjects in studies SAPPHIRE-II and PEARL-II.

Table 7. SVR12 rates for Selected Subgroups of Genotype 1-infected, Treatment-Experienced Subjects without Cirrhosis in SAPPHIRE-II and PEARL-II
Treatment Outcome SAPPHIRE-II
Genotype 1
PEARL-II
Genotype 1b
HOLKIRA PAK +
RBV
N=297
% (n/N)
HOLKIRA PAK +
RBV
N=88
% (n/N)
HOLKIRA PAK*
N=91
% (n/N)
IL28B
CC 91 (31/34) 100 (10/10) 100 (7/7)
Non-CC 97 (255/263) 96 (75/78) 100 (84/84)
Sex
Female 97 (126/130) 98 (44/45) 100 (37/37)
Male 96 (160/167) 95 (41/43) 100 (54/54)
Age
< 65 years 97 (269/277) 96 (70/73) 100 (76/76)
≥ 65 years 85 (17/20) 100 (15/15) 100 (15/15)
Race
Black 95 (21/22) 100 (3/3) 100 (5/5)
Non-black 96 (265/275) 96 (82/85) 100 (86/86)
Ethnicity
Hispanic or Latino 95 (21/22) 50 (1/ 2) 100 (1/ 1)
None of the above 96 (265/275) 98 (84/86) 100 (90/90)
Body mass index
< 30 kg/m2 97 (231/238) 96 (68/71) 100 (69/69)
≥ 30 kg/m2 93 (55/59) 100 (17/17) 100 (22/22)
Baseline HCV RNA
< 800000 IU/mL 100 (42/42) 100 (13/13) 100 (9/9)
≥ 800000 IU/mL 96 (244/255) 96 (72/75) 100 (82/82)
Baseline fibrosis stage
F0-F1 98 (197/202) 97 (61/63) 100 (59/59)
F2 94 (50/53) 100 (13/13) 100 (19/19)
≥ F3 93 (39/42) 92 (11/12) 100 (13/13)
History of depression or
bipolar disorder
No 96 (220/229) 97 (71/73) 100 (83/83)
Yes 97 (66/68) 93 (14/15) 100 (8/8)

* For subjects with GT1b infection without cirrhosis, HOLKIRA PAK alone for 12 weeks is the recommended regimen.

These baseline viral (genotype 1 subtype, baseline viral load) and host factors (prior treatment response, sex, race, ethnicity, age, IL28B allele, baseline body mass index, history of depression or bipolar disorder, fibrosis stage) were not associated with lower SVR12 rates across subgroups.

In addition, subjects who underwent ribavirin dose modifications did not have lower SVR12 rates.

Clinical Trial in Subjects with Cirrhosis

TURQUOISE-II was a randomized, global multicenter, open-label trial conducted exclusively in 380 genotype 1-infected subjects with cirrhosis (Child-Pugh A) who were either treatment-naïve or did not achieve SVR with prior treatment with pegIFN/RBV. HOLKIRA PAK in combination with ribavirin was administered for either 12 or 24 weeks of treatment.

Demographic and baseline characteristics for genotype 1-infected subjects with cirrhosis in study TURQUOISE-II are provided in Table 8.

Table 8. Demographic and Baseline Characteristics of Subjects with Cirrhosis in TURQUOISE-II
Characteristics TURQUOISE-II
HOLKIRA PAK + RBV
N = 380
Age (years)
Median (range) 58 (21 – 71)
Gender, n (%)
Male 267 (70.3)
Female 113 (29.7)
Race, n (%)
White 360 (94.7)
Black or African American 12 (3.2)
Asian 8 (2.1)
Ethnicity
Hispanic or Latino 45 (11.8)
None of the above 335 (88.2)
Body mass index
< 30 kg/m2 272 (71.6)
≥ 30 kg/m2 108 (28.4)
HCV genotype, n (%)
1 a 261 (68.7)
1 b 119 (31.3)
Baseline HCV RNA
Mean ± SD (log10 IU/mL) 6.47 ± 0.58
< 800000 IU/mL, n (%) 53 (13.9)
≥ 800000 IU/mL, n (%) 327 (86.1)
Prior HCV Therapy
Treatment-Naive 160 (42.1)
Treatment-experienced with pegIFN/RBV, n (%) 220 (57.9)
Null responder 137 (36.1)
Partial responder 31 (8.2)
Relapser 52 (13.7)
IL28B, n (%)
CC 69 (18.2)
CT 237 (62.4)
TT 74 (19.5)
Baseline platelet count, n (%)
< 90 x109/L 56 (14.7)
≥ 90 x109/L 324 (85.3)
Baseline albumin, n (%)
< 35 g/L 43 (11.3)
≥ 35 g/L 337 (88.7)
History of depression or bipolar disorder, n (%)
No 286 (75.3)
Yes 94 (24.7)

Study Results

Table 9 shows the SVR12 rates for genotype 1-infected subjects with cirrhosis who were treatment-naïve or previously treated with pegIFN/RBV. Both treatment groups met the primary efficacy endpoint.

Table 9. SVR12 for Genotype 1-Infected Subjects with Cirrhosis who were Treatment-Naïve or Previously Treated with pegIFN/RBV in TURQUOISE-II
Treatment Outcome HOLKIRA PAK with RBV
12 Weeks* 24 Weeks
% (n/N)% (n/N) % (n/N)
Overall SVR12 92 (191/208)d 96 (165/172)d
97.5% CI 87.6 to 96.1 92.6 to 99.3
HCV genotype 1a 89 (124/140) 94 (114/121)
Treatment naïve 92 (59/64) 93 (52/56)
Prior pegIFN/RBV null responders 80 (40/50) 93 (39/42)**
Prior pegIFN/RBV partial responders 100 (11/11) 100 (10/10)
Prior pegIFN/RBV prior relapsers 93 (14/15) 100 (13/13)
HCV genotype 1b 99 (67/68) 100 (51/51)
Treatment naïve 100 (22/22) 100 (18/18)
Prior pegIFN/RBV null responders 100 (25/25) 100 (20/20)
Prior pegIFN/RBV partial responders 86 (6/7) 100 (3/3)
Prior pegIFN/RBV prior relapsers 100 (14/14) 100 (10/10)
Outcome for subjects without SVR12
On-treatment VFa <1 (1/208) 2 (3/172)
Relapseb 6 (12/203) <1 (1/164)
Otherc 2 (4/208) 2 (3/172)

CI = confidence interval, VF = virologic failure

* 12 weeks of HOLKIRA PAK with RBV is the recommended regimen for all subjects with cirrhosis,except those with genotype 1a infection and prior null response to pegIFN/RBV.

** 24 weeks of HOLKIRA PAK + ribavirin is recommended for patients with genotype 1a-infection with cirrhosis who have had a previous null response to pegIFN/RBV.

a. On-treatment VF was defined as confirmed HCV ≥ 25 IU/mL after HCV RNA < 25 IU/mL during treatment, confirmed 1 log10 IU/mL increase in HCV RNA from nadir, or HCV RNA persistently ≥ 25 IU/mL with at least 6 weeks of treatment.

b. Relapse was defined as confirmed HCV RNA ≥ 25 IU/mL post-treatment before or during SVR12 window among subjects with HCV RNA < 25 IU/mL at last observation during at least 11 or 22 weeks of treatment, for subjects assigned to 12 or 24 weeks of treatment, respectively.

c. Other includes subjects not achieving SVR12 but not experiencing on-treatment VF or relapse (e.g. missing HCV RNA values in the SVR12 window).

d. Based on logistic regression, the difference between treatment arms was not statistically significant (p value = 0.089).

Table 10 presents the SVR12 rates by selected subgroups for genotype 1-infected subjects with cirrhosis who were treatment-naïve or previously treated with pegIFN/RBV.

Table 10. SVR12 rates for Selected Subgroups of Genotype 1-infected Subjects with Cirrhosis who were Treatment-Naïve or Previously Treated with pegIFN/RBV in TURQUOISE-II
Subgroup TURQUOISE-II
HOLKIRA PAK + RBV
12 Weeks
N = 208
24 Weeks
N = 172
n/N (%) n/N (%)
IL28B
CC 94 (33/35) 97 (33/34)
Non-CC 91 (158/173) 96 (132/138)
Sex
Female 94 (58/62) 96 (49/51)
Male 91 (133/146) 96 (116/121)
Age
< 65 years 91 (166/182) 95 (142/149)
≥ 65 years 96 (25/26) 100 (23/23)
Race
Black 100 (6/6 ) 83 (5/6)
Non-black 92 (185/202) 96 (160/166)
Ethnicity
Hispanic or Latino 84 (21/25) 95 (19/20)
None of the above 93 (170/183) 96 (146/152)
Body mass index
< 30 kg/m2 92 (135/146) 97 (122/126)
≥ 30 kg/m2 90 (56/62) 93 (43/46)
Baseline HCV RNA
< 800000 IU/mL 91 (31/34) 89 (17/19)
≥ 800000 IU/mL 92 (160/174) 97 (148/153)
Baseline platelet count
< 90 x 109/L 83 (25/30) 96 (25/26)
≥ 90 x 109/L 93 (166/178) 96 (140/146)
Baseline albumin
< 35 g/L 84 (21/25) 89 (16/18)
≥ 35 g/L 93 (170/183) 97 (149/154)
History of depression or bipolar
disorder
No 91 (143/157) 96 (124/129)
Yes 94 (48/51) 95 (41/43)

Subjects who underwent ribavirin dose modifications did not have lower SVR12 rates.

Pooled Analyses of Clinical Trials

Durability of Response

Overall, 660 subjects in Phase 2 and 3 clinical trials had HCV RNA results for both the SVR12 and SVR24 time points. Among these subjects, the positive predictive value of SVR12 on SVR24 was 99.8%.

Pooled Efficacy Analysis

In Phase 3 clinical trials, 1096 subjects (including 202 with cirrhosis) received the recommended regimen for their HCV subtype, cirrhosis status and previous treatment. Table 11 shows SVR rates for these subjects. Among subjects who received the recommended regimen in Phase 3 clinical trials, 97% achieved SVR (95% with cirrhosis and 97% without cirrhosis), while 0.5% demonstrated virologic breakthrough and 1.6% experienced post-treatment relapse.

Table 11. SVR12 Rates for Recommended Treatment Regimens
Genotype 1a Genotype 1b
No Cirrhosis
HOLKIRA PAK
with RBV
With Cirrhosis
HOLKIRA PAK
with RBV
No Cirrhosis
HOLKIRA PAK
With Cirrhosis
HOLKIRA
PAK with RBV
12 weeks 12 weeks* 12 weeks 12 weeks
Treatment-naïve 96% (402/420) 92% (61/66) 99% (208/210) 100% (22/22)
Treatment-
experienced
96% (166/173) 94% (64/68)* 100% (91/91) 98% (45/46)
Prior
pegIFN/RBV
relapser
94% (47/50) 93% (14/15) 100% (33/33) 100% (14/14)
Prior
pegIFN/RBV
partial responder
100% (36/36) 100% (11/11) 100% (26/26) 86% (6/7)
Prior
pegIFN/RBV
null responder
95% (83/87) 93% (39/42) (24 weeks) 100% (32/32) 100% (25/25)
TOTAL 96% (568/593) 93% (125/134)* 99% (299/301) 99% (67/68)

RBV = ribavirin

* All subjects received 12 weeks of therapy except for genotype 1a infected prior null responders with cirrhosis who received 24 weeks of therapy.

Impact of Ribavirin Dose Adjustment on Probability of SVR

In Phase 3 clinical trials, 91.5% of subjects did not require ribavirin dose adjustments during therapy. In the 8.5% of subjects who had ribavirin dose adjustments during therapy, the SVR rate (98.5%) was comparable to subjects who maintained their starting ribavirin dose throughout treatment.

Detailed Pharmacology

Pharmacodynamics

Ribavirin is a synthetic nucleoside analogue which has shown in vitro activity against some Deoxyribonucleic acid (DNA) and Ribonucleic acid (RNA) viruses. It is not incorporated into RNA or DNA. Inhibition of Hepatitis C Virus (HCV)-specific enzymes or HCV replication is also not seen with ribavirin or its intracellular nucleotide metabolites at physiologic concentrations.

Toxicology

Acute Toxicity

Single dose studies were conducted. The oral lethal dose (LD50) was ≥5000 mg/kg in rodents, >480 mg/kg in dogs and > 10,000 mg/kg in monkeys. When administered parenterally (intramuscular, intraperitoneal or intravenous), the LD50 was ≥800 mg/kg for those species evaluated.

Long-Term Toxicity

General toxicology studies were conducted in mice, rats, dogs and monkeys. The longest term studies along with the high dose and relationship to maximal recommended human dose (1400 mg) on a mg/m2 basis are listed in tabular format below.

Species and Duration High Dose (mg/kg/day) Multiple Compared to 1400 mg Clinical
Dose (Based on mg/m2)
Mouse (13 weeks) 600 2
Rat (26 weeks) 75 0.5
Dog (26 weeks) 20 0.5
Monkey (39 weeks) 60 0.8

Primary toxicities included effects on the erythron and testes. Erythroid effects (reduced red blood cell counts, hemoglobin, and/or hematocrit) were observed in the repeat-dose rodent studies. Anemia was indicated at the higher doses. The observed erythroid effects are similar to those reported in the literature for monkeys and patients following administration of ribavirin although it has been suggested that these erythroid effects are both dose- and duration-dependent, reversible upon dose reduction or withdrawal, and interspecies differences exist. In repeat dose studies in mice, abnormalities in sperm occurred at doses approximating human therapeutic doses. Upon cessation of treatment, essentially total recovery from ribavirin-induced testicular toxicity occurred within one or two spermatogenic cycles. Effects on erythroid parameters and testes occurred at dosages similar to below the maximal human dose of ribavirin.

Mutagenicity and Carcinogenicity

Mutagenicity

Genotoxic activity has been observed in Balb/3T3 in vitro cell transformation assays, the in vitro mouse lymphoma assay and in vivo mouse micronucleus assays. The high dose in the in vivo micronucleus assay was 2000 mg/kg. The estimated human equivalent of this dose was 167 mg/kg, based on a body surface area adjustment for a 60 kg adult, approximately 7 times the maximum recommended dose of ribavirin on a mg/m2 basis. Ribavirin was negative in the reverse bacterial mutation assay (Ames assay). In a study in rats, it was concluded that dominant lethality was not induced by ribavirin at doses up to 200 mg/kg. The estimated human equivalent of this dose was 33 mg/kg, based on a body surface area adjustment for a 60 kg adult, approximately 1.4 times the maximum recommended human daily dose of ribavirin.

Carcinogenicity

Ribavirin was not carcinogenic in a two-year study in rats at doses up to 60 mg/kg/day or in a 6-month study in p53 knockout mice at doses up to 100 mg/kg/day. The estimated human equivalents of these doses were 10 and 8.3 mg/kg, respectively, based on a body surface area adjustment for a 60 kg adult, approximately 0.4 times the maximum recommended human daily dose of ribavirin.

Reproduction and Teratology

Fertility has been assessed in a study in which males were administered ribavirin orally for 8 weeks, females for 2 weeks, prior to mating, during mating (males) and until gestation day 14 (females). Males in the 60 and 90 mg/kg/day groups exhibited paternal toxicity which consisted of decreased body weight gain; there was no evidence of maternal toxicity. There were no effects on male or female fertility in terms of mating parameters and the number of animals becoming pregnant at ribavirin doses as high as 90 mg/kg/day. Resorptions were increased at 90 mg/kg/day as evaluated on gestation day 14. The no observed adverse effect levels (NOAELs) for paternal and maternal toxicity were 30 and 90 mg/kg/day, respectively. The adult male and female NOAEL in rats for mating and fertility parameters was 90 mg/kg/day.

Ribavirin produces embryolethality and/or teratogenicity in most species tested and the dose levels at which such effects are seen are below the recommended human dose. Malformations observed in more than one rodent species included cleft palate, skeletal anomalies and CNS anomalies. The incidence and severity of teratogenic effects increased with escalation of the dose. The no observed adverse effect level (NOAEL) for embryo-fetal developmental toxicity in rats was 1 mg/kg/day.

While no effects on parturition or on lactation have been reported in terms of maternal responses in a study with prenatal and postnatal development endpoints, there was an increase in stillbirths and postnatal loss from birth to weaning on postnatal day 21 at 60 and 90 mg/kg/day. These are consistent with the findings in the developmental toxicity studies and are just later manifestations of the same activity. The NOAEL for viability and growth in the offspring in this study was 30 mg/kg/day.