Holkira Pak
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Holkira Pak - Scientific Information

Manufacture: AbbVie
Country: Canada
Condition: Hepatitis C, Hepatitis C, Chronic (Hepatitis C)
Class: Antiviral agents
Form: Tablets
Ingredients: ombitasvir, paritaprevir, ritonavir, colloidal silicon dioxide/anhydrous colloidal silica, copovidone, propylene glycol monolaurate, sodium stearyl fumarate, sorbitan monolaurate, vitamin E polyethylene glycol succinate, iron oxide red, polyethylene glycol/macrogol, polyvinyl alcohol, purified water, talc, and titanium dioxide

Pharmaceutical information

Ombitasvir

Common name:ombitasvir
Chemical name:Dimethyl ([(2S,5S)-1-(4-tert-butylphenyl) pyrrolidine-2,5-diyl]bis{benzene-4,1-diylcarbamoyl(2S)pyrrolidine-2,1-diyl[(2S)-3-methyl-1-oxobutane-1,2-diyl]})biscarbamate hydrate
Molecular formula and molecular mass:C50H67N7O8•4.5H2O (hydrate) 975.20 (hydrate)
Structural formula:



Physicochemical properties:Ombitasvir is white to light yellow to light pink powder, and is practically insoluble in aqueous buffers but is soluble in ethanol.

Paritaprevir

Common name:paritaprevir
Chemical name:(2R,6S,12Z,13aS,14aR,16aS)-N-(cyclopropylsulfonyl)-6-{[(5-methylpyrazin-2-yl)carbonyl]amino}-5,16-dioxo-2-(phenanthridin-6-yloxy)-1,2,3,6,7,8,9,10,11,13a,14,15,16,16a-tetradecahydrocyclopropa[e]pyrrolo[1,2-a][1,4] diazacyclopentadecine-14a(5H)-carboxamide dihydrate
Molecular formula and molecular mass:C40H43N7O7S•2H2O (dihydrate) 801.91 (dihydrate)
Structural formula:



Physicochemical properties:Paritaprevir is white to off-white powder with very low water solubility.

Ritonavir

Common name:ritonavir
Chemical name:[5S-(5R*,8R*,10R*,11R*)]10-Hydroxy-2-methyl-5-(1-methyethyl)-1-[2-(1-methylethyl)-4-thiazolyl]-3,6-dioxo-8,11-bis(phenylmethyl)-2,4,7,12-tetraazatridecan-13-oic acid,5-thiazolylmethyl ester
Molecular formula and molecular mass:C37H48N6O5S2 720.95
Structural formula:



Physicochemical properties:Ritonavir is white to off white to light tan powder practically insoluble in water and freely soluble in methanol and ethanol.

Dasabuvir

Common name:dasabuvir sodium monohydrate
Chemical name:Sodium 3-(3-tert-butyl-4-methoxy-5-{6-[(methylsulfonyl)amino]naphthalene-2-yl}phenyl)-2,6-dioxo-3,6-dihydro-2H-pyrimidin-1-ide hydrate (1:1:1)
Molecular formula and molecular mass:C26H26N3O5S•Na•H2O
(monosodium, monohydrate)
533.57 (monosodium,
monohydrate)
C26H27N3O5S (free acid,
anhydrate)
493.57 (free acid,
anhydrate)
Structural formula:



Physicochemical properties:Dasabuvir is white to pale yellow to pink powder, slightly soluble in water and very slightly soluble in methanol and isopropyl alcohol.

Clinical Trials

Trial Design

The efficacy and safety of HOLKIRA PAK was evaluated in six randomized Phase 3 clinical trials, including one trial exclusively in subjects with cirrhosis (Child-Pugh A), in over 2,300 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)
631GT1Double-blind, randomized, placebo controlledombitasvir/paritaprevir/ritonavir tablet: 25/150/100 mg or placebo QD;
dasabuvir tablet: 250 mg or placebo BID;
RBV tablet: 1,000 or 1,200 mg or placebo QD (divided BID);

Oral
12 weeks
PEARL-III
(M13-961)
419GT1bDouble-blind, randomized (RBV or RBV placebo)ombitasvir/paritaprevir/ritonavir tablet: 25/150/100 mg QD;
dasabuvir tablet: 250 mg BID;
RBV tablet: 1,000 to 1,200 mg or placebo QD (divided BID);

Oral
12 weeks
PEARL-IV
(M14-002)
305GT1aDouble-blind, randomized (RBV or RBV placebo)ombitasvir/paritaprevir/ritonavir tablet: 25/150/100 mg QD;
dasabuvir tablet: 250 mg BID;
RBV tablet: 1,000 to 1,200 mg or placebo QD (divided BID)

Oral
12 weeks
Treatment-Experiencedd, without Cirrhosis
SAPPHIRE-II
(M13-098)
394GT1Double-blind, randomized, placebo controlledombitasvir/paritaprevir/ritonavir tablet: 25/150/100 mg or placebo QD;
dasabuvir tablet: 250 mg or placebo BID;
RBV tablet: 1,000 or 1,200 mg or placebo QD (divided BID)

Oral
12 weeks
PEARL-II
(M13-389)
179GT1bOpen-label, randomized (with or without RBV)ombitasvir/paritaprevir/ritonavir tablet: 25/150/100 mg QD;
dasabuvir tablet: 250 mg BID;
RBV tablet: 1,000 or 1,200 mg QD (divided BID)

Oral
12 weeks
Treatment-Naïve and Treatment-Experiencedd, with Cirrhosis
TURQUOISE-II
(M13-099)
380GT1Open-label, randomized to 12 or 24 weeksombitasvir/paritaprevir/ritonavir tablet: 25/150/100 mg QD;
dasabuvir tablet: 250 mg BID;
RBV tablet: 1,000 to 1,200 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 SAPPHIRE-II and TURQUOISE-II, 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 (%)
Male344 (54.5)192 (45.8)199 (65.2)
Female287 (45.5)227 (54.2)106 (34.8)
Race, n (%)
White572 (90.6)394 (94.3)257 (84.3)
Black or African American34 (5.4)20 (4.8)36 (11.8)
Asian14 (2.2)2 (0.5)4 (1.3)
Other11 (1.7)2 (0.5)8 (2.6)
Ethnicity, n (%)
Hispanic or Latino32 (5.1)7 (1.7)28 (9.2)
None of the above599 (94.9)412 (98.3)277 (90.8)
Body mass index, n (%)
< 30 kg/m2529 (83.8)350 (83.5)245 (80.3)
≥ 30 kg/m2102 (16.2)69 (16.5)60 (19.7)
HCV genotype, n (%)
1a427 (67.7)N/A304 (99.7)
1b204 (32.3)419 (100)1 (0.3)
Baseline HCV RNA
Mean ± SD (log10 IU/mL)6.42 ± 0.636.31 ± 0.726.57 ± 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 (%)
CC194 (30.7)88 (21.0)94 (30.8)
Non-CC437 (69.3)331 (79.0)211 (69.2)
Baseline fibrosis stage, n (%)
F0-F1479 (75.9)291 (69.6)195 (63.9)
F297 (15.4)85 (20.3)56 (18.4)
≥ F355 (8.7)42 (10.0)54 (17.7)
History of depression or bipolar disorder, n (%)
No535 (84.8)380 (90.7)242 (79.3)
Yes96 (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 OutcomeSAPPHIRE-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 SVR1296 (455/473)99 (209/210)99 (207/209)97 (97/100)90 (185/205)
95% CI94.5 to 97.998.6 to 10097.7 to 10093.7 to 10086.2 to 94.3
HCV genotype 1a95 (307/322)N/AN/A97 (97/100)90 (184/204)
HCV genotype 1b98 (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)01 (1/100)3 (6/205)
Relapseb2 (7/463)d001 (1/98)5 (10/194)
Otherc2 (10/473)01 (2/209)1 (1/100)2 (4/205)

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.

** For subjects with GT1a infection without cirrhosis, HOLKIRA PAK with RBV 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).

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 OutcomeSAPPHIRE-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
CC97 (139/144)100 (44/44)98 (43/44)100 (31/31)97 (61/63)
Non-CC96 (316/329)99 (165/166)99 (164/165)96 (66/69)87 (124/142)
Sex
Female98 (197/202)99 (103/104)100 (123/123)100 (30/30)95 (72/76)
Male95 (258/271)100 (106/106)98 (84/86)96 (67/70)88 (113/129)
Age
< 65 years96 (437/454)99 (195/196)99 (188/190)97 (87/90)90 (172/192)
≥ 65 years95 (18/19)100 (14/14)100 (19/19)100 (10/10)100 (13/13)
Race
Black96 (27/28)100 (11/11)100 (11/11)100 (10/10)85 (23/27)
Non-black96 (428/445)99 (198/199)99 (196/197)97 (87/90)91 (162/178)
Ethnicity
Hispanic or Latino93 (25/27)100 (2/2)80 (4/5)90 (9/10)89 (16/18)
None of the above430/446 (96.4)99 (207/208)99 (203/204)98 (88/90)90 (169/187)
Body mass index
< 30 kg/m297 (390/402)100 (182/182)100 (168/168)99 (78/79)92 (153/166)
≥ 30 kg/m292 (65/71)96 (27/28)95 (39/41)90 (19/21)82 (32/39)
Baseline HCV RNA
< 800000 IU/mL98 (102/104)100 (51/51)100 (61/61)100 (8/8)91 (30/33)
≥ 800000 IU/mL96 (353/369)99 (158/159)99 (146/148)97 (89/92)90 (155/172)
Baseline fibrosis
stage
F0-F197 (352/363)99 (149/150)100 (141/141)97 (61/63)92 (122/132)
F294 (66/70)100 (38/38)100 (47/47)95 (20/21)83 (29/35)
≥ F393 (37/40)100 (22/22)90 (18/20)100 (16/16)89 (34/38)
History of
depression or
bipolar disorder
No97 (389/403)99 (189/190)99 (189/190)96 (80/83)89 (142/159)
Yes94 (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 (%)
Male227 (57.6)97 (54.2)
Female167 (42.4)82 (45.8)
Race, n (%)
White355 (90.1)165 (92.2)
Black or African American32 (8.1)7 (3.9)
Asian6 (1.5)3 (1.7)
Other1 (0.3)4 (2.3)
Ethnicity, n (%)
Hispanic or Latino25 (6.3)3 (1.7)
None of the above369 (93.7)176 (98.3)
Body mass index, n (%)
< 30 kg/m2316 (80.2)140 (78.2)
≥ 30 kg/m278 (19.8)39 (21.8)
HCV genotype, n (%)
1a230 (58.4)N/A
1b163 (41.4)179 (100)
Baseline HCV RNA
Mean ± SD (log10 IU/mL)6.55 ± 0.526.51 ± 0.55
< 800000 IU/mL, n (%)51 (12.9)22 (12.3)
≥ 800000 IU/mL, n (%)343 (87.1)157 (87.7)
IL28B, n (%)
CC41 (10.4)17 (9.5)
Non-CC353 (89.6)162 (90.5)
Type of response to previous pegIFN/RBV
treatment, n (%)
Null responder193 (49.0)63 (35.2)
Nonresponder/partial responder86 (21,8)51 (28.5)
Relapser115 (29.2)65 (36.3)
Baseline fibrosis stage, n (%)
F0-F1267 (67.8)122 (68.2)
F270 (17.8)32 (17.9)
≥ F357 (14.5)25 (14.0)
History of depression or bipolar disorder, n (%)
No313 (79.4)156 (87.2)
Yes81 (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 SVR1296 (286/297)97 (85/88)100 (91/91)
95% CI94.1 to 98.492.8 to 10095.9 to 100
HCV genotype 1a96 (166/173)N/AN/A
Prior pegIFN/RBV null responder95 (83/87)N/AN/A
Prior pegIFN/RBV partial responder100 (36/36)N/AN/A
Prior pegIFN/RBV relapser94 (47/50)N/AN/A
HCV genotype 1b97 (119/123)97 (85/88)100 (91/91)
Prior pegIFN/RBV null responder95 (56/59)94 (29/31)100 (32/32)
Prior pegIFN/RBV partial responder100 (28/28)96 (24/25)100 (26/26)
Prior pegIFN/RBV relapser97 (35/36)100 (32/32)100 (33/33)
Outcome for subjects without SVR12
On-treatment VFa000
Relapseb2 (7/293)00
Otherc1 (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
CC91 (31/34)100 (10/10)100 (7/7)
Non-CC97 (255/263)96 (75/78)100 (84/84)
Sex
Female97 (126/130)98 (44/45)100 (37/37)
Male96 (160/167)95 (41/43)100 (54/54)
Age
< 65 years97 (269/277)96 (70/73)100 (76/76)
≥ 65 years85 (17/20)100 (15/15)100 (15/15)
Race
Black95 (21/22)100 (3/3)100 (5/5)
Non-black96 (265/275)96 (82/85)100 (86/86)
Ethnicity
Hispanic or Latino95 (21/22)50 (1/ 2)100 (1/ 1)
None of the above96 (265/275)98 (84/86)100 (90/90)
Body mass index
< 30 kg/m297 (231/238)96 (68/71)100 (69/69)
≥ 30 kg/m293 (55/59)100 (17/17)100 (22/22)
Baseline HCV RNA
< 800000 IU/mL100 (42/42)100 (13/13)100 (9/9)
≥ 800000 IU/mL96 (244/255)96 (72/75)100 (82/82)
Baseline fibrosis stage
F0-F198 (197/202)97 (61/63)100 (59/59)
F294 (50/53)100 (13/13)100 (19/19)
≥ F393 (39/42)92 (11/12)100 (13/13)
History of depression or
bipolar disorder
No96 (220/229)97 (71/73)100 (83/83)
Yes97 (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 (%)
Male267 (70.3)
Female113 (29.7)
Race, n (%)
White360 (94.7)
Black or African American12 (3.2)
Asian8 (2.1)
Ethnicity
Hispanic or Latino45 (11.8)
None of the above335 (88.2)
Body mass index
< 30 kg/m2272 (71.6)
≥ 30 kg/m2108 (28.4)
HCV genotype, n (%)
1a261 (68.7)
1b119 (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-Naive160 (42.1)
Treatment-experienced with pegIFN/RBV, n (%)220 (57.9)
Null responder137 (36.1)
Partial responder31 (8.2)
Relapser52 (13.7)
IL28B, n (%)
CC69 (18.2)
CT237 (62.4)
TT74 (19.5)
Baseline platelet count, n (%)
< 90 x109/L56 (14.7)
≥ 90 x109/L324 (85.3)
Baseline albumin, n (%)
< 35 g/L43 (11.3)
≥ 35 g/L337 (88.7)
History of depression or bipolar disorder, n (%)
No286 (75.3)
Yes94 (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)
Overall SVR1292 (191/208)d96 (165/172)d
97.5% CI87.6 to 96.192.6 to 99.3
HCV genotype 1a89 (124/140)94 (114/121)
Treatment naïve92 (59/64)93 (52/56)
Prior pegIFN/RBV null responders80 (40/50)93 (39/42)**
Prior pegIFN/RBV partial responders100 (11/11)100 (10/10)
Prior pegIFN/RBV prior relapsers93 (14/15)100 (13/13)
HCV genotype 1b99 (67/68)100 (51/51)
Treatment naïve100 (22/22)100 (18/18)
Prior pegIFN/RBV null responders100 (25/25)100 (20/20)
Prior pegIFN/RBV partial responders86 (6/7)100 (3/3)
Prior pegIFN/RBV prior relapsers100 (14/14)100 (10/10)
Outcome for subjects without SVR12
On-treatment VFa<1 (1/208)2 (3/172)
Relapseb6 (12/203)<1 (1/164)
Otherc2 (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 HOLKIRA PAK with RBV
TURQUOISE-II
HOLKIRA PAK + RBV
12 Weeks
N = 208
24 Weeks
N = 172
% (n/N) % (n/N)
IL28B
CC94 (33/35)97 (33/34)
Non-CC91 (158/173)96 (132/138)
Sex
Female94 (58/62)96 (49/51)
Male91 (133/146)96 (116/121)
Age
< 65 years91 (166/182)95 (142/149)
≥ 65 years96 (25/26)100 (23/23)
Race
Black100 (6/6 )83 (5/6)
Nonblack92 (185/202)96 (160/166)
Ethnicity
Hispanic or Latino84 (21/25)95 (19/20)
None of the above93 (170/183)96 (146/152)
Body mass index
< 30 kg/m292 (135/146)97 (122/126)
≥ 30 kg/m290 (56/62)93 (43/46)
Baseline HCV RNA
< 800000 IU/mL91 (31/34)89 (17/19)
≥ 800000 IU/mL92 (160/174)97 (148/153)
Baseline platelet count
< 90 x 109/L83 (25/30)96 (25/26)
≥ 90 x 109/L93 (166/178)96 (140/146)
Baseline albumin
< 35 g/L84 (21/25)89 (16/18)
≥ 35 g/L93 (170/183)97 (149/154)
History of depression or bipolar
disorder
No91 (143/157)96 (124/129)
Yes94 (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 1aGenotype 1b
No Cirrhosis
HOLKIRA PAK
with RBV
With Cirrhosis
HOLKIRA PAK
with RBV
No Cirrhosis
HOLKIRA
PAK
With Cirrhosis
HOLKIRA PAK
with RBV
12 weeks12 weeks*12 weeks12 weeks
Treatment-naïve96% (402/420)92% (61/66)99% (208/210)100% (22/22)
Treatment-experienced96% (166/173)94% (64/68)*100% (91/91)98% (45/46)
Prior pegIFN/RBV relapser94% (47/50)93% (14/15)100% (33/33)100% (14/14)
Prior pegIFN/RBV partial responder100% (36/36)100% (11/11)100% (26/26)86% (6/7)
Prior pegIFN/RBV null responder95% (83/87)93% (39/42) (24 weeks)100% (32/32)100% (25/25)
TOTAL96% (568/593)93% (125/134)*99% (299/301)99% (67/68)

* 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

Effects on Electrocardiogram

The effect of a combination of paritaprevir, ombitasvir, ritonavir, and dasabuvir on QTc interval was evaluated in a randomized, double blind, placebo and active-controlled (moxifloxacin 400 mg) 4-way crossover thorough QT study in 60 healthy subjects receiving paritaprevir, ritonavir, ombitasvir and dasabuvir. In the trial, with demonstrated ability to detect small effects, supratherapeutic doses of paritaprevir 350 mg, ritonavir 150 mg, ombitasvir 50 mg and dasabuvir 500 mg did not show clinically significant QT prolongation.

Pharmacokinetics

For details regarding the ombitasvir/paritaprevir/ritonavir and dasabuvir pharmacokinetics refer to ACTION AND CLINICAL PHARMACOLOGY, Pharmacokinetics section.

Drug Interactions

See also CONTRAINDICATIONS;WARNINGS AND PRECAUTIONS, Hepatic/Biliary/Pancreatic, ALT Elevations; and DRUG INTERACTIONS.

Drug interaction studies were performed with HOLKIRA PAK and other drugs likely to be co-administered and drugs commonly used as probes for pharmacokinetic interactions. Drug interaction studies were performed with HOLKIRA PAK and antiretroviral drugs or immunosuppressants to facilitate dosing recommendations in special populations including HCV-HIV co-infected subjects or liver or kidney post-transplant subjects.

Effect of Concomitant Medications on HOLKIRA PAK

No clinically meaningful changes in exposures (Cmax and area under-the-curve [AUC]) warranting dose adjustment in HOLKIRA PAK were observed when administered with:

  • alprazolam, zolpidem
  • amlodipine
  • atazanavir once daily without ritonavir (co-dosed with ombitasvir/paritaprevir/ritonavir morning administration), tenofovir, emtricitabine raltegravir, emtricitabine/tenofovir, darunavir once daily or twice daily, rilpivirine
  • buprenorphine/naloxone, methadone
  • cyclosporine, tacrolimus
  • digoxin
  • duloxetine, escitalopram
  • furosemide
  • ketoconazole
  • norethindrone
  • omeprazole
  • pravastatin, rosuvastatin
  • warfarin

Co-administration of carbamazepine with HOLKIRA PAK led to approximately 66 to 71%, 83 to 88%, 30 to 32% and 55 to 70% decrease in paritaprevir, ritonavir, ombitasvir and dasabuvir exposures (Cmax and AUC), respectively. There was no clinically relevant change in carbamazepine exposures, however, exposures of carbamazepine’s metabolite, carbamazepine-10, 11-epoxide, decreased by 16 to 43%. Concomitant use of HOLKIRA PAK with carbamazepine may lead to loss of virologic response and is therefore contraindicated (see CONTRAINDICATIONS).

The effect of gemfibrozil was evaluated with paritaprevir/ritonavir in combination with dasabuvir. In the presence of gemfibrozil, paritaprevir exposures (Cmax and AUC) increased by 21 to 38% while dasabuvir Cmax and AUC showed an increase of 2-fold and 11-fold, respectively. Concomitant use of gemfibrozil is therefore contraindicated with HOLKIRA PAK (see CONTRAINDICATIONS).

Effect of HOLKIRA PAK on Concomitant Medications

Table 12 lists:

  • Drugs which do not require dose adjustment when co-administered with HOLKIRA™ PAK. Clinically relevant changes warranting dose adjustment were not observed in the exposures of these drugs when co-administered with HOLKIRA PAK.
  • Drugs which require dose adjustment when co-administered with HOLKIRA PAK. Clinically relevant changes were observed in the exposures of these drugs and hence dose adjustment is recommended for these drugs.
  • Drugs which are not recommended to be co-administered with HOLKIRA PAK.
Table 12. Effect of HOLKIRA PAK on Concomitant Medications
Drugs which do not require dose
adjustment when co-
dministered with
HOLKIRA PAK
Drugs for which dose
adjustments are recommended
when co-administered with
HOLKIRA PAK
Drugs which are not
recommended to be
administered with
HOLKIRA PAK
• buprenorphine
• digoxin (therapeutic drug
monitoring recommended)
• duloxetine
• emtricitabine
• escitalopram
• methadone
• norethindrone
• raltegravir
• tenofovir
• warfarin (INR monitoring
recommended)
• zolpidem
• alprazolam (clinical
monitoring recommended)
• amlodipine
• atazanavira
• cyclosporine
• darunavirb
• darunavir/ritonavirb
• furosemide
• ketoconazole
• omeprazole
• quetiapine
• rosuvastatin, pravastatin
• tacrolimus

(see Table 13 for pharmacokinetic
interactions)
• atazanavir/ritonavirc
• lopinavir/ritonavir (800/200
mg once daily or 400/100 mg
twice daily)d
• rilpivirine (morning or
evening administration)e


(see Table 13)

a. Atazanavir should be co-administered with ombitasvir/paritaprevir/ritonavir without additional ritonavir.

b. Ritonavir should NOT be administered with darunavir (once daily or twice daily) when dosed with ombitasvir/paritaprevir/ritonavir. When darunavir is not administered with ombitasvir/paritaprevir/ritonavir, 100 mg ritonavir should be administered with darunavir.

c. Atazanavir with ritonavir increased paritaprevir exposures up to 3.2-fold and hence atazanavir/ritonavir is not recommended to be administered with HOLKIRA PAK.

d. Lopinavir/ritonavir (800/200 mg once daily or 400/100 mg twice daily) is not recommended to be administered with HOLKIRA PAK because of an increase in paritaprevir exposures (Cmax and AUC increases up to 2.2-fold) and due to higher total doses of ritonavir (300 mg/day).

e. Co-administration of HOLKIRA PAK with rilpivirine once daily is not recommended due to potential for QT interval prolongation with higher exposures of rilpivirine.

Ethinyl estradiol-containing medications must be discontinued prior to starting therapy with HOLKIRA PAK (see CONTRAINDICATIONS and WARNINGS AND PRECAUTIONS, Hepatic/Biliary/Pancreatic, ALT Elevations).

Table 13 summarizes the effect of HOLKIRA PAK on the pharmacokinetics co-administered drugs which showed clinically relevant changes.

For information regarding clinical recommendations, refer to DRUG INTERACTIONS.

Table 13. Drug Interactions Pharmacokinetic Parameters for Co-administered Drug in the Presence of Combination of paritaprevir/ritonavir, ombitasvir, and dasabuvir
Co-administered DrugDose of Co-administered Drug (mg)Duration of Co-administrationnRatio (with or without HOLKIRA PAK) of Co-administered Drug Pharmacokinetic Parameters (90% CI); No Effect = 1.00
CmaxAUCCtrough
alprazolam0.51 day121.09 (1.03, 1.15)1.34 (1.15, 1.55)NA
amlodipine51 day141.26 (1.11, 1.44)2.57 (2.31, 2.86)NA
cyclosporine301 day101.01 (0.85, 1.20)5.69 (4.67, 6.93)15.8a (13.8, 18.1)
furosemide201 day121.42 (1.17, 1.72)1.08 (1.00, 1.17)NA
ketoconazole4001 day121.15 (1.09, 1.21)2.17 (2.05, 2.29)NA
omeprazole401 day110.62 (0.48, 0.80)0.62 (0.51, 0.75)NA
pravastatin1014 day121.37 (1.11, 1.69)1.82 (1.60, 2.08)NA
rosuvastatin514 day117.13 (5.11, 9.96)2.59 (2.09, 3.21)0.59 (0.51, 0.69)
rilpivirine25 (morning)14 day202.55 (2.08, 3.12)3.25 (2.80, 3.77)3.62 (3.12, 4.21)
25 (evening)14 day202.16 (1.79, 2.61)2.50 (2.05, 3.06)2.87 (2.28, 3.62)
25 (night: 4 hrs after dinner)14 day203.00 (2.50, 3.59)3.43 (3.03, 3.89)3.73 (3.16, 4.40)
tacrolimus21 day123.99 (3.21, 4.97)57.1 (45.5, 71.7)16.6a (13.0, 21.2)

NA: Not available

a. C24: concentration at 24 hours following single dose of cyclosporine or tacrolimus with or without ombitasvir/paritaprevir/ritonavir and dasabuvir.

Microbiology

Mechanism of Action

HOLKIRA PAK combines three direct-acting antiviral agents with distinct mechanisms of action and non-overlapping resistance profiles to target HCV at multiple steps in the viral lifecycle.

Ombitasvir

Ombitasvir is an inhibitor of HCV NS5A which is essential for viral replication. In replicon cell culture assays, ombitasvir has half maximal effective concentration (EC50) values of 14.1 and 5.0 pM against HCV genotypes 1a and 1b, respectively.

Paritaprevir

Paritaprevir is an inhibitor of HCV NS3/4A protease which is necessary for the proteolytic cleavage of the HCV encoded polyprotein (into mature forms of the NS3, NS4A, NS4B, NS5A, and NS5B proteins) and is essential for viral replication. In a biochemical assay, paritaprevir inhibited the proteolytic activity of the recombinant HCV genotype 1a and 1b NS3/4A protease enzymes with half maximal inhibitory concentration (IC50) values of 0.18 and 0.43 nM, respectively.

Dasabuvir

Dasabuvir is a non-nucleoside inhibitor of the HCV RNA-dependent RNA polymerase encoded by the NS5B gene, which is essential for replication of the viral genome. In a biochemical assay, dasabuvir inhibited the polymerase activity of the recombinant HCV genotype 1a and 1b HCV NS5B enzymes with IC50 values of 2.8 and 10.7 nM, respectively.

Activity in Cell Culture and/or Biochemical Studies

Ombitasvir

The EC50 of ombitasvir against genotype 1a-H77 and 1b-Con1 strains in HCV replicon cell culture assays was 14.1 and 5 pM, respectively. The activity of ombitasvir was attenuated 11- to 13-fold in the presence of 40% human plasma. The mean EC50 of ombitasvir against replicons containing NS5A from a panel of treatment-naïve genotype 1a and 1b isolates in the HCV replicon cell culture assay was 0.66 pM (range 0.35 to 0.88 pM; n = 11) and 1.0 pM (range 0.74 to 1.5 pM; n = 11), respectively. Ombitasvir has EC50 values of 12, 4.3, 19, 1.7, 3.2, and 366 pM against replicon cell lines constructed with NS5A from single isolates representing genotypes 2a, 2b, 3a, 4a, 5a, and 6a, respectively.

Paritaprevir

The EC50 of paritaprevir against genotype 1a-H77 and 1b-Con1 strains in the HCV replicon cell culture assay was 1.0 and 0.21 nM, respectively. The activity of paritaprevir was attenuated 24- to 27-fold in the presence of 40% human plasma. The mean EC50 of paritaprevir against replicons containing NS3 from a panel of treatment-naïve genotype 1a and 1b isolates in the HCV replicon cell culture assay was 0.86 nM (range 0.43 to 1.87 nM; n = 11) and 0.06 nM (range 0.03 to 0.09 nM; n = 9), respectively. Paritaprevir had an EC50 value of 5.3 nM against the 2a-JFH-1 replicon cell line, and EC50 values of 19, 0.09, and 0.68 nM against replicon cell lines containing NS3 from a single isolate each of genotype 3a, 4a, and 6a, respectively. In a biochemical assay, paritaprevir inhibited the activity of NS3/4A enzymes from single isolates of genotypes 2a, 2b, 3a, and 4a with IC50 values of 2.4, 6.3, 14.5, and 0.16 nM, respectively.

Ritonavir did not exhibit a direct antiviral effect on the replication of HCV subgenomic replicons, and the presence of ritonavir did not affect the in vitro antiviral activity of paritaprevir.

Dasabuvir

The EC50 of dasabuvir against genotype 1a-H77 and 1b-Con1 strains in HCV replicon cell culture assays was 7.7 and 1.8 nM, respectively. The replicon activity of dasabuvir was attenuated 12- to 13-fold in the presence of 40% human plasma. The mean EC50 of dasabuvir against replicons containing NS5B from a panel of treatment-naïve genotype 1a and 1b isolates in the HCV replicon cell culture assay was 0.77 nM (range 0.4 to 2.1 nM; n = 11) and 0.46 nM (range 0.2 to 2 nM; n = 10), respectively. In biochemical assays, dasabuvir inhibited a panel of genotype 1a and 1b polymerases with a mean IC50 value of 4.2 nM (range 2.2 to 10.7 nM; n = 7).

Combination Activity in vitro

All two-drug combinations of paritaprevir, ombitasvir, dasabuvir and ribavirin demonstrated additive to synergistic inhibition of HCV genotype 1 replicon at the majority of drug concentrations studied in short term cell culture assays. In long term replicon survival assays, the ability of drug-resistant cells to form colonies in the presence of a single drug or drugs in combination was evaluated. In pair-wise combinations of paritaprevir, ombitasvir, and dasabuvir at concentrations 10-fold over their respective EC50, colony numbers were reduced by more than 100-fold by two drugs as compared to each drug alone. When all three drugs were combined at concentrations of 5-fold above their respective EC50, no drug-resistant colonies survived.

Resistance in Cell Culture

Resistance to paritaprevir, ombitasvir, or dasabuvir conferred by variants in NS3, NS5A, or NS5B, respectively, selected in cell culture or identified in Phase 2b and 3 clinical trials were phenotypically characterized in the appropriate genotype 1a or 1b replicons.

In genotype 1a, substitutions F43L, R155K, A156T, and D168A/H/V/Y in HCV NS3 reduced susceptibility to paritaprevir. In the genotype 1a replicon, the activity of paritaprevir was reduced 20-, 37-, and 17-fold by the F43L, R155K and A156T substitutions, respectively. The activity of paritaprevir was reduced 96-fold by D168V, and 50- to 219-fold by each of the other D168 substitutions. The activity of paritaprevir in genotype 1a was not significantly affected (less than or equal to 3-fold) by single substitutions V36A/M, V55I, Y56H, Q80K or E357K. Double variants including combinations of V36M, Y56H, or E357K with R155K or with a D168 substitution reduced the activity of paritaprevir by an additional 2- to 3-fold relative to the single R155K or D168 substitution. In genotype 1b, substitutions R155Q, D168H, D168V, and Y56H in combination with D168V in HCV NS3 reduced susceptibility to paritaprevir. In the genotype 1b replicon, the activity of paritaprevir was reduced 76- and 159-fold by D168H and D168V, respectively. Y56H alone could not be evaluated due to poor replication capacity, however, the combination of Y56H and D168V reduced the activity of paritaprevir by 2472-fold.

In genotype 1a, substitutions M28T/V, Q30R, H58D, Y93C/H/N, and M28V + Q30R in HCV NS5A reduced susceptibility to ombitasvir. In the genotype 1a replicon, the activity of ombitasvir was reduced by 58- and 243-fold against the M28V and H58D substitutions, respectively, and 800- and 1675-fold by the Q30R and Y93C substitutions, respectively. Y93H, Y93N or M28V in combination with Q30R reduced the activity of ombitasvir by more than 40,000-fold. In genotype 1b, substitutions L31F/V, as well as Y93H alone or in combination with L28M, R30Q, L31F/M/V or P58S in HCV NS5A reduced susceptibility to ombitasvir. In the genotype 1b replicon, the activity of ombitasvir was reduced by less than 10-fold by variants at amino acid positions 30 and 31. The activity of ombitasvir was reduced by 77-, 284- and 142-fold against the genotype 1b substitutions Y93H, R30Q in combination with Y93H, and L31M in combination with Y93H, respectively. All other double substitutions of Y93H in combination with substitutions at positions 28, 31, or 58 reduced the activity of ombitasvir by more than 400-fold.

In genotype 1a, substitutions C316Y, M414T, Y448H, A553T, G554S, S556G/R, and Y561H in HCV NS5B reduced susceptibility to dasabuvir. In the genotype 1a replicon, the activity of dasabuvir was reduced 21- to 32-fold by the M414T, S556G or Y561H substitutions; 152- to 261-fold by the A553T, G554S or S556R substitutions; and 1472- and 975-fold by the C316Y and Y448H substitutions, respectively. G558R and D559G/N were observed as treatment-emergent substitutions but the activity of dasabuvir against these variants could not be evaluated due to poor replication capacity. In genotype 1b, substitutions C316N, C316Y, M414T, Y448H, and S556G in HCV NS5B reduced susceptibility to dasabuvir. The activity of dasabuvir was reduced by 5- and 11-fold by C316N and S556G, respectively; 46-fold by M414T or Y448H; and 1569-fold by the C316Y substitutions in the genotype 1b replicon. Dasabuvir retained full activity against replicons containing substitutions S282T in the nucleoside binding site, M423T in the lower thumb site, and P495A/S, P496S or V499A in the upper thumb site.

Effect of Baseline HCV Substitutions/Polymorphisms on Treatment Response

A pooled analysis of subjects in the Phase 2b and 3 clinical trials treated with paritaprevir, ombitasvir, and dasabuvir with or without ribavirin was conducted to explore the association between the baseline NS3/4A, NS5A or NS5B substitutions/polymorphisms and treatment outcome in recommended regimens.

In the greater than 500 genotype 1a baseline samples in this analysis, the most frequently observed resistance-associated variants were M28V (7.4%) in NS5A and S556G (2.9%) in NS5B. Q80K, although a highly prevalent polymorphism in NS3 (41.2% of samples), confers minimal resistance to paritaprevir. Resistance-associated variants at amino acid positions R155 and D168 in NS3 were rarely observed (less than 1%) at baseline. In the greater than 200 genotype 1b baseline samples in this analysis, the most frequently observed resistance-associated variants observed were Y93H (7.5%) in NS5A, and C316N (17.0%) and S556G (15%) in NS5B. Given the low virologic failure rates observed with recommended treatment regimens for HCV genotype 1a- and 1b-infected subjects, the presence of baseline variants appears to have little impact on the likelihood of achieving SVR.

Resistance in Clinical Studies

Of the 2,510 HCV genotype 1 infected subjects in the Phase 2b and 3 clinical trials treated with regimens containing paritaprevir, ombitasvir, and dasabuvir with or without ribavirin (for 8, 12, or 24 weeks), a total of 74 subjects (3%) experienced virologic failure (primarily post-treatment relapse). Treatment-emergent variants and their prevalence in these virologic failure populations are shown in Table 14. In the 67 genotype 1a infected subjects, NS3 variants were observed in 50 subjects, NS5A variants were observed in 46 subjects, NS5B variants were observed in 37 subjects, and treatment-emergent variants were seen in all 3 drug targets in 30 subjects. In the 7 genotype 1b infected subjects, treatment-emergent variants were observed in NS3 in 4 subjects, in NS5A in 2 subjects, and in both NS3 and NS5A in 1 subject. No genotype 1b infected subjects had treatment-emergent variants in all 3 drug targets.

Table 14. Treatment-Emergent Amino Acid Substitutions in the Pooled Analysis of HOLKIRA PAK with and without Ribavirin Regimens in Phase 2b and Phase 3 Clinical Trials (N = 2510)
Target Emergent Amino Acid Substitutionsa Genotype 1a
N = 67b
% (n)
Genotype 1b
N = 7
% (n)
NS3V55Ic6 (4)-
Y56Hc9 (6)42.9 (3)d
I132Vc6 (4)-
R155K13.4 (9)-
D168A6 (4)-
D168V50.7 (34) 42.9 (3)d
D168Y7.5 (5)-
V36Ac, V36Mc, F43Lc, D168H, E357Kc< 5%-
NS5AM28T20.9 (14)-
M28Ve9 (6)-
Q30Re40.3 (27)-
Y93H28.6 (2)
H58D, H58P, Y93N< 5%-
NS5BA553T6.1 (4)-
S556G33.3 (22)-
C316Y, M414T, G554S, S556R, G558R, D559G, D559N, Y561H< 5%-

a. Observed in at least 2 subjects of the same subtype.

b. N = 66 for the NS5B target.

c. Substitutions were observed in combination with other emergent substitutions at NS3 position R155 or D168.

d. Observed in combination in genotype 1b-infected subjects.

e. Observed in combination in 6% (4/67) of the subjects.

Note: The following variants were selected in cell culture but were not treatment-emergent: NS3 variants A156T in genotype 1a, and R155Q and D168H in genotype 1b; NS5A variants Y93C/H in genotype 1a, and L31F/V or Y93H in combination with L28M, L31F/V or P58S in genotype 1b; and NS5B variants Y448H in genotype 1a, and M414T and Y448H in genotype 1b.

Persistence of Resistance-Associated Substitutions

The persistence of paritaprevir, ombitasvir, and dasabuvir resistance-associated amino acid substitutions in NS3, NS5A, and NS5B, respectively, was assessed in genotype 1a-infected subjects in Phase 2b trials. Paritaprevir treatment-emergent variants V36A/M, R155K or D168V were observed in NS3 in 47 subjects. Ombitasvir treatment-emergent variants M28T, M28V or Q30R in NS5A were observed in 32 subjects. Dasabuvir treatment-emergent variants M414T, G554S, S556G, G558R or D559G/N in NS5B were observed in 34 subjects.

NS3 variants V36A/M and R155K and NS5B variants M414T and S556G remained detectable at post-treatment Week 48, whereas NS3 variant D168V and all other NS5B variants were not observed at post-treatment Week 48. All treatment-emergent variants in NS5A remained detectable at post-treatment Week 48. Due to high SVR rates in genotype 1b, trends in persistence of treatment-emergent variants in this genotype could not be established.

The lack of detection of virus containing a resistance-associated substitution does not indicate that the resistant virus is no longer present at clinically significant levels. The long-term clinical impact of the emergence or persistence of virus containing HOLKIRA PAK-resistance-associated substitutions is unknown.

Cross-resistance

Cross-resistance is expected among NS5A inhibitors, NS3/4A protease inhibitors, and non-nucleoside NS5B inhibitors by class. The impact of prior ombitasvir, paritaprevir or dasabuvir treatment experience on the efficacy of other NS5A inhibitors, NS3/4A protease inhibitors, or NS5B inhibitors has not been studied.

Toxicology

Repeat-Dose Toxicity

Paritaprevir/ritonavir

Paritaprevir/ritonavir was well tolerated in repeated-dose oral toxicity studies in mice, rats and dogs. No adverse findings were observed during paritaprevir/ritonavir repeat-dose toxicology studies up to and including 3-months duration in rats and CD-1 mice, and 9-months duration in dogs. The safety margins for studies in rat, mouse and dog were 15-, 60-, and 210-fold above the efficacious AUC of 7 mcg•hr/mL.

Paritaprevir/ritonavir associated adverse effects have been limited to the gallbladder of mice in a 6 month study in CD-1 mice. The adverse findings included focal erosion/ulceration, inflammation (both acute and chronic active), and epithelial hypertrophy/hyperplasia in some mice at paritaprevir exposures of 30-folds above the efficacious AUC. In contrast, gallbladder findings in the dog have been limited to minimal epithelial degeneration/necrosis. No evidence of disruption of the epithelial integrity has been noted in the dog, despite achieving exposures of up to 210-folds above the efficacious AUC. Importantly, the severity and character of the gallbladder change in the dog did not progress from the 1-month to the 9 month toxicology study, despite achieving higher exposures in the 9-month study as compared to the 1-month study.

Evaluation of paritaprevir/ritonavir in nonclinical species resulted in non-adverse changes in the rodent which were considered to be related to ritonavir. Findings in the rat and mouse included an increase in liver weight (microscopic correlate of hepatocellular hypertrophy) and an increase in serum triglycerides and cholesterol. Findings limited to the rat included hypertrophy of the thyroid follicular epithelium and an increase in transaminases (alanine aminotransferase and aspartate aminotransferase). Findings in both the rat and mouse were mild and reversible upon discontinuation of paritaprevir/ritonavir. The morphological changes in the liver and thyroid are consistent with adaptive findings reported in rodents administered compounds that result in hepatic microsomal enzyme induction. The thyroid follicular hypertrophy is considered to be secondary to disruption of thyroid hormone homeostasis secondary to hepatic enzyme induction and is not considered relevant for humans. Ritonavir-related effects were not present in the paritaprevir/ritonavir studies in dogs despite achieving higher exposures. The non-adverse effects in the rodent were present at ritonavir exposures approximately 2-fold above clinical exposure of 9.5 mcg•hr/mL. In contrast, these findings were not present in the dog at ritonavir exposures approximately 4-fold clinical exposure.

Ombistasvir

Ombitasvir was well tolerated without adverse effects in repeated-dose oral toxicity studies in mice, rats and dogs. Repeat dose toxicology studies were completed in mice (up to 6-months duration), rats (up to 3-months duration) and dogs (up to 6-months duration). Maximum achieved ombitasvir plasma exposures in the longest duration studies at least 20-fold or higher as compared to human exposure at the clinical dose.

Both inactive, major, disproportionate human metabolites of ombitasvir (M29, M36) were negative in in vitro and in vivo genetic toxicology tests and did not cause adverse effects in 1-month repeat-dose and embryo-fetal developmental oral toxicity studies at AUC exposures that were ≥ 25-fold relative to anticipated human exposures.

Dasabuvir

Dasabuvir was well tolerated in repeated-dose oral toxicity studies in mice, rats and dogs. Repeat dose toxicology studies were completed in mice (up to 3-months duration in CD-1 mice), rats (up to 6-months duration), dogs (up to 9-months duration) and monkeys (up to 1-month duration). The safety margins in these studies were approximately 30-fold for the rodent (mouse and rat), 120-fold for the dog, and 15-fold for the monkey as compared to human exposure at the clinical dose.

Mutagenicity and Carcinogenicity

Ombitasvir

Ombitasvir and its major inactive human metabolites (M29, M36) were not genotoxic in a battery of in vitro or in vivo assays, including bacterial mutagenicity, chromosome aberration using human peripheral blood lymphocytes and in vivo mouse micronucleus assays.

Ombitasvir was not carcinogenic in a 6-month transgenic mouse study up to the highest dosage tested (150 mg per kg per day), resulting in ombitasvir AUC exposures approximately 26-fold higher than those in humans at the recommended clinical dose of 25 mg.

The carcinogenicity study of ombitasvir in rats is ongoing.

Paritaprevir/ritonavir

Paritaprevir was positive in an in vitro human chromosome aberration test. Paritaprevir was negative in a bacterial mutation assay, and in two in vivo genetic toxicology assays (rat bone marrow micronucleus and rat liver Comet tests).

Ritonavir has been tested for genotoxicity in various in vitro and in vivo assays including bacterial mutation assay, mouse lymphoma assay, mouse micronucleus test and chromosomal aberration assay. Ritonavir was cytotoxic but not mutagenic in any of the tests performed.

Paritaprevir/ritonavir was not carcinogenic in a 6-month transgenic mouse study up to the highest dosage tested (300/30 mg per kg per day), resulting in paritaprevir AUC exposures approximately 38-fold higher and ritonavir exposure of 4-fold higher than those in humans at the clinical dose. Similarly, paritaprevir/ritonavir was not carcinogenic in a 2-year rat study up to the highest dosage tested (300/30 mg per kg per day), resulting in paritaprevir AUC exposures approximately 8-fold higher and ritonavir exposure of 4-fold higher than those in humans at the clinical dose.

Dasabuvir

Dasabuvir was not genotoxic in a battery of in vitro or in vivo assays, including bacterial mutagenicity, chromosome aberration using human peripheral blood lymphocytes and in vivo rat micronucleus assays.

Dasabuvir was not carcinogenic in a 6-month transgenic mouse study up to the highest dosage tested (2000 mg per kg per day), resulting in dasabuvir AUC exposures approximately 39-fold higher than those in humans at the recommended dose of 500 mg (250 mg twice daily).

The carcinogenicity study of dasabuvir in rats is ongoing.

Use with Ribavirin

Ribavirin was shown to be genotoxic in several in vitro and in vivo assays. Ribavirin was not carcinogenic in a 6-month p53+/- transgenic mouse study or a 2-year carcinogenicity study in rats. See the Product Monograph for ribavirin.

Reproduction and Teratology

Ombitasvir

Ombitasvir had no effects on embryo-fetal viability or on fertility when evaluated in mice up to the highest dose of 200 mg per kg per day. Ombitasvir AUC exposures at this dosage were approximately 25-fold the exposure in humans at the recommended clinical dose.

Paritaprevir/ritonavir

Paritaprevir/ritonavir had no effects on embryo-fetal viability or on fertility when evaluated in rats up to the highest dose of 450/45 mg per kg per day. Paritaprevir AUC exposures at this dosage were approximately 8-fold and ritonavir 2-fold higher than the exposure in humans at the recommended clinical dose.

Dasabuvir

Dasabuvir had no effects on embryo-fetal viability or on fertility when evaluated in rats up to the highest dosage of 800 mg per kg per day. Dasabuvir AUC exposures at this dosage were approximately 33-fold the exposure in humans at the recommended clinical dose.

Use with Ribavirin

In fertility studies in male animals, ribavirin induced reversible testicular toxicity. Refer to Product Monograph for ribavirin for additional information.