Drugs

Drug Trials Snapshots: ZEPATIER

HOW TO USE THIS SNAPSHOT
The information provided in Snapshots highlights who participated in the clinical trials that supported the FDA approval of this drug, and whether there were differences among sex, race, and age groups. The “MORE INFO” bar shows more detailed, technical content for each section. The Snapshot is intended as one tool for consumers to use when discussing the risks and benefits of the drugs.

LIMITATIONS OF THIS SNAPSHOT:
Do not rely on Snapshots to make decisions regarding medical care. Always speak to your health provider about the risks and benefits of a drug. Refer to the ZEPATIER Prescribing Information for complete information.

ZEPATIER (elbasvir and grazoprevir)
(ZEP-ah-teer)
Merck & Co
Approval date: January 28, 2016


DRUG TRIALS SNAPSHOT SUMMARY:

What is the drug for?

ZEPATIER is a drug used to treat adults who have a specific type of Hepatitis C virus (HCV) infection, called chronic Hepatitis C genotypes 1 or 4 infection.

ZEPATIER is a combination of two anti-viral drugs: elbasvir and grazoprevir. It is intended to be used on its own or in combination with another previously approved HCV drug called ribavirin.

Hepatitis C is a viral disease that causes inflammation of the liver that can lead to decreased liver function or liver failure.

How is this drug used?

ZEPATIER is a tablet that is taken once a day.

What are the benefits of this drug?

ZEPATIER may clear the body of the hepatitis C virus as measured by a blood test 12 weeks after finishing treatment.

What are the benefits of this drug (results of trials used to assess efficacy)?

The tables below (Tables 2, 3 and 4) summarize efficacy results for the clinical trials based on the total of 1373 patients.

Each table summarizes the percentage of subjects in specific trial(s) who achieved the primary efficacy endpoint. The primary endpoint was Sustained Virologic Response (SVR) measured at 12 weeks after cessation of treatment and was defined as HCV RNA below the lower limit of quantification (SVR12).

Table 2. C-EDGE TN and C-EDGE COINFECTION Trials: SVR12 in Treatment-Naïve Subjects with or without Cirrhosis with Genotype 1 HCV Treated with ZEPATIER for 12 Weeks

TrialC-EDGE TN
(Immediate Treatment Group)
3C-EDGE
COINFECTION
(HCV/HIV-1
Co-Infection)
RegimenZEPATIER
12 Weeks
N=288
ZEPATIER
12 Weeks
N=189
SVR in Genotype 195% (273/288)95% (179/189)
Outcome for subjects without SVR
On-treatment Virologic Failure*<1% (1/288)0% (0/189)
Relapse3% (10/288)3% (6/189)
Other1% (4/288)2% (4/189)
SVR by Genotype 1 Subtypes
GT 1a92% (144/157)94% (136/144)
GT 1b§98% (129/131)96% (43/45)
SVR by Cirrhosis status
Non-cirrhotic94% (207/220)94% (148/158)
Cirrhotic97% (66/68)100% (31/31)

*Includes subjects with virologic breakthrough.
Other includes subjects who discontinued due to adverse event, lost to follow-up, or subject withdrawal.
‡For the impact of baseline NS5A polymorphisms on SVR12, [see Microbiology (12.4)], Table 11 of PI.
§Includes genotype 1 subtypes other than 1a or 1b.
ZEPATIER Prescribing Information

Table 3. C-EDGE TE Trial: SVR12 in Treatment-Experienced Subjects who Failed Prior PegIFN with RBV with or without Cirrhosis, with or without HCV/HIV-1 Co-infection with Genotype 1 HCV Treated with ZEPATIER for 12 Weeks or ZEPATIER with Ribavirin (RBV) for 16 Weeks

RegimenZEPATIER
12 weeks
N=96
ZEPATIER + RBV
16 weeks
N=96
SVR in Genotype 194% (90/96)97% (93/96)
Outcome for subjects without SVR
On-treatment Virologic Failure*0% (0/96)0% (0/96)
Relapse5% (5/96)0% (0/96)
Other1% (1/96)3% (3/96)
SVR by Genotype 1 Subtypes
GT 1a90% (55/61)95% (55/58)
GT 1b§100% (35/35)100% (38/38)
SVR by Cirrhosis status
Non-cirrhotic94% (61/65)95% (61/64)
Cirrhotic94% (29/31)100% (32/32)
Response to Prior HCV Therapy
On-treatment Virologic Failure90% (57/63)95% (58/61)
Relapser100% (33/33)100% (35/35)

*Includes subjects with virologic breakthrough or rebound.
Other includes subjects who discontinued due to adverse event, lost to follow-up, or subject withdrawal.
For the impact of baseline NS5A polymorphisms on SVR, [see Microbiology (12.4)], Table 11 of the PI.
§Includes genotype 1 subtypes other than 1a or 1b.
Includes prior null responders and partial responders.
ZEPATIER Prescribing Information

Table 4. C-SURFER: SVR12 in Subjects with Severe Renal Impairment including Subjects on Hemodialysis who were Treatment-Naïve or had Failed Prior IFN** or PegIFN** ± RBV, with or without Cirrhosis, with Genotype 1 HCV Treated with ZEPATIER for 12 Weeks

RegimenZEPATIER
12 weeks
(Immediate Treatment Group)
N=122*
Overall SVR94% (115/122)†
Outcome for subjects without SVR
On-treatment Virologic Failure0% (0/122)
Relapse<1% (1/122)
Other5% (6/122)
SVR by Genotype
GT 1a97% (61/63)
GT 1b§92% (54/59)
SVR by Cirrhosis status
No95% (109/115)
Yes86% (6/7)
Prior HCV Treatment Status
Treatment-naïve95% (96/101)
Treatment-experienced90% (19/21)
Dialysis Status
No97% (29/30)
Yes93% (86/92)
Chronic Kidney Disease Stage
Stage 4100% (22/22)
Stage 593% (93/100)

*Includes subjects (n=11) in the intensive PK arm
** interferon (IFN) or peginterferon alfa (PegIFN)
SVR was achieved in 99% (115/116) of subjects in the pre-specified primary analysis population, which excluded subjects not receiving at least one dose of study treatment and those with missing data due to death or early study discontinuation for reasons unrelated to treatment response.
ZEPATIER Prescribing Information

Were there any differences in how well the drug worked in clinical trials among sex, race and age?

Subgroup analyses were conducted for sex, race, and age.

  • Sex: ZEPATIER worked similarly in men and women.
  • Race: ZEPATIER worked similarly in all races studied.
  • Age: ZEPATIER worked similarly in patients below and above 65 years of age.

Were there any differences in how well the drug worked in clinical trials among sex, race, and age groups?

The tables below (Tables 5, 6, 7, 8, and 9) summarize efficacy results from five trials by subgroup. Trials are presented separately due to differences in populations studied.

Table 5. Subgroup analysis of SVR12 for Trial C-EDGE TN

 Immediate Treatment Group (n=316) 
SVR12% (n/N)95% CI
Age (years)
< 6594.1 (270/287)90.7, 96.5
≥ 65100.0 (29/29)88.1, 100.0
Sex
Male93.0 (159/171)88.1, 96.3
Female96.6 (140/145)92.1, 98.9
Race
White94.2 (180/191)89.9, 97.1
Non-White95.2 (119/125)89.9, 98.2

Adapted from FDA Statistical Review

Table 6. Subgroup analysis of SVR12 for Trial C-EDGE CO-INFECTION

 ZEPATIER (n=218)
SVR12% (n/N)95% CI
Age (years)
< 6594.8 (201/212)90.9, 97.4
≥ 65100 (6/6)54.1, 100.0
Sex
Male94.0 (172/183)89.5, 97.0
Female100 (35/35)90.0, 100.0
Race
White94.6 (158/167)90.0, 97.5
Non-White96.1 (49/51)86.5 99.5

Adapted from FDA Statistical Review

Table 7. Subgroup analysis of SVR12 and SVR16 for Trial C-EDGE TE

% SVR12 (95% CI)ZEPATIER (N=105)ZEPATIER+ RBV (N=104)ZEPATIER (N=105)ZEPATIER + RBV (N=106)
Treatment Duration12 Weeks16 Weeks
Age (years)
< 6593.2 (85.8, 97.5)93.5 (86.3, 97.6)93.3 (85.9, 97.5)96.8 (91.0, 99.3)
≥ 6588.2 (63.6, 98.5)100.0 (73.5, 100.0)87.5 (61.7, 98.5)100.0 (73.5, 100.0)
Sex
Male90.9 (81.3, 96.6)91.7 (82.7, 96.9)91.3 (82.0, 96.7)96.9 (89.2, 99.6)
Female94.9 (82.7, 99.4)100.0 (89.1, 100.0)94.4 (81.3, 99.3)97.6 (87.4, 99.9)
Race
White89.4 (79.4, 95.6)92.9 (84.1, 97.6)93.1 (84.5, 97.7)97.4 (91.0, 99.7)
Asian100.0 (78.2, 100.0)100.0 (66.4, 100.0)86.4 (65.1, 97.1)100.0 (69.2, 100.0)
Black or African American95.6 (78.1, 100.0)100.0 (85.8, 100.0)100.0 (66.4, 100.0)100.0 (78.2, 100.0)

Adapted from FDA Statistical Review

Table 8. Subgroup analysis of SVR12 for Trial C-SURFER

 Immediate+ Intensive PK* ZEPATIER Arms (n=122)
SVR12% (n/N)95% CI
Age (years)
< 6595.0 (95/100)88.7, 98.4
≥ 6590.9 (20/22)70.8, 98.9
Sex
Male95.6 (88/92)89.2, 98.8
Female90.0 (27/30)73.5, 97.9
Race
White95.1 (58/61)86.3, 99.0
Non-White93.4 (57/61)84.1, 98.2

*pharmacokinetic
Adapted from FDA Statistical Review

Table 9. Subgroup Analyses of SVR12 for Trial C-SALVAGE

 SVR12
Characteristic% (n/N)95% CI*
Sex
Male93.5 (43/46)82.1, 98.6
Female100 (33/33)89.4, 100.0
Age
<6597.1 (66/68)89.9, 99.6
>=6590.9 (10/11)58.7, 99.8

*Confidence interval
Adapted from FDA Statistical Review

What are the possible side effects?

The most common side effects of ZEPATIER when used alone are fatigue, headache, and nausea.

The most common side effects of ZEPATIER when used with ribavirin are anemia and headache.

ZEPATIER may increase liver-related blood tests which could be a sign of a serious liver problem.

What are the possible side effects (results of trials used to assess safety)?

The tables below (Tables 10, 11 and 12) summarize adverse reactions in the clinical trials.

Table 10. Adverse Reactions (All Intensity) Reported in ≥5% of Treatment-Naïve Subjects with HCV Treated with ZEPATIER for 12 Weeks in C-EDGE TN Trial

 C-EDGE TN
 ZEPATIER
N=316
%
12 weeks
Placebo
N=105
%
12 weeks
Fatigue11%10%
Headache10%9%

ZEPATIER Prescribing Information

Table 11. Adverse Reactions (Moderate or Severe Intensity) Reported in ≥2% of PegIFN/RBV-Experienced Subjects with HCV Treated with ZEPATIER for 12 Weeks or ZEPATIER + Ribavirin for 16 Weeks in C-EDGE TE Trial

 C-EDGE TE
 ZEPATIER
N=105
%
12 weeks
ZEPATIER + Ribavirin
N=106
%
16 weeks
Anemia0%8%
Headache0%6%
Fatigue5%4%
Dyspnea0%4%
Rash or Pruritus0%4%
Irritability1%3%
Abdominal pain2%2%
Depression1%2%
Arthralgia0%2%
Diarrhea2%0%

ZEPATIER Prescribing Information

Table 12. Adverse Reactions (All Intensity) Reported in ≥5% of Treatment-Naïve or PegIFN/RBV-Experienced Subjects with Stage 4 or 5 Chronic Kidney Disease and HCV Treated with ZEPATIER for 12 Weeks in C-SURFER Trial

 ZEPATIER
N=122
%
12 weeks
Placebo
N=113
%
12 weeks
Nausea11%8%
Headache11%5%
Fatigue5%8%

ZEPATIER Prescribing Information

Were there any differences in side effects among sex, race and age?

Subgroup analyses were conducted for sex, race, and age.

  • Sex: The risk of increased liver-related blood tests was higher in women.
  • Race: The risk of increased liver-related blood tests was higher in Asian race than in other races studied.
  • Age: The risk of increased liver-related blood tests was higher in patients who were older than 65 years of age.

Were there any differences in side effects of the clinical trials among sex, race, and age groups?

The table below summarizes hepatic adverse reactions by subgroups.

Table 13. Subgroup Analysis of Adverse Reactions-Elevated ALT/AST *

 ZEPATIER   + /- RBV x 12-18 wPlacebo x 12w
 Pre-specified Late ALT/AST Elevation 1
N=12
Pre-specified
Hepatic Lab Abnormality or Event 2
N=18
Pooled Other Late ALT/AST Elevation 3
N=39
Pooled Other Late ALT/AST Elevation 3
N=38
Age (y)
18 - 64
> 65
 
9/1394 (0.6)
3/164  (1.8)
 
15/1394 (1.1)
3/164    (1.8)

33/1394 (2.4)
6/164    (3.7)

31/87 (36)
7/18 (39)
Sex
Male
Female
 
2/972 (0.2)
10/586 (1.7)

6/972 (0.6)
12/586 (2.0)

22/972 (2.3)
17/586 (2.9)

19/56 (34)
19/49 (40)
Race
White
Black
Asian
 
7/1190 (0.6)
1/204  (0.5)
4/133  (3.0)

10/1190 (0.8)
3/204    (1.5)
5/133    (3.8)

27/1190 (2.3)
6/204 (2.9)
6/133 (4.5)

28/73 (38)
5/18  (28)
4/13 (31)

*alanine aminotransferase/aspartate aminotransferase
1ALT or AST elevation >5 x ULN after treatment week 4 (TW4) with a normal ALT or AST between TW2 and TW4
2Late ALT/AST elevation1 or Hepatic Event of Clinical Interest (ECI) or Discontinuation due to Pre-specified Liver Event
3Pooled: ALT or AST elevation >5 x ULN after TW4 without a normal ALT or AST between TW2 and TW4 or ALT or AST elevation >2 x ULN after TW4 with or without a normal ALT or AST between TW2 and TW4
FDA Clinical Review

WHO WAS IN THE CLINICAL TRIALS?

Who participated in the clinical trials?

The FDA approved ZEPATIER based on evidence from thirteen clinical trials of 2704 patients with chronic hepatitis C infection. In these trials, some patients were previously treated for hepatitis C and some were never treated before. Some patients had cirrhosis and some did not. Some patients also had HIV infection and some had chronic kidney failure. The trials were conducted in the United States, Canada, Europe, Asia, Middle East, and Australia.

The figure below summarizes how many men and women were in the clinical trials.

Figure 1. Baseline Demographics by Sex

Pie chart summarizing how many men and women were in the clinical trials of the drug ZEPATIER. In total, 1657 men (61%) and 1047 women (39%) participated in the clinical trials used to evaluate the drug ZEPATIER.

FDA Clinical Review

Figure 2 and Table 1 summarize the percentage of patients by race enrolled in the clinical trials.

Figure 2. Baseline Demographics by Race

Pie chart summarizing the percentage of patients by race enrolled in the ZEPATIER clinical trials. In total, 2014 Whites (74%), 403 Blacks (15%), 235 Asian (9%), 35 Multiple (1%) and 17 Other (1%) participated in the clinical trials.

Table 1. Demographics of Trials by Race

RaceNumber of PatientsPercentage
White201474.5%
Black or African American40314.9%
Asian2358.7%
Multiple351.3%
Other170.6%

FDA Clinical Review

Figure 3 summarizes the percentage of patients by age in the clinical trials.

Figure 3. Baseline Demographics by Age

Pie chart summarizing how many individuals of certain age groups were enrolled in the ZEPATIER clinical trials.  In total, 2413 participants were below 65 years old (89%) and 291 participants were 65 and older (11%).

FDA Clinical Review

Who participated in the trials?

The table below summarizes demographics of patients enrolled in the clinical trials.

Table 14. Baseline Demographics of Patients in the Clinical Trials

Demographic SubgroupTotal (N=2704)
Sex, n (%)
Male1657 (61.3%)
Female1047 (38.7%)
Age Group, n (%)
18 - 64 years 2413(89.2%)
>=65 years291(10.8%)
Race, n(%)
White2014 (74.5%)
Black or African American403(14.9%)
Asian235 (8.7%)
Multiple35 (1.3%)
Other17 (0.6%)

FDA Clinical Review

How were the trials designed?

The benefits and side effects of ZEPATIER were evaluated in multiple clinical trials. In some trials patients received either ZEPATIER or placebo. Neither the patients nor the health care providers knew which treatment was being given until after the trials were completed. In other trials patients received only ZEPATIER. In addition, some patients also received the previously approved drug ribavirin.

The trials measured the blood level of hepatitis virus C before, during and after treatment.

How were the trials designed?

The safety of ZEPATIER was established on a total of 2704 adult patients who were treated with ZEPATIER with or without ribavirin in 13 trials.

The efficacy of ZEPATIER was established on a total of 1373 patients from 2 placebo-controlled and 4 uncontrolled Phase 2 and 3 clinical trials.

The patients had chronic Hepatitis C genotypes 1 or 4 infection. Across the trials, different populations were studied: treatment naïve, treatment experienced, HIV positive, and a population with advanced kidney disease that included patients on hemodialysis.

The primary efficacy outcome was sustained virologic response (SVR12) defined as HCV RNA less than lower limit of quantification 12 weeks after the cessation of treatment.

GLOSSARY

CLINICAL TRIAL: Voluntary research studies conducted in people and designed to answer specific questions about the safety or effectiveness of drugs, vaccines, other therapies, or new ways of using existing treatments.
COMPARATOR: A previously available treatment or placebo used in clinical trials that is compared to the actual drug being tested.
EFFICACY: How well the drug achieves the desired response when it is taken as described in a controlled clinical setting, such as during a clinical trial.
PLACEBO: An inactive substance or “sugar pill” that looks the same as, and is given the same way as, an active drug or treatment being tested. The effects of the active drug or treatment are compared to the effects of the placebo.
SUBGROUP: A subset of the population studied in a clinical trial. Demographic subsets include sex, race, and age groups.

PRESCRIBING INFORMATION

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