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
| Trial | C-EDGE TN (Immediate Treatment Group) | 3C-EDGE COINFECTION (HCV/HIV-1 Co-Infection) |
|---|---|---|
| Regimen | ZEPATIER 12 Weeks N=288 | ZEPATIER 12 Weeks N=189 |
| SVR in Genotype 1 | 95% (273/288) | 95% (179/189) |
| Outcome for subjects without SVR | ||
| On-treatment Virologic Failure* | 1%> | 0% (0/189) |
| Relapse | 3% (10/288) | 3% (6/189) |
| Other† | 1% (4/288) | 2% (4/189) |
| SVR by Genotype 1 Subtypes | ||
| GT 1a‡ | 92% (144/157) | 94% (136/144) |
| GT 1b§ | 98% (129/131) | 96% (43/45) |
| SVR by Cirrhosis status | ||
| Non-cirrhotic | 94% (207/220) | 94% (148/158) |
| Cirrhotic | 97% (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
| Regimen | ZEPATIER 12 weeks N=96 | ZEPATIER + RBV 16 weeks N=96 |
|---|---|---|
| SVR in Genotype 1 | 94% (90/96) | 97% (93/96) |
| Outcome for subjects without SVR | ||
| On-treatment Virologic Failure* | 0% (0/96) | 0% (0/96) |
| Relapse | 5% (5/96) | 0% (0/96) |
| Other† | 1% (1/96) | 3% (3/96) |
| SVR by Genotype 1 Subtypes | ||
| GT 1a‡ | 90% (55/61) | 95% (55/58) |
| GT 1b§ | 100% (35/35) | 100% (38/38) |
| SVR by Cirrhosis status | ||
| Non-cirrhotic | 94% (61/65) | 95% (61/64) |
| Cirrhotic | 94% (29/31) | 100% (32/32) |
| Response to Prior HCV Therapy | ||
| On-treatment Virologic Failure¶ | 90% (57/63) | 95% (58/61) |
| Relapser | 100% (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
| Regimen | ZEPATIER 12 weeks (Immediate Treatment Group) N=122* |
|---|---|
| Overall SVR | 94% (115/122)† |
| Outcome for subjects without SVR | |
| On-treatment Virologic Failure | 0% (0/122) |
| Relapse | 1%> |
| Other‡ | 5% (6/122) |
| SVR by Genotype | |
| GT 1a | 97% (61/63) |
| GT 1b§ | 92% (54/59) |
| SVR by Cirrhosis status | |
| No | 95% (109/115) |
| Yes | 86% (6/7) |
| Prior HCV Treatment Status | |
| Treatment-naïve | 95% (96/101) |
| Treatment-experienced | 90% (19/21) |
| Dialysis Status | |
| No | 97% (29/30) |
| Yes | 93% (86/92) |
| Chronic Kidney Disease Stage | |
| Stage 4 | 100% (22/22) |
| Stage 5 | 93% (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) | ||
| > | 94.1 (270/287) | 90.7, 96.5 |
| ≥ 65 | 100.0 (29/29) | 88.1, 100.0 |
| Sex | ||
| Male | 93.0 (159/171) | 88.1, 96.3 |
| Female | 96.6 (140/145) | 92.1, 98.9 |
| Race | ||
| White | 94.2 (180/191) | 89.9, 97.1 |
| Non-White | 95.2 (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) | ||
| > | 94.8 (201/212) | 90.9, 97.4 |
| ≥ 65 | 100 (6/6) | 54.1, 100.0 |
| Sex | ||
| Male | 94.0 (172/183) | 89.5, 97.0 |
| Female | 100 (35/35) | 90.0, 100.0 |
| Race | ||
| White | 94.6 (158/167) | 90.0, 97.5 |
| Non-White | 96.1 (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 Duration | 12 Weeks | 16 Weeks | ||
| Age (years) | ||||
| > | 93.2 (85.8, 97.5) | 93.5 (86.3, 97.6) | 93.3 (85.9, 97.5) | 96.8 (91.0, 99.3) |
| ≥ 65 | 88.2 (63.6, 98.5) | 100.0 (73.5, 100.0) | 87.5 (61.7, 98.5) | 100.0 (73.5, 100.0) |
| Sex | ||||
| Male | 90.9 (81.3, 96.6) | 91.7 (82.7, 96.9) | 91.3 (82.0, 96.7) | 96.9 (89.2, 99.6) |
| Female | 94.9 (82.7, 99.4) | 100.0 (89.1, 100.0) | 94.4 (81.3, 99.3) | 97.6 (87.4, 99.9) |
| Race | ||||
| White | 89.4 (79.4, 95.6) | 92.9 (84.1, 97.6) | 93.1 (84.5, 97.7) | 97.4 (91.0, 99.7) |
| Asian | 100.0 (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 American | 95.6 (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) | ||
| > | 95.0 (95/100) | 88.7, 98.4 |
| ≥ 65 | 90.9 (20/22) | 70.8, 98.9 |
| Sex | ||
| Male | 95.6 (88/92) | 89.2, 98.8 |
| Female | 90.0 (27/30) | 73.5, 97.9 |
| Race | ||
| White | 95.1 (58/61) | 86.3, 99.0 |
| Non-White | 93.4 (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 | ||
| Male | 93.5 (43/46) | 82.1, 98.6 |
| Female | 100 (33/33) | 89.4, 100.0 |
| Age | ||
| > | 97.1 (66/68) | 89.9, 99.6 |
| >=65 | 90.9 (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 | |
| Fatigue | 11% | 10% |
| Headache | 10% | 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 | |
| Anemia | 0% | 8% |
| Headache | 0% | 6% |
| Fatigue | 5% | 4% |
| Dyspnea | 0% | 4% |
| Rash or Pruritus | 0% | 4% |
| Irritability | 1% | 3% |
| Abdominal pain | 2% | 2% |
| Depression | 1% | 2% |
| Arthralgia | 0% | 2% |
| Diarrhea | 2% | 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 | |
|---|---|---|
| Nausea | 11% | 8% |
| Headache | 11% | 5% |
| Fatigue | 5% | 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 w | Placebo 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
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
Table 1. Demographics of Trials by Race
| Race | Number of Patients | Percentage |
|---|---|---|
| White | 2014 | 74.5% |
| Black or African American | 403 | 14.9% |
| Asian | 235 | 8.7% |
| Multiple | 35 | 1.3% |
| Other | 17 | 0.6% |
FDA Clinical Review
Figure 3 summarizes the percentage of patients by age in the clinical trials.
Figure 3. Baseline Demographics by Age
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 Subgroup | Total (N=2704) | |
|---|---|---|
| Sex, n (%) | ||
| Male | 1657 (61.3%) | |
| Female | 1047 (38.7%) | |
| Age Group, n (%) | ||
| 18 - 64 years | 2413(89.2%) | |
| >=65 years | 291(10.8%) | |
| Race, n(%) | ||
| White | 2014 (74.5%) | |
| Black or African American | 403(14.9%) | |
| Asian | 235 (8.7%) | |
| Multiple | 35 (1.3%) | |
| Other | 17 (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