Drug Trials Snapshots: VOSEVI

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 VOSEVI Prescribing Information for complete information.

VOSEVI (sofosbuvir, velpatasvir and voxilaprevir)
Vo-SEV-ee
Gilead Sciences
Approval date: July 18, 2017

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DRUG TRIALS SNAPSHOT SUMMARY:

What is the drug for?

VOSEVI is a drug for the treatment of adults who have a specific type of hepatitis C virus (HCV) infection, called chronic hepatitis C virus genotypes 1, 2, 3, 4, 5 or 6 infection. Hepatitis C is a viral disease that causes inflammation of the liver that can lead to decreased liver function, cirrhosis, liver failure, liver cancer or death.

VOSEVI is a combination of three anti-viral drugs: sofosbuvir and velpatasvir (previously approved drugs for HCV infection) and voxilaprevir (new drug for HCV infection). It is intended to be used in patients who were not successfully treated with other HCV drugs in the past and who do not have cirrhosis or who have early stage cirrhosis.

How is this drug used?

VOSEVI is a tablet that is taken once a day for 12 weeks.

What are the benefits of this drug?

VOSEVI 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 summarize efficacy results for the two clinical trials in patients with HCV and either no cirrhosis or with compensated cirrhosis. 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.

Table 2. Virologic Outcomes by HCV Genotype in VOSEVI-Treated Patients without Cirrhosis or with Compensated Cirrhosis (12 Weeks after Treatment) -Trial 1

	VOSEVI (N=263)
	Total (all GTs)a (N=263)	GT-1			GT-2 (N=5)	GT-3 (N=78)	GT-4 (N=22)	GT-5 (N=1)	GT-6 (N=6)
		GT-1a (N=101)	GT-1b (N=45)	Totalb(N=150)
SVR12	96% (253/263)	96% (97/101)	100% (45/45)	97% (146/150)	100% (5/5)	95% (74/78)	91% (20/22)	100% (1/1)	100% (6/6)
Outcome for Subjects without SVR
On-Treatment Virologic Failure	<> (1/263)	1% (1/101)	0/45	1% (1/150)	0/5	0/78	0/22	0/1	0/6
Relapsec	2% (6/261)	1% (1/100)	0/45	1% (1/149)	0/5	5% (4/78)	5% (1/21)	0/1	0/6
Otherd	1% (3/263)	2% (2/101)	0/45	1% (2/150)	0/5	0/78	5% (1/22)	0/1	0/6

GT: genotype

a. One subject with undetermined genotype achieved SVR12.
b. Four subjects had GT-1 subtypes other than GT-1a or GT-1b; all 4 subjects achieved SVR12.
c. The denominator for relapse is the number of subjects with HCV RNA
d. Other includes subjects with missing data and those who discontinued treatment prior to virologic suppression.

VOSEVI Prescribing Information
 

Table 3.  Virologic Outcomes by HCV Genotype in VOSEVI-Treated Patients* and - SOF/VEL-Treated Patients* Without Cirrhosis or With Compensated Cirrhosis (12 Weeks After Treatment) -Trial 2

*Patientsts with prior exposure to a SOF-containing regimen	VOSEVI  (N=139)	SOF/VEL  (N=125)
Overall (Genotypes 1, 2, and 3)
SVR12 Not achieving SVR12 On-treatment virologic failure Relapsea Otherb	97% (135/139)	88% (110/125)
	0% (0/139) 1% (1/139) 2% (3/139)	1% (1/125) 11% (14/124) 0% (0/125)
Genotype 1
SVR12	96% (52/54)	85% (34/40)
Not achieving SVR12
On-treatment virologic failure	0% (0/54)	0% (0/40)
Relapsea	2% (1/54)	13% (5/40)
Otherb	2% (1/54)	3% (1/40)
Genotype 1a
SVR12	97% (35/36)	82% (23/28)
Not achieving SVR12
On-treatment virologic failure	0% (0/36)	0% (0/28)
Relapsea	3% (1/36)	18% (5/28)
Otherb	0% (0/36)	0% (0/28)
Genotype 1b
SVR12	94% (17/18)	92% (11/12)
Not achieving SVR12
On-treatment virologic failure	0% (0/18)	0% (0/12)
Relapsea	0% (0/18)	0% (0/12)
Otherb	6% (1/18)	8% (1/12)
Genotype 2
SVR12	100% (31/31)	97% (32/33)
Not achieving SVR12
On-treatment virologic failure	0% (0/31)	3% (1/33)
Relapsea	0% (0/31)	0% (0/32)
Otherb	0% (0/31)	0% (0/33)
Genotype 3
SVR12	96% (52/54)	85% (44/52)
Not achieving SVR12
On-treatment virologic failure	0% (0/54)	0% (0/52)
Relapsea	0% (0/54)	15% (8/52)
Otherb	4% (2/54)	0% (0/52)

SOF/VEL = sofosbuvir/velpatasvir

^a The denominator for relapse is the number of patients with HCV RNA

^b Other includes patients who discontinued due to adverse even, lost to follow-up or patient withdrawal.

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

• Sex:  VOSEVI worked similarly in men and women.
• Race: The majority of patients were White. The number of patients in other races was limited; therefore, differences in response among races could not be determined.
• Age:  VOSEVI worked similarly in patients below and above 65 years of age.

Table 4. SVR12 Rates by Demographics in Trial 1 

Tables below present efficacy results by subgroup. Trials are presented separately due to differences in design and populations studied. 

	VOSEVI (N=263)	95% CI1
Age
<65>	95.9% (213/222)	92.4%, 98.1%
≥65 years	97.6% (40/41)	87.1%, 99.9%
Sex
Men	96.0% (192/200)	92.3%, 98.3%
Women	96.8% (61/63)	89.0%, 99.6%
Race
Black of African American	92.1% (35/38)	78.6%, 98.3%
All Other	96.9% (217/224)	93.7%, 98.7%
Ethnicity
Hispanic or Latino	100% (15/15)	78.2%, 100.0%
Not Hispanic or Latino	96.0% (237/247)	92.7%, 98.0%
Region
US	96.3% (130/135)	91.6%, 98.8%
Non-US	96.1% (123/128)	91.1%, 98.7%

¹ based on Clopper-Pearson method

Table 5. Subgroup analysis of SVR12 for Tria1 2

	VOSEVI (N=182)	Sofosbuvir/velpatasvir (N=151)	Diff in SVR12 rate (95% CI)2
Age
< 65="">	97.3% (145/149)	88.9% (120/135)	8.4% (2.7%, 15.5%)
[95% CI]1	[93.3%, 99.3%]	[82.3%, 93.6%]
≥ 65 years	100% (33/33)	100% (16/16)	0% (-11.1%, 21.9%)
[95% CI]1	[89.4%, 100.0%]	[79.4%, 100.0%]
Sex
Men	97.2% (139/143)	89.5% (102/114)	7.7% (1.8%, 15.2%)
[95% CI]1	[93.0%, 99.2%]	[82.3%, 94.4%]
Women	100% (39/39)	91.9% (34/37)	8.1% (-1.5%, 21.7%)
[95% CI]1	[91.0%, 100.0%]	[78.1%, 98.3%]
Race
Black or African American	93.8% (15/16)	69.2% (9/13)	24.5% (-5.3%, 55.3%)
[95% CI]1	[69.8%, 99.8%]	[38.6%, 90.9%]
All other	98.2% (163/166)	92.0% (127/138)	6.2 % (1.5%, 12.4%)
[95% CI]1	[94.8%, 99.6%]	[86.2%, 96.0%]
Ethnicity
Hispanic or Latino	100% (19/19)	75.0% (6/8)	25% (3.0%, 62.6%)
[95% CI]1	[82.4%, 100.0%]	[34.9%, 96.8%]
Not Hispanic or Latino	97.6% (159/163)	90.9% (130/143)	6.6% (1.5%, 12.8%)
[95% CI]1	[93.8%, 99.3%]	[85.0%, 95.1%]
Region
US	99.0% (100/101)	87.4% (76/87)	11.7% (5.1%, 20.6%)
[95% CI]1	[94.6%, 100%]	[78.5%, 93.5%]
Non-US	96.3% (78/81)	93.8% (60/64)	2.5% (-5.1%, 12.1%)
[95% CI]1	[89.6%, 99.2%]	[84.8%, 98.3%]

¹based on the Clopper-Pearson method
²The differences in SVR 12 rate between the two treatment arms in the subgroups and the corresponding exact 95% CIs based on inverting a two-sided test were calculated by the statistical reviewer.
Adapted from FDA Statistical review
 

What are the possible side effects?

VOSEVI may cause serious liver problems including liver failure and death in patients who had hepatitis B virus infection. This is because the hepatitis B virus could become active again (called reactivation) during or after treatment of hepatitis C virus with VOSEVI.

VOSEVI may cause serious slowing of the heart rate in patients who are taking medication amiodarone.

The most common side effects of VOSEVI are headache, tiredness, diarrhea and nausea.

Below is the summary of the most common adverse reactions with frequency of 5% or greater that were observed in patients who received VOSEVI or comparator for 12 weeks.

Table 6. Adverse Reactions (All Grades) Reported in ≥5% of Patients With HCV Without Cirrhosis or With Compensated Cirrhosis Receiving VOSEVI in Trial 1 and Trial 2

	Trial 1		Trial 2
	VOSEVI  (N=263)	Placebo  (N=152)	VOSEVI  (N=182)	Sofosbuvir/velpatasvir  (N=151)
Headache	21%	14%	23%	23%
Fatigue	17%	15%	19%	23%
Diarrhea	13%	9%	14%	3%
Nausea	13%	7%	10%	3%
Asthenia	6%	4%	4%	6%
Insomnia	6%	3%	3%	1%

VOSEVI Prescribing Information

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

• Sex:  The risk of side effects was similar in men and women.
• Race:  The majority of patients were White. The number of patients in other races was limited; therefore, differences in side effects among races could not be determined.
• Age: The risk of side effects was similar in patients younger and older than 65 years of age.

VOSEVI Prescribing Information

Table 7. Subgroup Analyses of Treatment Emergent Adverse Events –Trial 1

 The table below summarizes the frequency of all adverse events for Trial 1 by subgroup.

Subgroup	VOSEVI (N=445) x/n* (%)	Placebo (N=152) x/n* (%)
Sex
Men	257/343 (75)	84/121 (69)
Women	89/102 (87)	23/131 (74)
Age Group
<65>	285/371 (77)	82/121 (68)
≥65 years	61/74 (82)	25/31 (81)
Race
Black or African American	34/54 (63)	17/22 (77)
All other races combined	312/390 (80)	90/130 (69)

**x/n= number of patents with adverse reaction (x) in the subgroup (n)

Adapted from Clinical trial report

WHO WAS IN THE CLINICAL TRIALS?

Who participated in the clinical trials?

The FDA approved VOSEVI based on evidence from two clinical trials of 748 patients with chronic hepatitis C virus infection. In these trials, enrolled patients had previously failed treatment with another hepatitis drug.  Some patients had cirrhosis and some did not. The trials were conducted in the United States, Canada, Europe, Australia, and New Zealand.

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

Figure 1. Baseline Demographics by Sex 

 

Figure 2 and Table 1 summarize the percentage of patients in the clinical trials

FDA review

Figure 2. Baseline Demographics by Race

FDA review

Table 1. Demographics of Trials by Race

Race	Number of Patients	Percentage
White	626	84
Black or African American	89	12
Asian	20	2
American Indian or Alaska Native	5	1
Native Hawaiian or Pacific Islander	3	less than 1
Other	4	1
Not reported	1	Less than 1

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

Figure 3. Baseline Demographics by Age4

 

FDA review

Table 8. Patient Demographics

The table below summarizes demographics of patients enrolled in the 2 clinical trials.

	Trial 1 (N=415)	Trial  2 (N=333)
Age
Median	58 (8.3)	57 (8.3)
Min, Max	59	58
Min, Max	27,84	24,85
Age Group
<65>	343 (82.7%)	284 (85.3%)
≥ 65 years	72 (17.3%)	49 (14.7)
Sex
Men	321 (77.3%)	257 (77.2)
Women	94 (22.7%)	76 (22.8)
Race
White	335 (80.7%)	291 (87.4)
Black/African American	60 (14.5%)	29 (8.7)
Asian	14 (3.4%)	6 (1.8)
American Indian or Alaska Native	3 (0.7%)	2 (0.6)
Native Hawaiian or Pacific Islander	1 (0.2%)	2 (0.6)
Not disclosed	1 (0.2%)	-
Other	1 (0.2%)	3 (0.9)
Ethnicity
Hispanic/Latino	25 (6.0%)	27 (8.1)
Not Hispanic/Latino	389 (93.7%)	306 (91.9)
Not Disclosed	1 (0.2%)
Region
US	236 (56.9%)	188 (56.5%)
Non-US	179 (43.1%)	145 (43.5)

Adapted from FDA report and Clinical trial report

How were the trials designed?

The benefits and side effects of VOSEVI were evaluated in two clinical trials. Patients in both trials had previously failed treatment with direct-acting antiviral (DAA) drugs for hepatitis C. Some patients had cirrhosis and some did not.Each trial was designed differently.

In Trial 1, patients with genotypes 1, 2, 3, 4, 5 or 6 randomly received either VOSEVI or placebo pill once a day for 12 weeks. Neither the patients nor the health care providers knew which treatment was being given until after the trial was completed.

In Trial 2, patients with genotypes 1, 2 or 3 randomly received either VOSEVI for 12 weeks or the combination of previously approved drugs called sofosbuvir and velpatasvir for 12 weeks. In this trial, both patients and health care providers knew which treatment was given.

Both trials measured the blood level of hepatitis virus C before and after treatment.

The efficacy and safety of VOSEVI were established in 2 clinical trials with a total of 748 adult patients who had chronic hepatitis C genotypes 1-6 infection.  Enrolled population had a history of failed direct-acting antiviral (DAA) treatment and either compensated cirrhosis no cirrhosis.

Trial 1 was a randomized, multicenter, double blind, placebo controlled 12 week trial comparing   VOSEVI to placebo in patients with chronic HCV infection genotypes 1-6, without cirrhosis or with compensated cirrhosis who previously failed a regimen containing an NS5A inhibitor. 

Trial 2 was a randomized, multicenter, open-label 12 week trial comparing VOSEVI to sofosbuvir and velpatasvir combination treatment in patients with genotypes 1-3 HCV infection without cirrhosis or with compensated cirrhosis who had previously failed a HCV regimen that did not include an NS5A inhibitor.

In both trials, 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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