Version with corrected and formatted tables.
FDA recently approved changes to the VEMLIDY (tenofovir alafenamide) label to include long term safety data (96 -120 weeks) from Study GS-US-320-0108 and Study GS-US-320-0110 in adult subjects with chronic hepatitis B and compensated liver disease (Section 6.1) and update the drug interaction data between tenofovir alafenamide and the fixed-dose combination (FDC) sofosbuvir/velpatasvir/
Section 6: ADVERSE REACTIONS
Further safety assessment was based on pooled data from Studies 108 and 110 from subjects who continued to receive their original blinded treatment through Week 120 and additionally from subjects who received open-label VEMLIDY from Week 96 through Week 120 (n = 361 remained on VEMLIDY; n = 180 switched from TDF to VEMLIDY at Week 96).
Based on the Week 96 analysis, the most common adverse reaction (all Grades) reported in at least 10% of subjects in the VEMLIDY group was headache. The proportion of subjects who discontinued treatment with VEMLIDY or TDF due to adverse reactions of any severity was 1.5% and 0.9%, respectively. Table 1 displays the frequency of the adverse reactions (all Grades) greater than or equal to 5% in the VEMLIDY group.
Table 1 Adverse Reactionsa (All Grades) Reported in ≥5% of Subjects with Chronic HBV Infection and Compensated Liver Disease in Studies 108 and 110 (Week 96 analysisb)
a. Frequencies of adverse reactions are based on all treatment-emergent adverse events, regardless of relationship to study drug.
b. Double-blind phase
c. Grouped term including abdominal pain upper, abdominal pain, abdominal pain lower, and abdominal tenderness.
Additional adverse reactions occurring in less than 5% of subjects in Studies 108 and 110 included vomiting, rash, and flatulence.
The safety profile of VEMLIDY in subjects who continued to receive blinded treatment through Week 120 was similar to that at Week 96. The safety profile of VEMLIDY in subjects who remained on VEMLIDY in the open-label phase through Week 120 was similar to that in subjects who switched from TDF to VEMLIDY at Week 96.
Renal Laboratory Tests
In a pooled analysis of Studies 108 and 110 in adult subjects with chronic hepatitis B and a median baseline eGFR of 106 and 105 mL per minute (for the VEMLIDY and TDF groups, respectively), mean serum creatinine increased by less than 0.1 mg/dL and median serum phosphorus decreased by 0.1 mg/dL in both treatment groups at Week 96. Median change from baseline to Week 96 in eGFR was -1.2 mL per minute in the
VEMLIDY group and -4.8 mL per minute in those receiving TDF.
In subjects who remained on blinded treatment beyond Week 96 in Studies 108 and 110, change from baseline in renal laboratory parameter values in each group at Week 120 were similar to those at Week 96. In the open-label phase, median change in eGFR from Week 96 to Week 120 was -0.6 mL per minute in subjects who remained on VEMLIDY and 1.8 mL per minute in those who switched from TDF to VEMLIDY at Week 96. Mean serum creatinine and median serum phosphorus values at Week 120 were similar to those at Week 96 in subjects who remained on VEMLIDY and in subjects who switched from TDF to VEMLIDY.
The long-term clinical significance of these renal laboratory changes on adverse reaction frequencies between VEMLIDY and TDF is not known.
Bone Mineral Density Effects
In a pooled analysis of Studies 108 and 110, the mean percentage change in bone mineral density (BMD) from baseline to Week 96 as assessed by dual-energy X-ray absorptiometry (DXA) was -0.7% with VEMLIDY compared to -2.6% with TDF at the lumbar spine and -0.3% compared to -2.5% at the total hip. BMD declines of 5% or greater at the lumbar spine were experienced by 11% of VEMLIDY subjects and 25% of TDF subjects at Week 96. BMD declines of 7% or greater at the femoral neck were experienced by 5% of VEMLIDY subjects and 13% of TDF subjects at Week 96.
In subjects who remained on blinded treatment beyond Week 96 in Studies 108 and 110, mean percentage change in BMD in each group at Week 120 was similar to that at Week 96. In the open-label phase, mean percentage change in BMD from Week 96 to Week 120 in subjects who remained on VEMLIDY was 0.6% at the lumbar spine and 0% at the total hip, compared to 1.7% at the lumber spine and 0.6% at the total hip in those who switched from TDF to VEMLIDY.
The long-term clinical significance of these BMD changes is not known.
Laboratory Abnormalities
The frequency of laboratory abnormalities (Grades 3–4) occurring in at least 2% of subjects receiving VEMLIDY in Studies 108 and 110 are presented in Table 2.
Table 2 Laboratory Abnormalities (Grades 3–4) Reported in ≥2% of Subjects with Chronic HBV Infection and Compensated Liver Disease in Studies 108 and 110 (Week 96 analysisa)
ULN=Upper Limit of Normal
a. Double-blind phase
b. Frequencies are based on treatment-emergent laboratory abnormalities.
The overall incidence of blinded treatment ALT flares (defined as confirmed serum ALT greater than 2 × baseline and greater than 10 × ULN at 2 consecutive postbaseline visits, with or without associated symptoms) was similar between VEMLIDY (0.6%) and TDF (0.9%) through Week 96. ALT flares generally were not associated with coincident elevations in bilirubin, occurred within the first 12 weeks of treatment, and resolved without recurrence.
Based on the Week 120 analysis, the frequencies of lab abnormalities in subjects who remained on VEMLIDY in the open-label phase were similar to those in subjects who switched from TDF to VEMLIDY at Week 96.
Amylase and Lipase Elevations and Pancreatitis
At Week 96, in Studies 108 and 110, eight subjects treated with VEMLIDY with elevated amylase levels had associated symptoms, such as nausea, low back pain; abdominal tenderness, pain, and distension; and biliary pancreatitis and pancreatitis. Of these eight, two subjects discontinued VEMLIDY due to elevated amylase and/or lipase; one subject experienced recurrence of adverse events when VEMLIDY was restarted. No subject treated with tenofovir disoproxil fumarate had associated symptoms or discontinued treatment.
From Week 96 to Week 120, one additional subject who continued open-label VEMLIDY and none of the subjects who switched from TDF to VEMLIDY had elevated amylase levels and associated symptoms.
Serum Lipids
Changes from baseline in total cholesterol, HDL-cholesterol, LDL-cholesterol, triglycerides, and total cholesterol to HDL ratio among subjects treated with VEMLIDY and tenofovir disoproxil fumarate are presented in Table 3.
Table 3 Lipid Abnormalities: Mean Change from Baseline in Lipid Parameters in Patients with Chronic HBV Infection and Compensated Liver Disease in Studies 108 and 110 (Week 96 Analysis)
a. The change from baseline is the mean of within-subject changes from baseline for subjects with both baseline and Week 96 values.
In the open-label phase, lipid parameters at Week 120 in subjects who remained on VEMLIDY were similar to those at Week 96. In subjects who switched from TDF to VEMLIDY, mean change from Week 96 to Week 120 in total cholesterol was 23 mg/dL, HDL-cholesterol was 5 mg/dL, LDL-cholesterol was 16 mg/dL, triglycerides was 30 mg/dL, and total cholesterol to HDL ratio was 0 mg/dL.
Section 7.4 Drugs without Clinically Significant Interactions with VEMLIDY was updated to include sofosbuvir/velpatasvir, and sofosbuvir/velpatasvir/
FDA recently approved changes to the VEMLIDY (tenofovir alafenamide) label to include long term safety data (96 -120 weeks) from Study GS-US-320-0108 and Study GS-US-320-0110 in adult subjects with chronic hepatitis B and compensated liver disease (Section 6.1) and update the drug interaction data between tenofovir alafenamide and the fixed-dose combination (FDC) sofosbuvir/velpatasvir/
Section 6: ADVERSE REACTIONS
Further safety assessment was based on pooled data from Studies 108 and 110 from subjects who continued to receive their original blinded treatment through Week 120 and additionally from subjects who received open-label VEMLIDY from Week 96 through Week 120 (n = 361 remained on VEMLIDY; n = 180 switched from TDF to VEMLIDY at Week 96).
Based on the Week 96 analysis, the most common adverse reaction (all Grades) reported in at least 10% of subjects in the VEMLIDY group was headache. The proportion of subjects who discontinued treatment with VEMLIDY or TDF due to adverse reactions of any severity was 1.5% and 0.9%, respectively. Table 1 displays the frequency of the adverse reactions (all Grades) greater than or equal to 5% in the VEMLIDY group.
Table 1 Adverse Reactionsa (All Grades) Reported in ≥5% of Subjects with Chronic HBV Infection and Compensated Liver Disease in Studies 108 and 110 (Week 96 analysisb)
| VEMLIDY (N=866) | Tenofovir Disoproxil Fumarate (TDF) (N=432) | |
|---|---|---|
| Headache | 12% | 10% |
| Abdominal painc | 9% | 6% |
| Cough | 8% | 8% |
| Back pain | 6% | 6% |
| Fatigue | 6% | 5% |
| Nausea | 6% | 6% |
| Arthralgia | 5% | 6% |
| Diarrhea | 5% | 5% |
| Dyspepsia | 5% | 5% |
b. Double-blind phase
c. Grouped term including abdominal pain upper, abdominal pain, abdominal pain lower, and abdominal tenderness.
Additional adverse reactions occurring in less than 5% of subjects in Studies 108 and 110 included vomiting, rash, and flatulence.
The safety profile of VEMLIDY in subjects who continued to receive blinded treatment through Week 120 was similar to that at Week 96. The safety profile of VEMLIDY in subjects who remained on VEMLIDY in the open-label phase through Week 120 was similar to that in subjects who switched from TDF to VEMLIDY at Week 96.
Renal Laboratory Tests
In a pooled analysis of Studies 108 and 110 in adult subjects with chronic hepatitis B and a median baseline eGFR of 106 and 105 mL per minute (for the VEMLIDY and TDF groups, respectively), mean serum creatinine increased by less than 0.1 mg/dL and median serum phosphorus decreased by 0.1 mg/dL in both treatment groups at Week 96. Median change from baseline to Week 96 in eGFR was -1.2 mL per minute in the
VEMLIDY group and -4.8 mL per minute in those receiving TDF.
In subjects who remained on blinded treatment beyond Week 96 in Studies 108 and 110, change from baseline in renal laboratory parameter values in each group at Week 120 were similar to those at Week 96. In the open-label phase, median change in eGFR from Week 96 to Week 120 was -0.6 mL per minute in subjects who remained on VEMLIDY and 1.8 mL per minute in those who switched from TDF to VEMLIDY at Week 96. Mean serum creatinine and median serum phosphorus values at Week 120 were similar to those at Week 96 in subjects who remained on VEMLIDY and in subjects who switched from TDF to VEMLIDY.
The long-term clinical significance of these renal laboratory changes on adverse reaction frequencies between VEMLIDY and TDF is not known.
Bone Mineral Density Effects
In a pooled analysis of Studies 108 and 110, the mean percentage change in bone mineral density (BMD) from baseline to Week 96 as assessed by dual-energy X-ray absorptiometry (DXA) was -0.7% with VEMLIDY compared to -2.6% with TDF at the lumbar spine and -0.3% compared to -2.5% at the total hip. BMD declines of 5% or greater at the lumbar spine were experienced by 11% of VEMLIDY subjects and 25% of TDF subjects at Week 96. BMD declines of 7% or greater at the femoral neck were experienced by 5% of VEMLIDY subjects and 13% of TDF subjects at Week 96.
In subjects who remained on blinded treatment beyond Week 96 in Studies 108 and 110, mean percentage change in BMD in each group at Week 120 was similar to that at Week 96. In the open-label phase, mean percentage change in BMD from Week 96 to Week 120 in subjects who remained on VEMLIDY was 0.6% at the lumbar spine and 0% at the total hip, compared to 1.7% at the lumber spine and 0.6% at the total hip in those who switched from TDF to VEMLIDY.
The long-term clinical significance of these BMD changes is not known.
Laboratory Abnormalities
The frequency of laboratory abnormalities (Grades 3–4) occurring in at least 2% of subjects receiving VEMLIDY in Studies 108 and 110 are presented in Table 2.
Table 2 Laboratory Abnormalities (Grades 3–4) Reported in ≥2% of Subjects with Chronic HBV Infection and Compensated Liver Disease in Studies 108 and 110 (Week 96 analysisa)
| Laboratory Parameter Abnormalityb | VEMLIDY (N=866) | Tenofovir Disoproxil Fumarate (N=432) |
|---|---|---|
| ALT (>5 x ULN) | 8% | 10% |
| LDL-cholesterol (fasted) (>190 mg/dL) | 6% | 1% |
| Glycosuria (>3+) | 5% | 2% |
| AST (>5 x ULN) | 3% | 5% |
| Creatine Kinase (≥10 x ULN) | 3% | 3% |
| Serum Amylase (>2.0 x ULN) | 3% | 3% |
a. Double-blind phase
b. Frequencies are based on treatment-emergent laboratory abnormalities.
The overall incidence of blinded treatment ALT flares (defined as confirmed serum ALT greater than 2 × baseline and greater than 10 × ULN at 2 consecutive postbaseline visits, with or without associated symptoms) was similar between VEMLIDY (0.6%) and TDF (0.9%) through Week 96. ALT flares generally were not associated with coincident elevations in bilirubin, occurred within the first 12 weeks of treatment, and resolved without recurrence.
Based on the Week 120 analysis, the frequencies of lab abnormalities in subjects who remained on VEMLIDY in the open-label phase were similar to those in subjects who switched from TDF to VEMLIDY at Week 96.
Amylase and Lipase Elevations and Pancreatitis
At Week 96, in Studies 108 and 110, eight subjects treated with VEMLIDY with elevated amylase levels had associated symptoms, such as nausea, low back pain; abdominal tenderness, pain, and distension; and biliary pancreatitis and pancreatitis. Of these eight, two subjects discontinued VEMLIDY due to elevated amylase and/or lipase; one subject experienced recurrence of adverse events when VEMLIDY was restarted. No subject treated with tenofovir disoproxil fumarate had associated symptoms or discontinued treatment.
From Week 96 to Week 120, one additional subject who continued open-label VEMLIDY and none of the subjects who switched from TDF to VEMLIDY had elevated amylase levels and associated symptoms.
Serum Lipids
Changes from baseline in total cholesterol, HDL-cholesterol, LDL-cholesterol, triglycerides, and total cholesterol to HDL ratio among subjects treated with VEMLIDY and tenofovir disoproxil fumarate are presented in Table 3.
Table 3 Lipid Abnormalities: Mean Change from Baseline in Lipid Parameters in Patients with Chronic HBV Infection and Compensated Liver Disease in Studies 108 and 110 (Week 96 Analysis)
| VEMLIDY (N=866) | Tenofovir Disoproxil Fumarate (N=432) | |||
| Baseline | Week 96 | Baseline | Week 96 | |
| mg/dL | Changea | mg/dL | Changea | |
| Total Cholesterol (fasted) | 188 [n=835] | -1 [n=742] | 193 [n=423] | -25 [n=368] |
| HDL-Cholesterol (fasted) | 60 [n=835] | -5 [n=740] | 61 [n=423] | -12 [n=368] |
| LDL-Cholesterol (fasted) | 116 [n=835] | +7 [n=741] | 120 [n=423] | -10 [n=368] |
| Triglycerides (fasted) | 102 [n=836] | +13 [n=743] | 102 [n=423] | -7 [n=368] |
| Total Cholesterol to HDL ratio | 3 [n=835] | 0 [n=740] | 3 [n=423] | 0 [n=368] |
In the open-label phase, lipid parameters at Week 120 in subjects who remained on VEMLIDY were similar to those at Week 96. In subjects who switched from TDF to VEMLIDY, mean change from Week 96 to Week 120 in total cholesterol was 23 mg/dL, HDL-cholesterol was 5 mg/dL, LDL-cholesterol was 16 mg/dL, triglycerides was 30 mg/dL, and total cholesterol to HDL ratio was 0 mg/dL.
Section 7.4 Drugs without Clinically Significant Interactions with VEMLIDY was updated to include sofosbuvir/velpatasvir, and sofosbuvir/velpatasvir/
Kimberly Struble
Division of Antiviral Products
Food and Drug Administration
Elizabeth Thompson
Division of Antiviral Products
Food and Drug Administration
Food and Drug Administration
Michael Stanfield Jr.
Division of Antiviral Products
Food and Drug Administration
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