On November 10, 2016, the FDA approved VEMLIDY (tenofovir alafenamide) 25 mg tablets. VEMLIDY is a hepatitis B virus (HBV) nucleoside analog reverse transcriptase inhibitor and is indicated for the treatment of chronic hepatitis B virus infection in adults with compensated liver disease.
Prior to initiation of VEMLIDY, test patients for HIV infection. VEMLIDY alone should not be used in patients with HIV infection. Assess serum creatinine, serum phosphorous, estimated creatinine clearance, urine glucose, and urine protein before initiating VEMLIDY and during therapy in all patients as clinically appropriate.
The recommended dosage is 25 mg (one tablet) taken orally once daily with food
No dosage adjustment of VEMLIDY is required in patients with mild, moderate, or severe renal impairment. VEMLIDY is not recommended in patients with end stage renal disease (estimated creatinine clearance below 15 mL per minute)
No dosage adjustment of VEMLIDY is required in patients with mild hepatic impairment (Child-Pugh A). VEMLIDY is not recommended in patients with decompensated (Child-Pugh B or C) hepatic impairment
WARNINGS AND PRECAUTIONS
- HBV and HIV-1 coinfection: VEMLIDY alone is not recommended for the treatment of HIV-1 infection. HIV-1 resistance may develop in these patients.
- New onset or worsening renal impairment: Assessment of serum creatinine, serum phosphorus, estimated creatinine clearance, urine glucose, and urine protein is recommended before initiating VEMLIDY therapy and during therapy as clinically appropriate.
ADVERSE REACTIONS
Most common adverse reactions (incidence greater than or equal to 5%, all grades) are headache, abdominal pain, fatigue, cough, nausea, and back pain.
DRUG INTERACTIONS
VEMLIDY is a substrate of P-glycoprotein (P-gp) and BCRP. Drugs that strongly affect P-gp and BCRP activity may lead to changes in VEMLIDY absorption. Consult the full prescribing information prior to and during treatment for potential drug-drug interactions Established and Other Potentially Significant Drug Interactionsa
Concomitant Drug Class: Drug Name
|
Effect on Concentrationb
|
Clinical Comment
|
Anticonvulsants:
carbamazepinec*
oxcarbazepine*
phenobarbital*
phenytoin*
|
↓ tenofovir alafenamide
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When coadministered with carbamazepine, the tenofovir alafenamide dose should be increased to two tablets once daily.
Coadministration of VEMLIDY with oxcarbazepine, phenobarbital, or phenytoin is not recommended.
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Antimycobacterial:
Rifabutin*
Rifampin*
Rifapentine*
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↓ tenofovir alafenamide
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Coadministration of VEMLIDY with rifabutin, rifampin or rifapentine is not recommended.
|
Herbal Products:
St. John’s wort* (Hypericum perforatum)
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↓ tenofovir alafenamide
|
Coadministration of VEMLIDY with St. John’s wort is not recommended.
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a. This table is not all inclusive.
b. ↓= decrease.
c. Indicates that a drug interaction study was conducted.
* P-gp inducer
b. ↓= decrease.
c. Indicates that a drug interaction study was conducted.
* P-gp inducer
CLINICAL STUDIES
14.1 Clinical Trials in Adults with Chronic Hepatitis B Virus Infection and Compensated Liver Disease
The efficacy and safety of VEMLIDY in the treatment of adults with chronic hepatitis B virus infection with compensated liver disease are based on 48-week data from two randomized, double-blind, active-controlled studies, Study 108 (N=425) and Study 110 (N=873). In both studies, besides study treatment, patients were not allowed to receive other nucleosides, nucleotides, or interferon.
In Study 108, HBeAg-negative treatment-naïve and treatment-experienced subjects with compensated liver disease (no evidence of ascites, hepatic encephalopathy, variceal bleeding, INR <1 .5x="" 2.5x="" albumin="" and="" bilirubin="" total="" uln=""> 3.0 mg/dL) were randomized in a 2:1 ratio to receive VEMLIDY 25 mg (N=285) once daily or tenofovir disoproxil fumarate 300 mg (N=140) once daily for 48 weeks. The mean age was 46 years, 61% were male, 72% were Asian, 25% were White, 2% were Black, and 1% were other races. 24%, 38%, and 31% had HBV genotype B, C, and D, respectively. 21% were treatment experienced [previous treatment with oral antivirals, including entecavir (N=41), lamivudine (N=42), tenofovir disoproxil fumarate (N=21), or other (N=18)]. At baseline, mean plasma HBV DNA was 5.8 log10 IU/mL, mean serum ALT was 94 U/L, and 9% of subjects had a history of cirrhosis.
In Study 110, HBeAg-positive treatment-naïve and treatment-experienced subjects with compensated liver disease were randomized in a 2:1 ratio to receive VEMLIDY 25 mg (N=581) once daily or tenofovir disoproxil fumarate 300 mg (N=292) once daily for 48 weeks. The mean age was 38 years, 64% were male, 82% were Asian, 17% were White, and 1% were Black or other races. 17%, 52%, and 23% had HBV genotype B, C, and D, respectively. 26% were treatment experienced [previous treatment with oral antivirals, including adefovir (N=42), entecavir (N=117), lamivudine (N=84), telbivudine (N=25), tenofovir disoproxil fumarate (N=70), or other (n=17)]. At baseline, mean plasma HBV DNA was 7.6 log10 IU/mL, mean serum ALT was 120 U/L, and 7% of subjects had a history of cirrhosis.
In both studies, randomization was stratified on prior treatment history (nucleoside naïve or experienced) and baseline HBV DNA (< 7, ≥7 to < 8, and ≥8 log10 IU/mL in Study 108; and < 8 and ≥8 log10 IU/mL in Study 110). The efficacy endpoint in both trials was the proportion of subjects with plasma HBV DNA levels below 29 IU/mL at Week 48. Additional efficacy endpoints include the proportion of subjects with ALT normalization, HBsAg loss and seroconversion, and HBeAg loss and seroconversion in Study 110.
Treatment outcomes of Studies 108 and 110 at Week 48 are presented in Table 9 and Table 10.
Table 9 Studies 108 and 110: HBV DNA Virologic Outcome at Week 48a in Patients with Chronic HBV Infection and Compensated Liver Disease
| Study 108 (HBeAg-Negative) | Study 110 (HBeAg-Positive) | |||
| VEMLIDY(N=285) | Tenofovir Disoproxil Fumarate(N=140) | VEMLIDY (N=581) | Tenofovir Disoproxil Fumarate(N=292) | |
| HBV DNA < 29 IU/mL | 94% | 93% | 64% | 67% |
| Treatment Differenceb | 1.8% (95% CI = -3.6% to 7.2%) | -3.6% (95% CI = -9.8% to 2.6%) | ||
| HBV DNA ≥ 29 IU/mL | 2% | 3% | 31% | 30% |
| Baseline HBV DNA < 7 log10 IU/mL ≥7 log10 IU/mL | 96% (221/230) 85% (47/55) | 92% (107/116) 96% (23/24) | N/A | N/A |
| Baseline HBV DNA < 8 log10 IU/mL ≥8 log10 IU/mL | N/A | N/A | 82% (254/309) 43% (117/272) | 82% (123/150) 51% (72/142) |
| Nucleoside Naïvec Nucleoside Experienced | 94% (212/225) 93% (56/60) | 93% (102/110) 93% (28/30) | 68% (302/444) 50% (69/137) | 70% (156/223) 57% (39/69) |
| No Virologic Data at Week 48d | 4% | 4% | 5% | 3% |
a. Missing = failure analysis
b. Adjusted by baseline plasma HBV DNA categories and oral antiviral treatment status strata.
c. Treatment-naïve subjects received < 12 weeks of oral antiviral treatment with any nucleoside or nucleotide analog including TDF or VEMLIDY.
d. Includes subjects who discontinued due to lack of efficacy, adverse event or death, for reasons other than an AE, death or lack or loss of efficacy, e.g., withdrew consent, loss to follow-up, etc., or missing data during Week 48 window but still on study drug.
b. Adjusted by baseline plasma HBV DNA categories and oral antiviral treatment status strata.
c. Treatment-naïve subjects received < 12 weeks of oral antiviral treatment with any nucleoside or nucleotide analog including TDF or VEMLIDY.
d. Includes subjects who discontinued due to lack of efficacy, adverse event or death, for reasons other than an AE, death or lack or loss of efficacy, e.g., withdrew consent, loss to follow-up, etc., or missing data during Week 48 window but still on study drug.
In Study 108, the proportion of subjects with cirrhosis who achieved HBV DNA < 29 IU/mL at Week 48 was 92% (22/24) in the VEMLIDY group and 93% (13/14) in the TDF group. The corresponding proportions in Study 110 were 63% (26/41) and 67% (16/24) in the VEMLIDY and TDF groups, respectively.
Table 10 Additional Efficacy Parameters at Week 48a
| Study 108 (HBeAg-Negative) | Study 110 (HBeAg-Positive) | |||
| VEMLIDY(N=285) | Tenofovir Disoproxil Fumarate (N=140) | VEMLIDY (N=581) | Tenofovir Disoproxil Fumarate (N=292) | |
| ALT Normalized ALT (Central Lab)b | 83% | 75% | 72% | 67% |
| Normalized ALT (AASLD)c | 50% | 32% | 45% | 36% |
| Serology HBeAg Loss / Seroconversiond | N/A | N/A | 14% / 10% | 12% / 8% |
| HBsAg Loss / Seroconversion | 0 / 0 | 0 / 0 | 1% / 1% | < 1% / 0 |
N/A = not applicable
a. Missing = failure analysis
b. The population used for analysis of ALT normalization included only subjects with ALT above upper limit of normal (ULN) of the central laboratory range (> 43 U/L for males aged 18 to < 69 years and > 35 U/L for males ≥69 years; > 34 U/L for females 18 to < 69 years and > 32 U/L for females ≥69 years) at baseline.
c. The population used for analysis of ALT normalization included only subjects with ALT above ULN of the American Association of the Study of Liver Diseases (AASLD) criteria (> 30 U/L males and > 19 U/L females) at baseline.
d. The population used for serology analysis included only subjects with antigen (HBeAg) positive and anti-body (HBeAb) negative or missing at baseline.
b. The population used for analysis of ALT normalization included only subjects with ALT above upper limit of normal (ULN) of the central laboratory range (> 43 U/L for males aged 18 to < 69 years and > 35 U/L for males ≥69 years; > 34 U/L for females 18 to < 69 years and > 32 U/L for females ≥69 years) at baseline.
c. The population used for analysis of ALT normalization included only subjects with ALT above ULN of the American Association of the Study of Liver Diseases (AASLD) criteria (> 30 U/L males and > 19 U/L females) at baseline.
d. The population used for serology analysis included only subjects with antigen (HBeAg) positive and anti-body (HBeAb) negative or missing at baseline.
Steve Morin
Office of Health and Constituent Affairs
Food and Drug Administration
Office of Health and Constituent Affairs
Food and Drug Administration
Kimberly Struble
Division of Antiviral Products
Food and Drug Administration
Division of Antiviral Products
Food and Drug Administration
Richard Klein
Office of Health and Constituent Affairs
Food and Drug Administration
Office of Health and Constituent Affairs
Food and Drug Administration
For more information about the Hepatitis Liaison Program visit the FDA Patient Network
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