VEMLIDY Film-coated tablet Ref.[7482] Active ingredients: Tenofovir alafenamide

Pharmacotherapeutic group: Antiviral for systemic use, nucleoside and nucleotide reverse transcriptase inhibitors
ATC code: J05AF13

Mechanism of action

Tenofovir alafenamide is a phosphonamidate prodrug of tenofovir (2'-deoxyadenosine monophosphate analogue). Tenofovir alafenamide enters primary hepatocytes by passive diffusion and by the hepatic uptake transporters OATP1B1 and OATP1B3. Tenofovir alafenamide is primarily hydrolysed to form tenofovir by carboxylesterase 1 in primary hepatocytes. Intracellular tenofovir is subsequently phosphorylated to the pharmacologically active metabolite tenofovir diphosphate. Tenofovir diphosphate inhibits HBV replication through incorporation into viral DNA by the HBV reverse transcriptase, which results in DNA chain termination.

Tenofovir has activity that is specific to HBV and HIV (HIV-1 and HIV-2). Tenofovir diphosphate is a weak inhibitor of mammalian DNA polymerases that include mitochondrial DNA polymerase γ and there is no evidence of mitochondrial toxicity in vitro based on several assays including mitochondrial DNA analyses.

Antiviral activity

The antiviral activity of tenofovir alafenamide was assessed in HepG2 cells against a panel of HBV clinical isolates representing genotypes A-H. The EC₅₀ (50% effective concentration) values for tenofovir alafenamide ranged from 34.7 to 134.4 nM, with an overall mean EC₅₀ of 86.6 nM. The CC₅₀ (50% cytotoxicity concentration) in HepG2 cells was >44,400 nM.

Resistance

In patients receiving tenofovir alafenamide, sequence analysis was performed on paired baseline and on-treatment HBV isolates for patients who either experienced virologic breakthrough (2 consecutive visits with HBV DNA ≥69 IU/mL after having been <69 IU/mL, or 1.0 log10 or greater increase in HBV DNA from nadir) or patients with HBV DNA ≥69 IU/mL at Week 48, or Week 96 or at early discontinuation at or after Week 24.

In a pooled analysis of patients receiving tenofovir alafenamide in Study 108 and Study 110 at Week 48 (N=20) and Week 96 (N=72), no amino acid substitutions associated with resistance to tenofovir alafenamide were identified in these isolates (genotypic and phenotypic analyses).

In virologically suppressed patients receiving tenofovir alafenamide following switch from tenofovir disoproxil treatment in Study 4018, through 96 weeks of tenofovir alafenamide treatment one patient in the tenofovir alafenamide-tenofovir alafenamide group experienced a virologic blip (one visit with HBV DNA ≥69 IU/mL) and one patient in the tenofovir disoproxil-tenofovir alafenamide group experienced a virologic breakthrough. No HBV amino acid substitutions associated with resistance to tenofovir alafenamide or tenofovir disoproxil were detected through 96 weeks of treatment.

In paediatric Study 1092, 30 patients aged 12 to <18 years and 9 patients aged 6 to <12 years receiving tenofovir alafenamide qualified for resistance analysis at Week 24. No HBV amino acid substitutions associated with resistance to tenofovir alafenamide were detected through 24 weeks of treatment. At Week 48, 31 patients aged 12 to <18 years and 12 patients aged 6 to <12 years qualified for resistance analysis (both tenofovir alafenamide group and placebo roll over to tenofovir alafenamide group at Week 24). No HBV amino acid substitutions associated with resistance to tenofovir alafenamide were detected through 48 weeks of treatment.

Cross-resistance

The antiviral activity of tenofovir alafenamide was evaluated against a panel of isolates containing nucleos(t)ide reverse transcriptase inhibitor mutations in HepG2 cells. HBV isolates expressing the rtV173L, rtL180M, and rtM204V/I substitutions associated with resistance to lamivudine remained susceptible to tenofovir alafenamide (<2-fold change in EC₅₀). HBV isolates expressing the rtL180M, rtM204V plus rtT184G, rtS202G, or rtM250V substitutions associated with resistance to entecavir remained susceptible to tenofovir alafenamide. HBV isolates expressing the rtA181T, rtA181V, or rtN236T single substitutions associated with resistance to adefovir remained susceptible to tenofovir alafenamide; however, the HBV isolate expressing rtA181V plus rtN236T exhibited reduced susceptibility to tenofovir alafenamide (3.7-fold change in EC₅₀). The clinical relevance of these substitutions is not known.

Clinical data

The efficacy and safety of tenofovir alafenamide in patients with CHB are based on 48- and 96-week data from two randomised, double-blind, active-controlled studies, Study 108 and Study 110. The safety of tenofovir alafenamide is also supported by pooled data from patients in Studies 108 and 110 who remained on blinded treatment from Week 96 through Week 144 and additionally from patients in the open-label phase of Studies 108 and 110 from Week 96 through Week 144 (N=360 remained on tenofovir alafenamide; N=180 switched from tenofovir disoproxil to tenofovir alafenamide at Week 96).

In Study 108, HBeAg-negative treatment-naïve and treatment-experienced patients with compensated liver function were randomised in a 2:1 ratio to receive tenofovir alafenamide (25 mg; N=285) once daily or tenofovir disoproxil (245 mg; N=140) once daily. The mean age was 46 years, 61% were male, 72% were Asian, 25% were White and 2% (8 patients) were Black. 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 (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 patients had a history of cirrhosis.

In Study 110, HBeAg-positive treatment-naïve and treatment-experienced patients with compensated liver function were randomised in a 2:1 ratio to receive tenofovir alafenamide (25 mg; N=581) once daily or tenofovir disoproxil (245 mg; N=292) once daily. The mean age was 38 years, 64% were male, 82% were Asian, 17% were White and <1% (5 patients) were Black. 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 (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 patients had a history of cirrhosis.

The primary efficacy endpoint in both studies was the proportion of patients with plasma HBV DNA levels below 29 IU/mL at Week 48. Tenofovir alafenamide met the non-inferiority criteria in achieving HBV DNA less than 29 IU/mL when compared to tenofovir disoproxil. Treatment outcomes of Study 108 and Study 110 through Week 48 are presented in Table 3 and Table 4.

Table 3. HBV DNA efficacy parameters at Week 48^a:

N/A = not applicable
TDF = tenofovir disoproxil
TAF = tenofovir alafenamide
^a Missing = failure analysis.
^b Adjusted by baseline plasma HBV DNA categories and oral antiviral treatment status strata.
^c Treatment-naïve patients received <12 weeks of oral antiviral treatment with any nucleoside or nucleotide analogue including tenofovir disoproxil or tenofovir alafenamide.
^d Includes patients who discontinued for reasons other than an adverse event (AE), death or lack or loss of efficacy, e.g. withdrew consent, loss to follow-up, etc.

Table 4. Additional efficacy parameters at Week 48^a:

N/A = not applicable
TDF = tenofovir disoproxil
TAF = tenofovir alafenamide
^a Missing = failure analysis.
^b The population used for analysis of ALT normalisation included only patients with ALT above upper limit of normal (ULN) of the central laboratory range at baseline. Central laboratory ULN for ALT are as follows: ≤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.
^c The population used for analysis of ALT normalisation included only patients with ALT above ULN of the 2016 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 patients with antigen (HBeAg) positive and antibody (HBeAb) negative or missing at baseline.

Experience beyond 48 weeks in Study 108 and Study 110

At Week 96, viral suppression as well as biochemical and serological responses were maintained with continued tenofovir alafenamide treatment (see Table 5).

Table 5. HBV DNA and additional efficacy parameters at Week 96^a:

N/A = not applicable
TDF = tenofovir disoproxil
TAF = tenofovir alafenamide
^a Missing = failure analysis
^b Treatment-naïve patients received <12 weeks of oral antiviral treatment with any nucleoside or nucleotide analogue including tenofovir disoproxil or tenofovir alafenamide.
^c The population used for analysis of ALT normalisation included only patients with ALT above ULN of the central laboratory range at baseline. Central laboratory ULN for ALT are as follows: ≤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.
^d The population used for analysis of ALT normalisation included only patients with ALT above ULN of the 2016 AASLD criteria (>30 U/L males and >19 U/L females) at baseline.
^e The population used for serology analysis included only patients with antigen (HBeAg) positive and antibody (HBeAb) negative or missing at baseline.

Changes in measures of bone mineral density in Study 108 and Study 110

In both studies tenofovir alafenamide was associated with smaller mean percentage decreases in BMD (as measured by hip and lumbar spine dual energy X ray absorptiometry [DXA] analysis) compared to tenofovir disoproxil after 96 weeks of treatment.

In patients who remained on blinded treatment beyond Week 96, mean percentage change in BMD in each group at Week 144 was similar to that at Week 96. In the open-label phase of both studies, mean percentage change in BMD from Week 96 to Week 144 in patients who remained on tenofovir alafenamide was +0.4% at the lumbar spine and -0.3% at the total hip, compared to +2.0% at the lumbar spine and +0.9% at the total hip in those who switched from tenofovir disoproxil to tenofovir alafenamide at Week 96.

Changes in measures of renal function in Study 108 and Study 110

In both studies tenofovir alafenamide was associated with smaller changes in renal safety parameters (smaller median reductions in estimated CrCl by Cockcroft-Gault and smaller median percentage increases in urine retinol binding protein to creatinine ratio and urine beta-2-microglobulin to creatinine ratio) compared to tenofovir disoproxil fumarate after 96 weeks of treatment (see also section 4.4).

In patients who remained on blinded treatment beyond Week 96 in Studies 108 and 110, changes from baseline in renal laboratory parameter values in each group at Week 144 were similar to those at Week 96. In the open-label phase of Studies 108 and 110, the mean (SD) change in serum creatinine from Week 96 to Week 144 was +0.002 (0.0924) mg/dL in those who remained on tenofovir alafenamide, compared to -0.018 (0.0691) mg/dL in those who switched from tenofovir disoproxil to tenofovir alafenamide at Week 96. In the open-label phase, the median change in eGFR from Week 96 to Week 144 was -1.2 mL/min in patients who remained on tenofovir alafenamide, compared to +4.2 mL/min in patients who switched from tenofovir disoproxil to tenofovir alafenamide at Week 96.

Changes in lipid laboratory tests in Study 108 and Study 110

In a pooled analysis of Studies 108 and 110, median changes in fasting lipid parameters from baseline to Week 96 were observed in both treatment groups. For patients who switched to open label tenofovir alafenamide at Week 96, changes from double-blind baseline for patients randomised initially to tenofovir alafenamide and tenofovir disoproxil at Week 96 and Week 144 in total cholesterol, HDL-cholesterol, LDL-cholesterol, triglycerides, and total cholesterol to HDL ratio are presented in Table 6. At Week 96, the end of the double-blind phase, decreases in median fasting total cholesterol and HDL, and increases in median fasting direct LDL and triglycerides were observed in the tenofovir alafenamide group, while the tenofovir disoproxil group demonstrated median reductions in all parameters.

In the open-label phase of Studies 108 and 110, where patients switched to open-label tenofovir alafenamide at Week 96, lipid parameters at Week 144 in patients who remained on tenofovir alafenamide were similar to those at Week 96, whereas median increases in fasting total cholesterol, direct LDL, HDL, and triglycerides were observed in patients who switched from tenofovir disoproxil to tenofovir alafenamide at Week 96. In the open label phase, median (Q1, Q3) change from Week 96 to Week 144 in total cholesterol to HDL ratio was 0.0 (-0.2, 0.4) in patients who remained on tenofovir alafenamide and 0.2 (-0.2, 0.6) in patients who switched from tenofovir disoproxil to tenofovir alafenamide at Week 96.

Table 6. Median changes from double-blind baseline in lipid laboratory tests at Weeks 96 and 144 for patients who switched to open-label tenofovir alafenamide at Week 96:

TAF = tenofovir alafenamide
TDF = tenofovir disoproxil
^a P-value was calculated for change from double blind baseline at Week 96, from Wilcoxon Signed Rank test and was statistically significant (p<0.001).
^b P-value was calculated for change from double blind baseline at Week 144, from Wilcoxon Signed Rank test and was statistically significant (p<0.001).

Virologically suppressed adult patients in Study 4018

The efficacy and safety of tenofovir alafenamide in virologically suppressed adults with chronic hepatitis B is based on 48-week data from a randomised, double-blind, active-controlled study, Study 4018 (N=243 on tenofovir alafenamide; N=245 on tenofovir disoproxil), including data from patients who participated in the open-label phase of Study 4018 from Week 48 through Week 96 (N=235 remained on tenofovir alafenamide [TAF-TAF]; N=237 switched from tenofovir disoproxil to tenofovir alafenamide at Week 48 [TDF-TAF]).

In Study 4018 virologically suppressed adults with chronic hepatitis B (N=488) were enrolled who had been previously maintained on 245 mg tenofovir disoproxil once daily for at least 12 months, with HBV DNA < lower limit of quantification (LLOQ) by local laboratory assessment for at least 12 weeks prior to screening and HBV DNA <20 IU/mL at screening. Patients were stratified by HBeAg status (HBeAg-positive or HBeAg-negative) and age (≥50 or <50 years) and randomized in a 1:1 ratio to switch to 25 mg tenofovir alafenamide (N=243) or remain on 245 mg tenofovir disoproxil once daily (N=245). Mean age was 51 years (22% were ≥60 years), 71% were male, 82% were Asian, 14% were White, and 68% were HBeAg-negative. At baseline, median duration of prior tenofovir disoproxil treatment was 220 and 224 weeks in the tenofovir alafenamide and tenofovir disoproxil groups, respectively. Previous treatment with antivirals also included interferon (N=63), lamivudine (N=191), adefovir dipivoxil (N=185), entecavir (N=99), telbivudine (N=48), or other (N=23). At baseline, mean serum ALT was 27 U/L, median eGFR by Cockcroft-Gault was 90.5 mL/min; 16% of patients had a history of cirrhosis.

The primary efficacy endpoint was the proportion of patients with plasma HBV DNA levels ≥20 IU/mL at Week 48 (as determined by the modified US FDA Snapshot algorithm). Additional efficacy endpoints included the proportion of patients with HBV DNA levels <20 IU/mL, ALT normal and ALT normalisation, HBsAg loss and seroconversion, and HBeAg loss and seroconversion. Tenofovir alafenamide was non-inferior in the proportion of patients with HBV DNA ≥20 IU/mL at Week 48 when compared to tenofovir disoproxil as assessed by the modified US FDA Snapshot algorithm. Treatment outcomes (HBV DNA <20 IU/mL by missing=failure) at Week 48 between treatment groups were similar across subgroups by age, sex, race, baseline HBeAg status, and ALT.

Treatment outcomes of Study 4018 at Week 48 and Week 96 are presented in Table 7 and Table 8.

Table 7. HBV DNA efficacy parameters at Week 48^a,b and Week 96^b,c:

TDF = tenofovir disoproxil
TAF = tenofovir alafenamide
^a Week 48 window was between Day 295 and 378 (inclusive).
^b As determined by the modified US FDA-defined snapshot algorithm.
^c Open-label phase, Week 96 window is between Day 589 and 840 (inclusive).
^d No patient discontinued treatment due to lack of efficacy.
^e Adjusted by baseline age groups (<50, ≥50 years) and baseline HBeAg status strata.
^f Includes patients who discontinued for reasons other than an AE, death or lack of efficacy, e.g., withdrew consent, loss to follow-up, etc.

Table 8. Additional efficacy parameters at Week 48 and Week 96^a:

TDF = tenofovir disoproxil
TAF = tenofovir alafenamide
^a Missing = failure analysis
^b The population used for analysis of ALT normalization included only patients with ALT above upper limit of normal (ULN) of the central laboratory range (>43 U/L males 18 to <69 years and >35 U/L males ≥69 years; >34 U/L females 18 to <69 years and >32 U/L females ≥69 years) at baseline.
^c Proportion of patients at Week 48: TAF, 16/32; TDF, 7/19.
^d Proportion of patients at Week 96: TAF, 18/32; TDF, 15/19.
^e The population used for analysis of ALT normalization included only patients with ALT above ULN of the 2018 American Association of the Study of Liver Diseases (AASLD) criteria (35 U/L males and 25 U/L females) at baseline.
^f Proportion of patients at Week 48: TAF, 26/52; TDF, 14/53.
^g Proportion of patients at Week 96: TAF, 29/52; TDF, 39/53
^h The population used for serology analysis included only patients with antigen (HBeAg) positive and anti-body (HBeAb) negative or missing at baseline.

Changes in bone mineral density in Study 4018

The mean percentage change in BMD from baseline to Week 48 as assessed by DXA was +1.7% with tenofovir alafenamide compared to −0.1% with tenofovir disoproxil at the lumbar spine and +0.7% compared to −0.5% at the total hip. BMD declines of greater than 3% at the lumbar spine were experienced by 4% of tenofovir alafenamide patients and 17% of tenofovir disoproxil patients at Week 48. BMD declines of greater than 3% at the total hip were experienced by 2% of tenofovir alafenamide patients and 12% of tenofovir disoproxil patients at Week 48.

In the open-label phase, mean percentage change in BMD from baseline to Week 96 in patients who remained on tenofovir alafenamide was +2.3% at the lumbar spine and +1.2% at the total hip, compared to +1.7% at the lumbar spine and +0.2% at the total hip in those who switched from tenofovir disoproxil to tenofovir alafenamide at Week 48.

Changes in renal laboratory tests in Study 4018

The median change from baseline to Week 48 in eGFR by Cockcroft-Gault method was +2.2 mL per minute in the tenofovir alafenamide group and −1.7 mL per minute in those receiving tenofovir disoproxil. At Week 48, there was a median increase from baseline in serum creatinine among patients randomised to continue treatment with tenofovir disoproxil (0.01 mg/dL) compared with a median decrease from baseline among those who were switched to tenofovir alafenamide (−0.01 mg/dL).

In the open-label phase, the median change in eGFR from baseline to Week 96 was 1.6 mL/min in patients who remained on tenofovir alafenamide, compared to +0.5 mL/min in patients who switched from tenofovir disoproxil to tenofovir alafenamide at Week 48. The median change in serum creatinine from baseline to Week 96 was −0.02 mg/dL in those who remained on tenofovir alafenamide, compared to −0.01 mg/dL in those who switched from tenofovir disoproxil to tenofovir alafenamide at Week 48.

Changes in lipid laboratory tests in Study 4018

Changes from double-blind baseline to Week 48 and Week 96 in total cholesterol, HDL-cholesterol, LDL-cholesterol, triglycerides, and total cholesterol to HDL ratio are presented in Table 9.

Table 9. Median changes in lipid laboratory tests at Week 48 and Week 96:

TDF = tenofovir disoproxil
TAF = tenofovir alafenamide
^a P-value was calculated for the difference between the TAF and TDF groups at Week 48, from Wilcoxon Rank Sum test and was statistically significant (p<0.001) for median changes (Q1, Q3) from baseline in total cholesterol, HDL-cholesterol, LDL-cholesterol, triglycerides and total cholesterol to HDL ratio.
^b Number of patients for triglycerides (fasted) for TAF group was N=235 at baseline, N=225 at Week 48 and N=218 for TAF-TAF group at Week 96.

Renal and/or hepatic impairment Study 4035

Study 4035 was an open-label clinical study to evaluate the efficacy and safety of switching from another antiviral regimen to tenofovir alafenamide in virologically suppressed HBV-infected patients. Part A of the study included patients with moderate to severe renal impairment (eGFR by CockcroftGault method between 15 and 59 mL/min; Cohort 1, N=78) or ESRD (eGFR by Cockcroft-Gault method <15 mL/min) on hemodialysis (Cohort 2, N=15). Part B of the study included patients (N=31) with moderate or severe hepatic impairment (Child-Pugh Class B or C at screening or a history of CPT score ≥7 with any CPT score ≤ 12 at screening).

The primary endpoint was the proportion of patients with HBV DNA <20 IU/mL at Week 24. Secondary efficacy endpoints at Weeks 24 and 96 included the proportion of patients with HBV DNA <20 IU/mL and target detected/not detected (ie, < LLOD), the proportion of patients with biochemical response (normal ALT and normalised ALT), the proportion of patients with serological response (loss of HBsAg and seroconversion to anti-HBs and loss of HBeAg and seroconversion to anti-HBe in HBeAg-positive patients) and change from baseline in CPT and Model for End StageLiver Disease (MELD) scores for hepatically impaired patients in Part B.

Renally impaired adult patients in Study 4035, Part A

At baseline, 98% (91/93) of patients in Part A had HBV DNA <20 IU/mL and 66% (61/93) had an undetectable HBV DNA level. Median age was 65 years, 74% were male, 77% were Asian, 16% were White, and 83% were HBeAg-negative. The most commonly used HBV medication oral antivirals included tenofovir disoproxil (N=58), lamivudine (N=46), adefovir dipivoxil (N=46), and entecavir (N=43). At baseline, 97% and 95% of patients had ALT ≤ ULN based on central laboratory criteria and 2018 AASLD criteria, respectively; median eGFR by Cockcroft-Gault was 43.7 mL/min (45.7 mL/min in Cohort 1 and 7.32 mL/min in Cohort 2); and 34% of patients had a history of cirrhosis.

Treatment outcomes of Study 4035 Part A at Weeks 24 and 96 are presented in Table 10.

Table 10. Efficacy parameters for Renally Impaired Patients at Weeks 24 and 96:

^a Part A Cohort 1 includes patients with moderate or severe renal impairment
^b Part A Cohort 2 includes patients with ESRD on hemodialysis
^c Missing = Failure analysis
^d The denominator includes 12 subjects (11 for Cohort 1 and 1 for Cohort 2) who prematurely discontinued study drug.
^e 2018 American Association of the Study of Liver Diseases (AASLD) criteria

Hepatically impaired adult patients in Study 4035, Part B

At baseline, 100% (31/31) of patients in Part B had baseline HBV DNA <20 IU/mL and 65% (20/31) had an undetectable HBV DNA level. Median age was 57 years (19% ≥65 years), 68% were male, 81% were Asian, 13% were White, and 90% were HBeAg-negative. The most commonly used HBV medication oral antivirals included tenofovir disoproxil (N=21), lamivudine (N=14), entecavir (N=14), and adefovir dipivoxil (N=10). At baseline, 87% and 68% of patients had ALT ≤ ULN based on central laboratory criteria and 2018 AASLD criteria, respectively; median eGFR by Cockcroft-Gault was 98.5 mL/min; 97% of patients had a history of cirrhosis, median (range) CPT score was 6 (5−10), and median (range) MELD score was 10 (6−17).

Treatment outcomes of Study 4035 Part B at Weeks 24 and 96 are presented in Table 11.

Table 11. Efficacy parameters for Hepatically Impaired Patients at Weeks 24 and 96:

CPT = Child-Pugh Turcotte;
MELD = Model for End-Stage Liver Disease
^a Missing = Failure analysis
^b The denominator includes 6 subjects who prematurely discontinued study drug
^c 2018 American Association of the Study of Liver Diseases (AASLD) criteria

Changes in lipid laboratory tests in Study 4035

Small median increases from baseline to Week 24 and Week 96 in total cholesterol, HDL-cholesterol, LDL-cholesterol, triglycerides, and total cholesterol to HDL ratio among patients with renal or hepatic impairment are consistent when compared with results observed from other studies involving switch to tenofovir alafenamide (see section 5.1 for Studies 108, 110 and 4018), whereas decreases from baseline in total cholesterol, LDL-cholesterol, triglycerides, and total cholesterol to HDL ratio were observed in patients with ESRD on haemodialysis at Week 24 and Week 96.

Paediatric population

In Study 1092, the efficacy and safety of tenofovir alafenamide were evaluated in a randomised, double-blind, placebo-controlled clinical study of treatment-naïve and treatment-experienced HBV-infected patients between the ages of 12 to <18 years weighing ≥35 kg (Cohort 1; N=47 tenofovir alafenamide, N=23 placebo), and 6 to <12 years weighing ≥25 kg (Cohort 2 Group 1; N=12 tenofovir alafenamide, N=6 placebo). Patients were randomised to receive tenofovir alafenamide or placebo to match once daily. Baseline demographics and HBV disease characteristics were comparable between the two treatment arms; 58% were male, 66% were Asian, and 25% were White; 7%, 23%, 24%, and 44% had HBV genotype A, B, C, and D, respectively. Overall, 99% were HBeAg positive. At baseline, median HBV DNA was 8.1 log10 IU/mL, mean ALT was 107 U/L, median HBsAg was 4.5 log10 IU/mL. Previous treatment included oral antivirals (23%), including entecavir (N=10), lamivudine (N=12), and tenofovir disoproxil (N=3), and/or interferons (15%). After receiving double-blind treatment for 24 weeks (either tenofovir alafenamide or placebo), patients rolled over with no interruption in treatment to open-label tenofovir alafenamide.

The primary efficacy endpoint was the proportion of patients with plasma HBV DNA <20 IU/mL at Week 24. Additional efficacy endpoints included change from baseline in HBV DNA and ALT, ALT normalisation, HBeAg loss and seroconversion, and HBsAg loss and seroconversion.

Treatment outcomes of Study 1092 at Week 24 and Week 48 are presented in Table 12 and Table 13.

Table 12. Efficacy Parameters for Paediatric Patients at Week 24:

TAF = tenofovir alafenamide
^a Missing = Failure analysis
^b The population used for analysis of ALT normalisation included only patients with ALT above ULN of the central laboratory range at baseline. Central laboratory ULN for ALT are as follows: 34 U/L for females aged 2 or older or males aged 1-9 years old and 43 U/L for males aged older than 9 years.
^c The population used for analysis of ALT normalisation included only patients with ALT above ULN of the AASLD criteria (30 U/L for males and females based on the range for paediatric participants) at baseline.
^d American Association of the Study of Liver Diseases (AASLD) criteria.
^e No patient in either group had HBsAg loss or seroconversion at Week 24.
^f The population used for serology analysis included only patients with antigen (HBeAg) positive and antibody (HBeAb) negative or missing at baseline.

Table 13. Efficacy Parameters for Paediatric Patients at Week 48:

TAF = tenofovir alafenamide
^a Missing = Failure analysis
^b The population used for analysis of ALT normalisation included only patients with ALT above ULN of the central laboratory range at baseline. Central laboratory ULN for ALT are as follows: 34 U/L for females aged 2 or older or males aged 1-9 years old and 43 U/L for males aged older than 9 years.
^c The population used for analysis of ALT normalisation included only patients with ALT above ULN of the AASLD criteria (30 U/L for males and females based on the range for paediatric participants) at baseline.
^d American Association of the Study of Liver Diseases (AASLD) criteria.
^e No patient in either group had HBsAg loss or seroconversion at Week 48.
^f The population used for serology analysis included only patients with antigen (HBeAg) positive and antibody (HBeAb) negative or missing at baseline.

Changes in bone mineral density in Study 1092

Among the patients treated with tenofovir alafenamide and placebo, the mean percent increase in BMD from baseline to Week 24 was +1.6% (N=48) and +1.9% (N=23) for lumbar spine, and +1.9% (N=50) and +2.0% (N=23) for whole body, respectively. At Week 24, mean changes from baseline BMD Z-scores were +0.01 and -0.07 for lumbar spine, and -0.04 and -0.04 for whole body, for the tenofovir alafenamide and placebo groups, respectively.

In the open-label phase, mean percentage increase in BMD from baseline to Week 48 for lumbar spine and whole body was +3.8% (N=52) and +3.0% (N=54) in patients who remained on tenofovir alafenamide, compared to +2.8% (N=27) and +3.7% (N=27) in those who switched from placebo to tenofovir alafenamide at Week 24, respectively. At Week 48, mean changes from baseline BMD-Z scores for lumbar spine and whole body were -0.05 and -0.15 for patients who remained on tenofovir alafenamide, compared to -0.12 and -0.07 for those who switched to tenofovir alafenamide, respectively.

BMD declines of 4% or greater at lumbar spine and whole body at Week 24 and Week 48 are presented in Table 14.

Table 14. Bone Mineral Density Decreases of 4% or Greater for Paediatric Patients at Weeks 24 and 48 (Whole Body/Lumbar Spine DXA Analysis Set):

TAF = tenofovir alafenamide
Denominator is the number of patients with nonmissing postbaseline values.
^a N=42 for Lumbar Spine DXA Analysis Set in Cohort 1 TAF
^b Only patients with nonmissing whole body bone mineral density at baseline were included in the Whole Body DXA Analysis Set.
^c Only patients with nonmissing lumbar spine bone mineral density at baseline were included in the Lumbar Spine DXA Analysis Set.