Pharmacological properties : תכונות פרמקולוגיות

Pharmacodynamic Properties

5.1   Pharmacodynamic properties

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.

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 48a

Study 108 (HBeAg-Negative)           Study 110 (HBeAg-Positive)
TAF                TDF              TAF               TDF
(N = 285)          (N = 140)        (N = 581)         (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                                                                          N/A              N/A < 7 log10 IU/mL                      96% (221/230)          92% (107/116) ≥ 7 log10 IU/mL                       85% (47/55)            96% (23/24) Baseline HBV DNA                           N/A                    N/A < 8 log10 IU/mL                                                                   82% (254/309)          82% (123/150) ≥ 8 log10 IU/mL                                                                   43% (117/272)          51% (72/142) Nucleoside naïvec                      94% (212/225)          93% (102/110)         68% (302/444)          70% (156/223) Nucleoside experienced                  93% (56/60)            93% (28/30)           50% (69/137)           57% (39/69) No Virologic data                           4%                     4%                    5%                     3% at Week 48
Discontinued study drug                     0                      0                   < 1%                     0 due to lack of efficacy
Discontinued study drug                    1%                     1%                    1%                     1% due to AE or death
Discontinued study drug                    2%                     3%                    3%                     2% due to other reasonsd
Missing data during                      < 1%                     1%                   < 1%                     0 window but on study drug
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 patientsreceived < 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 48a

Study 108 (HBeAg-Negative)                      Study 110 (HBeAg-Positive) TAF              TDF                            TAF              TDF
(N = 285)        (N = 140)                     (N = 581)         (N = 292) ALT                                            83%              75%                            72%              67% Normalised ALT (Central lab)b
Normalised ALT (AASLD)c                          50%                    32%                  45%                     36% Serology                                         N/A                    N/A                14% / 10%               12% / 8% HBeAg loss / seroconversiond
HBsAg loss / seroconversion                      0/0                    0/0                  1% / 1%                < 1% / 0 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 96a

Study 108 (HBeAg-Negative)                    Study 110 (HBeAg-Positive) TAF                   TDF                   TAF                    TDF 
(N = 285)             (N = 140)            (N = 581)             (N = 292) HBV DNA < 29 IU/mL                         90%                   91%                  73%                   75% Baseline HBV DNA                                                                      N/A                   N/A < 7 log10 IU/mL                      90% (207/230)        91% (105/116) ≥ 7 log10 IU/mL                       91% (50/55)          92% (22/24) Baseline HBV DNA                           N/A                  N/A
< 8 log10 IU/mL                                                                84% (260/309)         81% (121/150) ≥ 8 log10 IU/mL                                                                60% (163/272)         68% (97/142) Nucleoside naïveb                      90% (203/225)        92% (101/110)        75% (331/444)         75% (168/223) Nucleoside experienced                  90% (54/60)          87% (26/30)          67% (92/137)          72% (50/69) ALT
Normalised ALT (Central lab)c               81%                   71%                75%                   68% Normalised ALT (AASLD)d                     50%                   40%                52%                   42% Serology                                    N/A                   N/A              22% / 18%             18% / 12% HBeAg loss / seroconversione
HBsAg loss / seroconversion              <1% / <1%                0/0                1% / 1%                1% / 0 N/A = not applicable
TDF = tenofovir disoproxil
TAF = tenofovir alafenamide a. Missing = failure analysis b. Treatment-naïve patientsreceived < 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 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-TAF
(N=360)
Double blind baseline               Week 96                     Week 144 Median (Q1, Q3)            Median change (Q1, Q3)      Median change (Q1, Q3) (mg/dL)                        (mg/dL)                     (mg/dL)
Total Cholesterol (fasted)          185 (166, 210)                  0 (-18, 17)                  0 (-16, 18) HDL-Cholesterol (fasted)              59 (49, 72)                   -5 (-12,   1)a               -5 (-12,2)b LDL-Cholesterol (fasted)             113 (95, 137)                  6 (-8,   21)a                8 (-6, 24)b Triglycerides (fasted)                87 (67, 122)                  8 (-12, 28)a                11 (-11, 40)b Total Cholesterol to HDL ratio       3.1 (2.6, 3.9)                0.2 (0.0,   0.6)a           0.3 (0.0, 0.7)b TDF-TAF
(N=180)
Double blind baseline               Week 96                     Week 144 Median (Q1, Q3)            Median change (Q1, Q3)      Median change (Q1, Q3) (mg/dL)                        (mg/dL)                     (mg/dL)
Total Cholesterol (fasted)          189 (163, 215)                 -23 (-40, -1)a                1 (-17, 20) HDL-Cholesterol (fasted)              61 (49, 72)                  -12 (-19, -3)a               -8 (-15, -1)b LDL-Cholesterol (fasted)             120 (95, 140)                  -7 (-25, 8)a                 9 (-5, 26)b Triglycerides (fasted)                89 (69, 114)                 -11 (-31,   11)a             14 (-10, 43)b Total Cholesterol to HDL ratio       3.1 (2.5, 3.7)               0.2 (-0.1, 0.7)a             0.4 (0.0, 1.0)b 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 randomised 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 48a,b and Week 96b,c

TAF                      TDF                TAF-TAF                TDF-TAF (N=243)                  (N=245)               (N=243)                (N=245) Week 48                                        Week 96
HBV DNA ≥ 20 IU/mLb,d                    1 (0.4%)          1 (0.4%)                     1 (0.4%)          1 (0.4%) Treatment Differencee            0.0% (95% CI = -1.9% to 2.0%)                  0.0% (95% CI = -1.9% to 1.9%) HBV DNA < 20 IU/mL                     234 (96.3%)       236 (96.3%)                  230 (94.7%)       230 (93.9%) Treatment Differencee            0.0% (95% CI = -3.7% to 3.7%)                  0.9% (95% CI = -3.5% to 5.2%) No Virologic Data                        8 (3.3%)          8 (3.3%)                    12 (4.9%)         14 (5.7%) Discontinued Study
Drug Due to AE or
Death and Last                     2 (0.8%)                    0                  3 (1.2%)               1 (0.4%) Available HBV DNA
< 20 IU/mL
Discontinued Study
Drug Due to Other
Reasonsf and Last                  6 (2.5%)                 8 (3.3%)              7 (2.9%)              11 (4.5%) Available HBV DNA
< 20 IU/mL
Missing Data During
Window but on Study                     0                      0                  2 (0.8%)               2 (0.8%) Drug
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 96a

TAF                    TDF               TAF-TAF               TDF-TAF (N=243)                (N=245)              (N=243)               (N=245) Week 48                                     Week 96
ALT
Normal ALT (Central Lab)                  89%                   85%                   88%                    91% Normal ALT (AASLD)                        79%                   75%                   81%                    87% Normalised ALT (Central
50%                   37%                   56%                    79% Lab)b,c,d
Normalised ALT (AASLD)e,f,g               50%                   26%                   56%                    74% Serology
HBeAg Loss /
8% / 3%                6% / 0              18% / 5%               9% / 3% Seroconversionh
HBsAg Loss /
0/0                  2% / 0               2% / 1%              2% / < 1% Seroconversion
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 (> 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 normalisation 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 
TAF (N=236)      TAF (N=226)        TAF-TAF           TDF          TDF (N=222)       TDF-TAF (N=220)        (N=230)                           N=219)
Baseline         Week 48              Week 96     Baseline         Week 48         Week 96 (Q1, Q3)         Median            Median         (Q1, Q3)         Median           Median (mg/dL)        changea (Q1,      change (Q1,      (mg/dL)        changea (Q1,       change Q3) (mg/dL)           Q3)                         Q3) (mg/dL)       (Q1, Q3) (mg/dL)                                         (mg/dL)
Total Cholesterol          166 (147,         19 (6, 33)       16 (3, 30)     169 (147,        −4 (−16, 8)      15 (1, 28) (fasted)                     189)                                              188) HDL-Cholesterol            48 (41, 56)       3 (−1, 8)        4 (−1, 10)     48 (40, 57)       −1 (−5, 2)       4 (0, 9) (fasted)
LDL-Cholesterol           102 (87,123)       16 (5, 27)       17 (6, 28)      103 (87,         1 (−8, 12)      14 (3, 27) (fasted)                                                                       120) Triglycerides (fasted)b   90 (66, 128)      16 (−3, 44)       9 (−8, 28)    89 (68, 126)     −2 (−22, 18)      8 (−8, 38) Total Cholesterol to      3.4 (2.9, 4.2)   0.2 (−0.1, 0.5)    0.0 (−0.3,    3.4 (2.9, 4.2)   0.0 (−0.3, 0.3)   0.0 (−0.3, HDL ratio                                                        0.3)                                             0.3) 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 Cockcroft- Gault 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 subjects) and change from baseline in CPT and Model for End Stage Liver 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 
Cohort 1a                        Cohort 2b                           Total (N=78)                          (N= 15)                           (N=93) Week 24     Week 96              Week 24      Week 96             Week 24      Week 96d HBV DNAc
HBV DNA < 20                  76/78           65/78             15/15           13/15            91/93             78/93 IU/mL                        (97.4%)         (83.3%)          (100.0%)         (86.7%)          (97.8%)           (83.9%) ALTc
Normal ALT                    72/78           64/78            14/15            13/15            86/93             77/93 (Central Lab)                (92.3%)         (82.1%)          (93.3%)          (86.7%)          (92.5%)           (82.8%) Normal ALT                    68/78           58/78            14/15            13/15            82/93             71/93 (AASLD)e                     (87.2%)         (74.4%)          (93.3%)          (86.7%)          (88.2%)           (76.3%) 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 patients (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 
Part B
(N=31)
Week 24                            Week 96b a
HBV DNA
HBV DNA < 20 IU/mL                                          31/31 (100.0%)                        24/31 (77.4%) ALTa
Normal ALT (Central Lab)                                     26/31 (83.9%)                        22/31 (71.0%) Normal ALT (AASLD)c                                          25/31 (80.6%)                        18/31 (58.1%) CPT and MELD Score
Mean change from Baseline in CPT Score                             0 (1.1)                            0 (1.2) (SD)
Mean change from Baseline in MELD Score                          -0.6 (1.94)                        -1.0 (1.61) (SD)
CPT = Child-Pugh Turcotte;
MELD = Model for End-Stage Liver Disease a. Missing = Failure analysis b. The denominator includes 6 patients 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.

Pharmacokinetic Properties

5.2   Pharmacokinetic properties

Absorption
Following oral administration of tenofovir alafenamide under fasted conditions in adult patients with chronic hepatitis B, peak plasma concentrations of tenofovir alafenamide were observed approximately 0.48 hours post-dose. Based on Phase 3 population pharmacokinetic analysis in patients with chronic hepatitis B, mean steady state AUC0-24 for tenofovir alafenamide (N = 698) and tenofovir (N = 856) were 0.22 µg•h/mL and 0.32 µg•h/mL, respectively. Steady state Cmax for tenofovir alafenamide and tenofovir were 0.18 and 0.02 µg/mL, respectively. Relative to fasting conditions, the administration of a single dose of tenofovir alafenamide with a high fat meal resulted in a 65% increase in tenofovir alafenamide exposure.

Distribution

The binding of tenofovir alafenamide to human plasma proteins in samples collected during clinical studies was approximately 80%. The binding of tenofovir to human plasma proteins is less than 0.7% and is independent of concentration over the range of 0.01–25 μg/mL.

Biotransformation

Metabolism is a major elimination pathway for tenofovir alafenamide in humans, accounting for > 80% of an oral dose. In vitro studies have shown that tenofovir alafenamide is metabolised to tenofovir (major metabolite) by carboxylesterase-1 in hepatocytes; and by cathepsin A in peripheral blood mononuclear cells (PBMCs) and macrophages. In vivo, tenofovir alafenamide is hydrolysed within cells to form tenofovir (major metabolite), which is phosphorylated to the active metabolite, tenofovir diphosphate.

In vitro, tenofovir alafenamide is not metabolised by CYP1A2, CYP2C8, CYP2C9, CYP2C19, or CYP2D6. Tenofovir alafenamide is minimally metabolised by CYP3A4.

Elimination

Renal excretion of intact tenofovir alafenamide is a minor pathway with < 1% of the dose eliminated in urine. Tenofovir alafenamide is mainly eliminated following metabolism to tenofovir. Tenofovir alafenamide and tenofovir have a median plasma half-life of 0.51 and 32.37 hours, respectively.
Tenofovir is renally eliminated from the body by the kidneys by both glomerular filtration and active tubular secretion.

Linearity/non-linearity

Tenofovir alafenamide exposures are dose proportional over the dose range of 8 to 125 mg.
Pharmacokinetics in special populations

Age, gender and ethnicity
No clinically relevant differences in pharmacokinetics according to age or ethnicity have been identified. Differences in pharmacokinetics according to gender were not considered to be clinically relevant.

Hepatic impairment
In patients with severe hepatic impairment, total plasma concentrations of tenofovir alafenamide and tenofovir are lower than those seen in patients with normal hepatic function. When corrected for 

protein binding, unbound (free) plasma concentrations of tenofovir alafenamide in severe hepatic impairment and normal hepatic function are similar.

Renal impairment
No clinically relevant differences in tenofovir alafenamide or tenofovir pharmacokinetics were observed between healthy patients and patients with severe renal impairment (estimated CrCl > 15 but < 30 mL/min) in studies of tenofovir alafenamide (Table 12).

Exposures of tenofovir in patients with ESRD (estimated creatinine clearance < 15 mL/min) on chronic haemodialysis who received tenofovir alafenamide (N = 5) were substantially higher than in patients with normal renal function (Table 12). No clinically relevant differences in tenofovir alafenamide pharmacokinetics were observed in patients with ESRD on chronic haemodialysis as compared to those with normal renal function.

Table 12: Pharmacokinetics of Tenofovir Alafenamide and its Metabolite Tenofovir in Patients with Renal Impairment as Compared to Patients with Normal Renal Function 
AUC (mcg•hour per mL)
Mean (CV%)
Normal renal function          Severe renal impairment          ESRD on haemodialysis Estimated Creatinine            ≥ 90 mL per minute             15–29 mL per minute              < 15 mL per minute Clearancea                           (N = 13)b                        (N = 14)b                        (N = 5)c Tenofovir alafenamide              0.27 (49.2)d                    0.51 (47.3)d                     0.30 (26.7)e 0.34 (27.2)d                    2.07 (47.1)d               18.8 (30.4)f Tenofovir
CV = coefficient of variation a. By Cockcroft-Gault method.
b. PK assessed on a single dose of tenofovir alafenamide 25 mg in patients with normal renal function and in patients with severe renal impairment in Study GS-US-120-0108.
c. PK assessed prior to haemodialysis following multiple-dose administration of tenofovir alafenamide 25 mg in 5 HBV infected patients in Study GS-US-320-4035. These patients had a median baseline eGFR by Cockcroft-Gault of 7.2 mL/min (range, 4.8 to 12.0).
d. AUCinf.
e. AUClast.
f. AUCtau

Paediatric population
The pharmacokinetics of tenofovir alafenamide and tenofovir were evaluated in HIV-1-infected, treatment-naïve adolescents who received tenofovir alafenamide (10 mg) given with elvitegravir, cobicistat and emtricitabine as a fixed-dose combination tablet (E/C/F/TAF; Gendevra). No clinically relevant differences in tenofovir alafenamide or tenofovir pharmacokinetics were observed between adolescent and adult HIV-1-infected subjects.