VEMLIDY: REDUCED EFFECT ON RENAL SAFETY PARAMETERS

CLINICAL STUDY DESIGN

The efficacy and safety of VEMLIDY in the treatment of adults with chronic HBV infection with compensated liver disease are based on data from 2 randomized, double-blind, active-controlled, noninferiority studies, Study 108 (N=425 HBeAg−) and Study 110 (N=873 HBeAg+). The original study design consisted of a 96-week, double-blind phase followed by an open-label phase to Week 144. The original study design was then amended to extend the double-blind phase from 96 to 144 weeks and the open-label phase to Week 384. However, before the amendment to the double-blind phase was implemented, 540 patients had already entered the open-label phase at Week 96; 360 patients remained on VEMLIDY 25 mg and 180 patients switched from TDF (tenofovir disoproxil fumarate) 300 mg to VEMLIDY 25 mg at Week 96.1-3

The primary endpoint for both studies was HBV DNA <29 IU/mL and noninferiority to TDF (10% margin; 95% CI approach) at Week 48; this was also one of the key secondary endpoints at Weeks 96 and 144.1-8,a Learn more about the VEMLIDY clinical study design

aEfficacy endpoints evaluated at Week 48, Week 96, and Week 144 for both studies include the proportion of patients with HBV DNA <29 IU/mL, ALT normalization, and HBsAg loss and seroconversion. HBeAg loss and seroconversion were also assessed in Study 110. Key inclusion criteria: HBV DNA ≥20,000 IU/mL; ALT>60 U/L (males) or >38 U/L (females) and ≤10× ULN by central laboratory range.1-3,8

RENAL SAFETY PARAMETERS: COMPARING VEMLIDY VS TDF

Effects of VEMLIDY and TDF were compared in a pooled analysis of Studies 108 and 110 (median baseline eGFRCG: 106 mL/min and 105 mL/min for each group, respectively)1:

  • In adult patients with chronic HBV, the mean increase in serum creatinine was <0.1 mg/dL in both treatment groups at both Week 96 and Week 1441,8
  • The median change in eGFRCG from baseline was smaller for VEMLIDY vs TDF

Decrease in eGFRCG from baseline at Weeks 96 and 1441,8


Median changes in eGFRCG from baseline for VEMLIDY® (tenofovir alafenamide) vs TDF (tenofovir disoproxil fumarate) Median changes in eGFRCG from baseline for VEMLIDY® (tenofovir alafenamide) vs TDF (tenofovir disoproxil fumarate)
TDF=tenofovir disoproxil fumarate. bThe Week 144 analysis did not include the 66 patients from the TDF group in Study 108 and the 114 patients from the TDF group in Study 110 who had rolled over from double-blind TDF to open-label VEMLIDY at Week 96 prior to the study amendment.8
  • The long-term clinical significance of these renal laboratory changes on adverse reaction frequencies between VEMLIDY and TDF is not known.1

NO DOSAGE ADJUSTMENT OF
VEMLIDY IS REQUIRED

  • For patients with mild, moderate, or severe renal impairmentc
  • For patients with ESRDd who are receiving chronic hemodialysis
    • On days of hemodialysis, administer VEMLIDY after completion of hemodialysis treatment

VEMLIDY is not recommended in patients with ESRD who are not receiving chronic hemodialysis.

cEstimated creatinine clearance ≥15 mL/min.1 dEnd stage renal disease; estimated creatinine clearance <15 mL/min.1

PATIENTS WHO SWITCHED FROM TDF TO VEMLIDY AT WEEK 96: IMPROVEMENT IN RENAL FUNCTION

Effects of VEMLIDY and TDF were compared in a pooled analysis of patients on open-label treatment from Week 96 through Week 144 (48-week safety data)1,8,e:

Improvement in eGFRCG at Week 144 in patients who switched from TDF to VEMLIDY at Week 961,8


Change in eGFRCG from baseline8,e

Graph depicting eGFRCG change from baseline Graph depicting eGFRCG change from baseline
eThe graph shows changes in eGFRCG from baseline for the subset population of patients who entered the open-label phase at Week 96.

Median change in eGFRCG from Week 96 to Week 1201

-0.6 mL/min
Patients who remained on VEMLIDY
+1.8 mL/min
Patients 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 known1

ROBERT GISH, MD

World-renowned expert in hepatology
Longstanding leader in AASLD, EASL, APASL, and the American Society of Transplantation

Explore additional VEMLIDY open-label safety data in this presentation by Dr. Gish.

Explore additional open-label safety data in this video presented by Robert Gish, MD, a world-renowned expert in hepatology. Dr. Gish is a longstanding leader in AASLD, EASL, APASL, and the American Society of Transplantation.

Watch the previous video on clinical data through year 3.
  1. Agarwal K, Brunetto M, Seto WK, et al. 96 weeks treatment of tenofovir alafenamide vs. tenofovir disoproxil fumarate for hepatitis B virus infection. J Hepatol. 2018;68:672-681.
  2. American Association for the Study of Liver Diseases. Posters (Abstracts 301-2389). Hepatology. 2018;68:S184-S1353.
  3. Buti M, Gane E, Seto WK, et al. Tenofovir alafenamide versus tenofovir disoproxil fumarate for the treatment of patients with HBeAg-negative chronic hepatitis B virus infection: a randomised, double-blind, phase 3, non-inferiority trial. Lancet Gastroenterol Hepatol. 2016;1:196-206.
  4. Chan HLY, Fung S, Seto WK, et al. Tenofovir alafenamide versus tenofovir disoproxil fumarate for the treatment of HBeAg-positive chronic hepatitis B virus infection: a randomised, double-blind, phase 3, non-inferiority trial. Lancet Gastroenterol Hepatol. 2016;1:185-195.
  5. Chan HLY, Lim YS, Seto WK, et al. 3-year efficacy and safety of tenofovir alafenamide compared with tenofovir disoproxil fumarate in HBeAg-negative and -positive patients with chronic hepatitis B. Poster presented at: AASLD 2018; November 9-13, 2018; San Francisco, CA. Poster 381.
  6. Chan HLY, Marcellin P, Pan CQ, et al. No resistance to tenofovir alafenamide detected through 144 weeks of treatment in patients with chronic hepatitis B. Poster presented at: AASLD 2018; November 9-13, 2018; San Francisco, CA. Poster 386.
  7. Data on file. Gilead Sciences, Inc.
  8. Seto WK, Buti M, Izumi N, et al. Bone and renal safety are improved in chronic HBV patients 1 year after switching to tenofovir alafenamide from tenofovir disoproxil fumarate. Poster presented at: AASLD 2018; November 9-13, 2018; San Francisco, CA. Poster 404.
  9. VEMLIDY Prescribing Information, Foster City, CA: Gilead Sciences, Inc.; February 2019.

Warnings and Precautions

  • New Onset or Worsening Renal Impairment: Cases of acute renal failure and Fanconi syndrome have been reported with the use of tenofovir prodrugs. In clinical trials of VEMLIDY, there have been no cases of Fanconi syndrome or proximal renal tubulopathy (PRT). Patients with impaired renal function and/or taking nephrotoxic agents (including NSAIDs) are at increased risk of renal-related adverse reactions. Discontinue VEMLIDY in patients who develop clinically significant decreases in renal function or evidence of Fanconi syndrome. Monitor renal function in all patients – See Dosage and Administration.

IMPORTANT SAFETY INFORMATION

BOXED WARNING: POST TREATMENT SEVERE ACUTE EXACERBATION OF HEPATITIS B

  • Discontinuation of anti-hepatitis B therapy, including VEMLIDY, may result in severe acute exacerbations of hepatitis B. Hepatic function should be monitored closely with both clinical and laboratory follow-up for at least several months in patients who discontinue anti-hepatitis B therapy, including VEMLIDY. If appropriate, resumption of anti-hepatitis B therapy may be warranted.

Warnings and Precautions

  • Risk of Development of HIV-1 Resistance in HBV/HIV-1 Coinfected Patients: Due to this risk, VEMLIDY alone should not be used for the treatment of HIV-1 infection. Safety and efficacy of VEMLIDY have not been established in HBV/HIV-1 coinfected patients. HIV antibody testing should be offered to all HBV-infected patients before initiating therapy with VEMLIDY, and, if positive, an appropriate antiretroviral combination regimen that is recommended for HBV/HIV-1 coinfected patients should be used.
  • New Onset or Worsening Renal Impairment: Cases of acute renal failure and Fanconi syndrome have been reported with the use of tenofovir prodrugs. In clinical trials of VEMLIDY, there have been no cases of Fanconi syndrome or proximal renal tubulopathy (PRT). Patients with impaired renal function and/or taking nephrotoxic agents (including NSAIDs) are at increased risk of renal-related adverse reactions. Discontinue VEMLIDY in patients who develop clinically significant decreases in renal function or evidence of Fanconi syndrome. Monitor renal function in all patients – See Dosage and Administration.
  • Lactic Acidosis and Severe Hepatomegaly with Steatosis: Fatal cases have been reported with the use of nucleoside analogs, including tenofovir DF. Discontinue VEMLIDY if clinical or laboratory findings suggestive of lactic acidosis or pronounced hepatotoxicity develop, including hepatomegaly and steatosis in the absence of marked transaminase elevations.

Adverse Reactions

Most common adverse reactions (incidence ≥5%; all grades) were headache, abdominal pain, cough, back pain, fatigue, nausea, arthralgia, diarrhea, and dyspepsia.

Drug Interactions

  • Coadministration of VEMLIDY with drugs that reduce renal function or compete for active tubular secretion may increase concentrations of tenofovir and the risk of adverse reactions.
  • Coadministration of VEMLIDY is not recommended with the following: oxcarbazepine, phenobarbital, phenytoin, rifabutin, rifampin, rifapentine, or St. John’s wort. Such coadministration is expected to decrease the concentration of tenofovir alafenamide, reducing the therapeutic effect of VEMLIDY. Drugs that strongly affect P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP) activity may lead to changes in VEMLIDY absorption.

Consult the full prescribing information for VEMLIDY for more information on potentially significant drug interactions, including clinical comments.

Dosage and Administration

  • Testing Prior to Initiation: HIV infection.
  • Prior to or when initiating, and during treatment: On a clinically appropriate schedule, assess serum creatinine, estimated creatinine clearance, urine glucose, and urine protein in all patients. In patients with chronic kidney disease, also assess serum phosphorus.
  • Dosage in Adults: 1 tablet taken once daily with food.
  • Renal Impairment: Not recommended in patients with end stage renal disease (ESRD; eCrCl <15 mL/min) who are not receiving chronic hemodialysis; in patients on chronic hemodialysis, on hemodialysis days, administer VEMLIDY after completion of hemodialysis treatment.
  • Hepatic Impairment: Not recommended in patients with decompensated (Child-Pugh B or C) hepatic impairment.

INDICATION

VEMLIDY is indicated for the treatment of chronic hepatitis B virus (HBV) infection in adults with compensated liver disease.

Please click here to see full Prescribing Information for VEMLIDY, including BOXED WARNING.