Clinical Trials

Date: 2017-04-20

Type of information: Presentation of results at a congress

phase: 3

Announcement: presentation of results at The International Liver Congress 2017

Company: Gilead Sciences (USA - CA)

Product: tenofovir alafenamide (TAF)

Action mechanism: nucleotide reverse transcriptase inhibitor. Tenofovir alafenamide (TAF) is a nucleotide reverse transcriptase inhibitor. It is an investigational novel prodrug of tenofovir, the active agent in Viread® (tenofovir disoproxil fumarate). It has demonstrated high antiviral efficacy at a dose 10 times lower than Viread®, as well as improved renal and bone laboratory parameters in clinical trials.

Disease: hepatitis B

Therapeutic area: Infectious diseases

Country:

Trial details: The two randomized, double-blinded Phase 3 studies (Studies 108 and 110) from which the data are presented evaluated the use of Vemlidy® given once-daily versus Gilead's Viread® given once-daily in treatment-naïve and treatment-experienced adults with HBeAg-negative and HBeAg-positive chronic HBV infection.

Latest news:

• • On April 20, 2017, Gilead Sciences announced 96-week results from two ongoing Phase 3 studies evaluating the safety and efficacy of daily Vemlidy® (tenofovir alafenamide, TAF 25mg) in immune active patients and in patients switching from Gilead's Viread® (tenofovir disoproxil fumarate, TDF 300mg). Data are being presented at The International Liver CongressTM 2017 in Amsterdam .
• Vemlidy® has already demonstrated antiviral efficacy that is noninferior to that of Viread® at Week 48 in patients with chronic HBV. Analyses now conducted at Week 96 of treatment demonstrate continued benefits of Vemlidy® including high rates of viral suppression, with no evidence of resistance, and less impact on renal and bone safety parameters as compared to Viread®. Additionally, patients switching from Viread® to Vemlidy® after Week 96 demonstrated maintenance of viral suppression, improvement in serum alanine aminotransferase (ALT) normalization rates, and improvement in bone and renal parameters 24 weeks after switching to Vemlidy®. Results demonstrate continued advantages of treatment with Vemlidy® over Viread® between Week 48 and Week 96. Virologic response rates at Week 96 were 90 percent (n=257/285) and 91 percent (n=127/140) in HBeAg-negative patients (Study 108) receiving Vemlidy® and Viread®, respectively. In HBeAg-positive patients (Study 110), virologic response rates at Week 96 were 73 percent (n=423/581) and 75 percent (n=218/292) in the Vemlidy® and Viread® groups, respectively. In both studies, a greater percentage of patients taking Vemlidy® achieved normalization of ALT levels relative to patients taking Viread® as measured by both central laboratory criteria, and by the American Association for the Study of Liver Diseases (AASLD) criteria. Patients receiving Vemlidy® also demonstrated ongoing benefits at Week 96 in bone and renal safety parameters, including smaller declines from baseline in hip and spine bone mineral density (BMD) and smaller declines from baseline in estimated creatinine clearance compared with patients taking Viread® in both studies. Similar rates of adverse events and low and similar rates of adverse events leading to discontinuation were observed in both treatment arms. Viral resistance analyses showed no resistance to Vemlidy® or Viread® at Week 96. A post-hoc analysis evaluated a subset of 541 patients from Studies 108 and 110 who completed 96 weeks of treatment with double-blind Vemlidy® or Viread® and were then switched to open-label treatment with Vemlidy. Among patients switched from Viread® to Vemlidy® at Week 96 (n=180), virologic suppression was maintained and the rates of ALT normalization by central laboratory criteria and AASLD criteria significantly increased during the subsequent 24 weeks of Vemlidy therapy. These patients also demonstrated further improvements in hip and spine BMD and had significant improvements in estimated creatinine clearance. Longer-term data are required to confirm the benefits of switching from Viread® to Vemlidy® for the treatment of chronic HBV.
• • On April 15, 2016, Gilead Sciences announced detailed 48-week results from two large Phase 3 clinical trials (Studies 108 and 110) evaluating once-daily tenofovir alafenamide (TAF) 25 mg in treatment-naïve and treatment-experienced adults with HBeAg-negative and HBeAg-positive chronic hepatitis B virus (HBV) infection. Data were presented  during two oral sessions (GS06 and GS12) at The International Liver Congress™ 2016 in Barcelona, Spain. Both studies met their primary endpoints of non-inferiority to Gilead’s Viread® (tenofovir disoproxil fumarate, TDF) 300 mg based on the percentage of patients with HBV DNA levels below 29 IU/mL at 48 weeks of therapy. In addition, TAF demonstrated improved renal and bone laboratory safety parameters compared to Viread. Discontinuations due to adverse events were uncommon in both treatment arms. The most commonly reported adverse events in both studies included headache, upper respiratory tract infection, nasopharyngitis and cough, and occurred at similar rates in patients receiving either TAF or Viread.
• Studies 108 and 110, led by Maria Buti, MD, PhD, Liver Unit, Hospital General Universitario Vall d'Hebron, Barcelona, Spain, and Henry L.Y. Chan, MD, Head, Division of Gastroenterology and Hepatology, The Chinese University of Hong Kong, respectively, are randomized, double-blind, 96-week clinical trials among 1,298 treatment-naïve and treatment-experienced patients with chronic HBV infection. In Study 108, 425 HBeAg-negative patients were randomized 2:1 to receive TAF (n=285) or Viread (n=140). In Study 110, 873 HBeAg-positive patients were randomized 2:1 to receive TAF (n=581) or Viread (n=292).
• The primary efficacy endpoint of both studies is the proportion of subjects with plasma HBV DNA levels below 29 IU/mL. Key secondary endpoints include change from baseline in bone mineral density at the hip and spine at week 48, and change from baseline in serum creatinine at week 48. Other secondary endpoints include alanine aminotransferases (ALT, an enzyme that serves as a measure of liver damage) normalization and change from baseline in eGFR at week 48.
• Based on the results of Studies 108 and 110, Gilead submitted a New Drug Application to the FDA for TAF and the FDA has set a target review date under the Prescription Drug User Fee Act (PDUFA) of November 11, 2016. Gilead also has submitted regulatory applications for TAF in the European Union and Japan.
• • On January 5, 2016, Gilead Sciences announced that two Phase 3 clinical trials (Studies 108 and 110) evaluating investigational use of once-daily tenofovir alafenamide (TAF) 25 mg in treatment-naïve and treatment-experienced adults with HBeAg-negative and HBeAg-positive chronic hepatitis B virus (HBV) infection met their primary objectives. The studies demonstrated that TAF was non-inferior to Gilead's Viread® (tenofovir disoproxil fumarate, TDF) based on the percentage of patients with HBV DNA levels below 29 IU/mL at 48 weeks of therapy. In addition, TAF demonstrated improved renal and bone laboratory safety parameters compared to Viread. In Study 108, evaluating HBeAg-negative patients, 94.0 percent (n=268/285) of patients receiving TAF and 92.9 percent (n=130/140; CI -3.6 percent to +7.2 percent, p=0.47) of patients receiving Viread achieved HBV DNA below 29 IU/mL at week 48. In Study 110, evaluating HBeAg-positive patients, 63.9 percent (n=371/581) of TAF patients and 66.8 percent (n=195/292; CI -9.8 percent to +2.6 percent, p=0.25) of Viread patients achieved HBV DNA below 29 IU/mL at week 48. Two criteria were used to evaluate normalization of serum ALT levels: a central laboratory cut-off value and the American Association for the Study of Liver Diseases (AASLD) criteria. In both studies, treatment with TAF showed a statistically significant increase in ALT normalization relative to the Viread arms when using the AASLD criteria. The ALT normalization was not statistically significant using the central laboratory cut-off value, which defines normalization at a higher ALT level. Discontinuations due to adverse events were uncommon in both treatment arms (0.7 percent (n=2) for TAF vs. 0.7 percent (n=1) for Viread in Study 108, and 1.0 percent (n=6) for TAF vs. 1.0 percent (n=3) for Viread in Study 110). The most commonly reported adverse events in both studies included headache, upper respiratory tract infection, nasopharyngitis and cough, and occurred at similar rates in patients receiving either TAF or Viread. Changes in bone and renal laboratory parameters favored the TAF regimen. In both studies, patients receiving TAF experienced a significantly smaller mean percentage decrease from baseline in hip and spine bone mineral density at week 48 (p<0.001) compared to patients receiving Viread. Smaller increases in serum creatinine were observed in patients receiving TAF in Study 110 (p=0.02). Additionally, the median change in estimated glomerular filtration rate (eGFR) from baseline to week 48 favored TAF in both studies (p<0.01).

Is general: Yes