Tenofovir Alafenamide Is Effective Against Hepatitis B with Less Kidney and Bone Toxicity

A pair of Phase 3 studies have shown that Gilead Sciences' new tenofovir alafenamide (TAF) suppresses hepatitis B virus (HBV) as well as the current tenofovir disoproxil fumarate (TDF) formulation, but with less detrimental effects on the kidneys and bones, the company announced this week.

TAF is a pro-drug that delivers its active agent, tenofovir diphosphate, to infected cells more efficiently than the TDF formulation (Viread). TDF is considered generally safe and well-tolerated, but it can cause a small amount of bone loss soon after starting therapy and can lead to kidney problems in susceptible individuals. TAF produces adequate intracellular drug levels with smaller doses than TDF, which means lower concentrations in the blood and less drug exposure for the kidneys, bones, and other organs and tissues.

TDF is an approved treatment for hepatitis B. It is highly effective in suppressing HBV long-term, though like other nucleoside/nucleotide analog antivirals it usually does not lead to a cure, as indicated by hepatitis B surface antigen loss and development of anti-HBs antibodies.

Study 108 and 110 showed that TAF and TDF were equally likely to reduce HBV DNA levels to below the limit of detection in treatment-naive and previously treated hepatitis B patients. But TAF led to somewhat greater improvement in ALT liver enzyme levels, as well as more favorable kidney lab tests and less hip and spine bone loss.

In November the U.S. Food and Drug Administration approved Genvoya, the first combination pill containing TAF for the treatment of HIV. Gilead has also requested approval of another HIV single-tablet regimen containing TAF and a dual coformulation of TAF and emtricitabine (a successor to Truvada). TAF is being developed as a stand-alone drug for hepatitis B treatment.

[Editor's note: On January 12 Gilead requested FDA approval of stand-alone tenofovir alafenamide for hepatitis B.]

Below is an edited excerpt from a Gilead press release describing the studies and their findings in more detail.

Gilead Announces Top-Line Results From Two Phase 3 Studies Evaluating Tenofovir Alafenamide (TAF) for Patients With Chronic Hepatitis B Infection

-- U.S. and EU Filings Planned for Q1 2016

Foster City, Calif. -- January 5, 2016 -- Gilead Sciences, Inc. (Nasdaq:GILD) today announced that two Phase 3 clinical trials (Studies 108 and 110) evaluating investigational use of once-daily tenofovir alafenamide (TAF) 25 mg in treatment-naive 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.

"An estimated 350 million people are living with chronic hepatitis B worldwide, and Viread is an effective treatment option for those appropriate to receive therapy," said Norbert Bischofberger, PhD, Executive Vice President, Research and Development and Chief Scientific Officer, Gilead Sciences. "We are pleased that the TAF Phase 3 study results reflect high efficacy and improved renal and bone safety parameters similar to those seen in clinical studies evaluating TAF-based regimens for HIV. Like HIV, HBV is a chronic condition that requires prolonged therapy and we look forward to the opportunity to offer patients an improved option that has the potential to advance the long-term treatment of HBV."

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).

Based on the results of Studies 108 and 110, Gilead plans to submit regulatory applications for TAF for chronic HBV in the United States and the European Union in the first quarter of 2016. Gilead also plans to submit data from both studies for presentation to a scientific conference in 2016.

About Studies 108 and 110

Studies 108 and 110 are randomized, double-blind, 96-week clinical trials among 1,298 treatment-naive and treatment-experienced patients with chronic HBV. 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 the 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 ALT normalization and change from baseline in eGFR at week 48.

TAF as a single-agent for chronic HBV is an investigational product and its safety and efficacy have not been established.

About Gilead Sciences

Gilead Sciences is a biopharmaceutical company that discovers, develops and commercializes innovative therapeutics in areas of unmet medical need. The company’s mission is to advance the care of patients suffering from life-threatening diseases worldwide. Gilead has operations in more than 30 countries worldwide, with headquarters in Foster City, California.

U.S. full prescribing information for Viread, including BOXED WARNING, is available at www.gilead.com.

For more information on Gilead Sciences, please visit the company’s website at www.gilead.com, follow Gilead on Twitter (@GileadSciences) or call Gilead Public Affairs at 1-800-GILEAD-5 or 1-650-574-3000.

1/6/16

Source

Gilead Sciences. Gilead Announces Top-Line Results From Two Phase 3 Studies Evaluating Tenofovir Alafenamide (TAF) for Patients With Chronic Hepatitis B Infection. Press release. January 5, 2016.