New Tenofovir Prodrug Shows Potency, Plus Better Kidney and Bone Safety Than Current Formulation

Tenofovir alafenamide (TAF), an investigational oral prodrug of tenofovir disoproxil fumarate (TDF, Viread), showed similar efficacy to -- and better renal and bone safety than -- TDF, according to phase 2 study results presented at CROI 2013 in Atlanta.

Tenofovir itself is not bioavailable. TDF is a prodrug -- an inactive compound that breaks down into its active form when metabolized in the blood -- that delivers tenofovir to the blood plasma. In the plasma, the free tenofovir is then able to access cells in a non-specific manner. The next-generation prodrug of tenofovir, TAF, goes one step further by delivering tenofovir straight into the cells.

"Inside the cell, it has been recently described that the metabolism of TAF is driven by [the enzyme] cathepsin A. Cathepsin A releases the tenofovir. Tenofovir is then phosphorylated into its active form inside the cell. Therefore, based on this pharmacology, we would anticipate that cells, like lymphoid cells, that are relatively rich in cathepsin A would tend to concentrate tenofovir," explained lead author Andrew Zolopa, M.D.

Earlier studies found TAF to be well tolerated and more potent at lower dosages than TDF (25 mg vs. 300 mg).

This study compared TAF, when formulated into a single-tablet regimen with elvitegravir, cobicistat and emtricitabine (FTC, Emtriva), to elvitegravir/cobicistat/emtricitabine/TDF (Stribild). In this formulation, the TAF dosage was lowered to 10 mg because cobicistat boosts TAF levels by about 2.2-fold, Zolopa said.

The study followed 170 patients and randomized them into two groups: 112 were in the TAF arm, while 58 patients were in the TDF arm. The participants were over 96% male, and all were in their mid-to-late 30s. About 30% were African American and about 20% were Latino.

At 24 weeks, the percentage of patients who achieved viral suppression (defined as a viral load below 50 copies/mL) was similar for both groups: 87% in the TAF group and 90% in the TDF group. Zolopa noted that this was not designed to be a non-inferiority study, and with a large confidence interval, the difference was not statistically significant.

About 81% of both groups experienced adverse events. However, the adverse events were mostly grade 1 or 2; they included nausea, diarrhea, fatigue, headache, upper respiratory tract infection and flatulence. Only four patients (3.6%) in the TAF group discontinued because of adverse events compared to zero in the TDF arm. However, Zolopa stated that probably only one of the discontinuations was related to treatment. Moreover, neither group had any serious adverse events, he noted.

When looking at pharmacokinetics, the levels of tenofovir in the PBMCs (peripheral blood mononuclear cells) was 5.3-fold higher in the TAF group than in the TDF group. As expected, the plasma levels of tenofovir were about 10-fold lower for TAF than TDF.

In terms of changes in lipid values, the median total cholesterol (TC), LDL and HDL increases were higher in the TAF group than the TDF group. However, Zolopa pointed out that the resulting TC-to-HDL ratio was similar in both arms, as were increases to triglycerides and fasting serum glucose.

In terms of renal safety, for both groups, median serum creatinine levels rose relatively fast within the first four weeks, but then stabilized from that point. However, at 24 weeks, there was a difference between the median serum creatinine increases in each study arm: .07 mg/dL in the TAF group compared to .12 mg/dL in the TDF group (P = .02).

These changes were reflected when looking at the estimated glomerular filtration rate (GFR). For both groups there was a relatively rapid decline within the first four weeks, which stabilized from that point. But at week 24, the TAF group had lower decreases in estimated GFR when compared to TDF: -4.8 mL/min vs. -11.8 mL/min (P = .04).

In terms of bone safety, there were declines in bone mineral density (BMD) for both groups, but less so for those taking TAF. The median percentage of change in BMD in the spine was -0.8% for the TAF group and -2.8% in the TDF group (P = .002). In addition, the median percentage of change in BMD in the hip was -0.3% for the TAF group and -2.0% in the TDF group (P < .001).

What's more, there were no decreases in spine BMD for 38% of those taking TAF compared to 12% of those taking TDF, and no decreases in hip BMD for 41% of those taking TAF compared to 23% of those taking TDF.

While these findings are promising in that they show better renal and bone safety for TAF than TDF, the results are early and the sample size is small. Zolopa stated that there are two confirmatory phase 3 studies underway -- and that proactive efforts are being made to increase female participation.