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Position Paper on NDA 21-356 for Gilead Sciences' Viread™ Brand Tenofovir Disoproxil Fumarate
By Yvette Delph, M.D.

October 3, 2001

Introduction

In May 2001, Gilead Sciences submitted New Drug Application (NDA) 21-356 to the FDA for its Viread™ brand of tenofovir disoproxil fumarate (TDF). Gilead is seeking accelerated approval for TDF to be indicated, in combination with other antiretroviral agents, for the treatment of HIV infected adults. TDF is a nucleotide reverse transcriptase inhibitor.


Overview of Issues

In Gilead studies 902 and 907, when TDF was added to the failing antiretroviral regimens of individuals who had had about 5 year's experience with anti-retroviral agents, it produced a mean decline in viral load of 0.6 log10 copies/ml. The sponsor, Gilead, is to be highly commended for conducting pivotal registrational trials of TDF in such highly treatment experienced individuals. TDF has a highly favorable resistance profile, both in vitro and in vivo and has demonstrated its efficacy against multi nucleoside-resistant HIV. Subjects with lamivudine (3TC)-, zidovudine (AZT)-, NNRTI- or PI resistance experienced mean declines in viral load of between 0.52 and 0.65 log10 copies/ml. The only resistance mutation that TDF seems to select for is K65R mutation in reverse transcriptase (RT), which results in 3 to 4-fold decline in sensitivity to TDF. However, the emergence of this mutation does not seem to be associated with virologic rebound. Information correlating IC50 with plasma levels of TFV is not available.

Administered as one tablet once per day, TDF makes a substantial contribution to the simplification of antiretroviral regimens. Since TFV inhibits HIV-1 reverse transcriptase at concentrations approximately 3000-fold lower than that needed to inhibit DNA polymerases beta and gamma, it has very low potential for mitochondrial toxicity and, to date, there has been no evidence of mitochondrial toxicity due to TDF.

TDF has a favorable side effect profile and in both Studies 902 and 907, the occurrence of clinical adverse events and laboratory abnormalities in the TDF 300 mg daily arm was similar to that in the placebo arm. The only adverse event that occurred in >5% of the study population was depression, which occurred after 48 weeks of Study 902 in 6% of subjects in the TDF 300 mg daily arm. This compared with 0% in the first 24 weeks in the placebo arm. In Study 907, during the first 24 weeks, no adverse event occurred in >2% of the population in either arm.

There is no hepatic metabolism of TFV and it is excreted unchanged by the kidneys. Thus, there is potential for interaction with other drugs that are renally excreted and there is likely to be a need for dosage adjustment in individuals with renal impairment. TFV is not a substrate, inhibitor or inducer of the cytochrome P450 family of liver enzymes. It therefore has a low potential for drug-drug interactions involving this family of liver enzymes.

TDF has been studied in very few persons with viral loads >50,000 copies/ml. Therefore, there are not enough data to assess the efficacy of TDF in this population. Because of earlier concerns about possible bone toxicity, TDF has not been studied in children.


Summary of TAG Position

TAG is in favor of accelerated approval of TDF for use, in combination with other antiretrovirals, in the treatment of adults with HIV infection.

The FDA should require the sponsor to complete the following studies in the post-marketing period:

There are several additional issues that TAG wishes to raise:


Overview of the Data

Safety

The two pivotal studies of the safety and efficacy of TDF, Studies 902 and 907, were conducted in individuals with 4.6 and 5.4 years, respectively, of prior antiretroviral therapy. Study 902 enrolled 189 HIV-infected subjects with viral loads of 400-100,000 copies/ml on stable antiretroviral therapy consisting of <4 drugs for >8 weeks. They were randomized 2:2:2:1 to receive one of three daily doses of TDF(75mg, 150 mg or 300 mg) or placebo in addition to their existing antiretroviral treatment regimen for 48 weeks. At week 24, all subjects receiving placebo were switched the TDF 300mg daily arm. After the end of the 48-week blinded study, 135 subjects rolled over into an open label extension phase and received 300 mg of TDF daily.

Study 907 enrolled 552 subjects with viral loads of 400-10,000 copies/mL on stable antiretroviral therapy for at least eight weeks prior to entering the study. Subjects were randomized (2:1) to receive TDF 300mg once daily, or placebo, in addition to their existing antiretroviral therapy. After 24 weeks, all subjects had the option of receiving TDF for the remainder of the 48-week study period; 170 subjects who received placebo rolled over to receive treatment with TDF.

For the first 24 weeks of Study 907, rates of drug discontinuation, of serious adverse events (SAEs), and of Grade 3 or 4 laboratory abnormalities in the 368 subjects who received TDF 300 mg daily were all comparable to those for placebo. Two SAEs in Study 902 were considered by the investigator to be possibly related to TDF: liver failure in one subject in the TDF 75 mg group and acute pancreatitis in a subject in the TDF 300 mg group. During this study, there was also one suicide, which was judged by the investigator not to be related to TDF. As of September 28, 2001, over 4 900 patients worldwide have enrolled in the TDF Expanded Access Program (EAP) which opened to accrual in March 2001. Globally, SAEs have been reported in 122 (2%) patients and all individual events were reported in < 1% patients.

Since osteomalacia (softening of the bones due to demineralization) was observed in rats and dogs dosed at doses equivalent to 6- to 10-fold greater than human exposure and in juvenile monkeys at 12 to 50-fold greater than human exposure, close monitoring for bone toxicity in humans was done in Studies 902 and 907. There was no evidence of bone abnormalities. All fractures seen were due to high impact trauma and the rate of fractures for TDF 300mg daily was 1.9 per 100 patient-years compared with 3.0 per 100 patient-years for placebo.

Because of the nephrotoxicity of adefovir, another nucleotide RTI, and because there was evidence of nephrotoxicity in newborn and juvenile monkeys dosed with TFV equivalent to 12- to 50-fold greater than human therapeutic doses, individuals with renal impairment were excluded from Studies 902 and 907. In addition, subjects were closely monitored for evidence of renal toxicity. No nephrotoxicity was seen and changes in serum creatinine and phosphate were similar to those seen in the placebo arm.

Efficacy

The primary efficacy endpoint for both studies was DAVG24, a measurement of the average change in viral load between 0 and 24 weeks.

DAVG24 by intent-to-treat (ITT) analysis among the 54 subjects treated with TDF 300 mg in Study 902 was -0.58 log10 copies/ml while for placebo it was +0.02 log10 (p<0.001). For Study 907, it was -0.59 log10 copies/ml for the TDF arm and -0.01 log10 in the placebo group (p<0.0001). In Study 907, 45% (155/346) of subjects treated with TDF achieved viral load reductions to <400 copies/ml at 24 weeks, compared with 13% (23/172) in the placebo group (p<0.0001). Reduction in viral load to <50 copies/ml was achieved by 22% (76/346) of subjects in the TDF group compared to 1% (2/172) in the placebo group (p<0.0001). DAVG24 for both non-Caucasians (35% study population) and women (15%) was -0.6 log10 by ITT analysis of 907. DAVG48 for subjects who received TDF 300 mg in Study 902 was -0.62 log10 copies/ml.

TDF has demonstrated good efficacy against drug resistant HIV. Subjects in Study 902 with virus resistant to AZT, NNRTIs, or PIs experienced DAVG24 of -0.52 to -0.61 log10 copies/ml. Individuals with HIV exhibiting >10-fold change in susceptibility to AZT had DAVG of -0.58 log10 copies/ml. DAVG24 was -0.65 and -0.48 log10 cells/ml, respectively, for subjects in 907 with and without the M184V mutation on TDF 300 mg and -0.20 and +0.28 log10, respectively, for those on placebo.

In the TDF arm of Study 907, the DAVG24 for CD4 cells was an increase of 12.6 cells/ml compared with a decrease of 10.6 cells/ml in the placebo arm (p=0.0008).

Pharmacokinetics and Drug-Drug Interactions

TFV is only about 6% bioavailable when administered orally. It is therefore administered as TDF which is rapidly converted to TFV by esterases in the intestinal lumen and plasma. TDF is 20-40% orally bioavailable. Food enhances the absorption of TDF and oral bioavailability with a high fat meal is 40%. The time to maximum serum concentration (Tmax) in the fasted state is 1 hour. After a high fat meal (50% calories from fat), the Tmax is 2 hours and the area under the curve (AUC) is increased by 40%. Gilead recommends that TDF be taken with food.

Following single oral doses of TDF 300 mg with food in HIV-infected subjects, mean peak TFV plasma levels were 362 ng/mL, respectively. After dosing fasted subjects with TDF 300mg once daily until steady state, the Cmax was 350-380ng/ml, the Cmin was 50-70 ng/ml and the AUC0-24 was 2 500-3 000 ng.h/ml. When dosed with food, the Cmax was 300ng/ml and the AUC was 3300 ng.hr/ml. The volume of distribution was 600-800 ml/kg. and the serum half-life (T½) 12-18 hours. The intracellular (IC) T½ of PMPApp was 15-50 hours in resting cells and 10 hours in dividing cells. The PK in uninfected volunteers is similar to that in HIV-infected subjects.

Drug interactions between TFV and agents from all three licensed classes of antiretrovirals have been conducted. Among the NRTIs, interactions with 3TC and ddI, which are both excreted primarily by the kidneys, were studied. The NNRTI, EFV, and the PIs, IDV and LPV/rtv, were also studied. All studies were randomized, multiple-dose, open-label, 3-way cross over Phase I studies.

There was no clinically relevant effect of 3TC 150 mg BID on the PK of TDF 300 mg QD. 3TC absorption was delayed increasing Tmax by 0.9 hr and decreasing Cmax 24%. There was no significant change in 3TC exposure as measured by AUC(o-t). There was no clinically relevant effect of ddI (Videx™) 400 mg (250 mg if weight <60 mg) QD taken 1 hour prior to TDF on the PK of TDF 300 mg QD. The Cmax of ddI was increased by 28% and the AUC(o-t) was increased by 44%.

The PK parameters for TDF 300 mg QD were not affected by administration with IDV 800 mg Q8H. The IDV Cmax was slightly reduced when IDV was administered with TDF, but the AUC(o-t) was unchanged. TDF AUC(o-t) and Cmax were approximately 30% higher when TDF 300 mg QD was given with LPV/r 400/100 mg BID. Co-administration with TDF resulted in 15% lower LPV AUC(o-t) and Cmax and 11% lower Cmin. The decrease in Cmin was not statistically significant.

The PK of TDF 300 mg QD was not affected by administration with EFV 600 mg QD. Neither was the PK of EFV affected by administration with TDF.


Further Studies Planned or in Progress


Recommendations for Post-Marketing Studies

Studies which should be conducted on TDF in the post-marketing period include:




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