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Position Paper on NDA 21-356 for Gilead Sciences' Viread brand Tenofovir disoproxil fumarate

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By Yvette Delph, MD

October 3, 2001

1. INTRODUCTION

In May 2001, Gilead Sciences submitted New Drug Application (NDA) 21-356 to the FDA for its VireadTM 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.

2. 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.

3. 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:

  • A safety and efficacy study in individuals with viral loads >50, 000 copies/m
  • A safety and efficacy study in treatment-naive individuals — such a study (903) was fully enrolled in January 2001 
  • Safety, efficacy and pharmacokinetic studies in children 
  • Safety and pharmacokinetic studies in individuals with renal or hepatic impairment 
  • Studies to identify long-term toxicities of TDF 
  • Drug-drug interaction studies with drugs that inhibit renal tubular secretion such as trimethoprim (or cotrimoxazole) and probenecid; drugs that are excreted by the kidneys and are likely to be used concomitantly by some HIV-infected individuals, such as stavudine (d4T), certain antibiotics (including aminoglycosides, cephalosporins, and penicillins) narcotic analgesics (such as demerol and morphine) lithium and digoxin; and the studies which the sponsor has indicated that it plans to conduct with ddI EC, methadone, oral contraceptives and adefovir
  • Correlation of the IC50 or IC90 with plasma levels of TFV  

There are several additional issues that TAG wishes to raise:

1. Gilead is the first sponsor to respond to the calls from the community to study investigational agents in highly treatment-experienced individuals and should be congratulated, not penalized, for this.

2. TAG is concerned that a 48-week dose-finding study was conducted in individuals, virtually all of whom had HIV resistant to at least one class to antiretroviral agents and many who had resistance to more than one class. The FDA should require sponsors to determine the appropriate adult dose for antiretroviral agents before proceeding to large Phase III studies — especially in individuals with limited treatment options.

3. There is not yet enough evidence that TDF should be used only with nucleoside RT inhibitors. Until there is more evidence, TDF should be used in conjunction with at least one protease inhibitor or a non-nucleoside reverse transcriptase inhibitor and
at least one NRTI.

4. Some have questioned whether broad approval for TDF should be granted when the data submitted to date focus on experienced individuals. Here are several reasons TAG would urge the FDA to grant accelerated approval for use of TDF, in combination with other antiretrovirals, in the treatment of adults with HIV infection.

  • Precedent.Since the 1995 approvals of 3TC and saquinavir (SQV), the FDAhas used this language for approving new antiretroviral agents even though pivotal studies were not done in certain important HIV-infected populations. Although some thought these broad indications would let industry off the hook for post-marketing studies, both Glaxo and Roche continued developing 3TC and SQV, respectively (unlike what Roche had done with ddC after 1992). With the advent of HAART these indications proved useful.
  • Timing.Gilead did not have 24-week pivotal data on naive patients in May 2001 when it submitted the NDA. However, its pivotal study in treatment-naive individuals fully accrued in January and so 24 week data is likely to be available within few months. Gilead could not, therefore, avoid doing the necessary study in naive individuals.
  • Logicsuggests that if the drug reduces HIV RNA by ˜0.6 log10 in treatment-experienced individuals it will reduce RNA by even more in naive individuals.
  • Safetydata are available in both populations in real time; to date there has been no serious safety problem in either population. In fact, TDF has a very favorable safety profile in the treatment-experienced — the population for which safety data have been analyzed.
  • Weight of Evidence.Cumulatively, the drug has good potency, a favorable resistance and safety profile, is easy to take and generally well tolerated.
  • Consistency.For years, the community has been asking industry to study new drugs in experienced patients AS WELL AS in naive patients. Unlike Abbott, a giant pharmaceutical company with lots of resources, which could therefore submit a NDA for lopinavir/ritonavir containing pivotal data on naive and experienced patients, Gilead is a relatively small company with fewer resources. We might wish Gilead had studied both populations in parallel, but they had just had a setback with adefovir and had been required to get 48-week safety data in TDF for renal and bone toxicity. We should not penalize them for going sequentially.

 
4. 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.

5. 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).

6. 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.

7. Further Studies Planned or in Progress

  • Study 903:To evaluate the potential role of tenofovir DF in treatment-naïve subjects, Gilead initiated a randomized, double-blind, multi-center, Phase III clinical trial in June 2000. This trial is designed to compare the safety and tolerability of two treatment regimens, TDF, efavirenz and lamivudine (3TC) versus stavudine (d4T), efavirenz and lamivudine. It was fully enrolled in January 2001 with 601 treatment-naíve subjects.
  • Study 910:Open-label rollover of Studies 902 and 907. N=575.
  • Expanded Access Program:In January 2001, after protracted discussions with the community, Gilead initiated an expanded access program (EAP) for individuals >18 years of age who required TDF to construct a viable treatment regimen and had failed treatment with at least two PIs or one PI and one NNRTI. Individuals were required to have a viral load of >10,000 copies/ml (by PCR) and CD4 count <100 cells/ml. Additionally, individuals with CD4 count between 100 and 200 cells/ml, and documented evidence of an AIDS-defining opportunistic infection within the past 90 days were eligible. Individuals were also eligible for the EAP if they had completed a clinical trial including TDF and desired continued access to the medication. Individuals receive TDF 300 mg once daily. In April 2001, after some start up difficulties, Gilead announced that the company had broadened the entry criteria for its US EAP to provide TDF to individuals who had failed prior antiretroviral therapy, regardless of their CD4 cell count or viral load. To date, nearly 5000 individuals have enrolled in TDF EAPs in the United States, Canada, Europe the United Kingdom.
  • Pediatric Studies:A pediatric formulation of TDF is in development and Gilead has said that they expect it to be ready early in 2002. The study of TDF in infants and children was deferred pending the outcome of bone toxicology studies in animals.


8. Recommendations for Post-Marketing Studies

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

  • A safety and efficacy study in individuals with viral loads >50, 000 copies/ml
  • A safety and efficacy study in treatment-naive individuals — such a study (903) wasfully enrolled in January 2001
  • Safety, efficacy and pharmacokinetic studies in children
  • Safety and pharmacokinetic studies in individuals with renal or hepatic impairment
  • Studies to identify long-term toxicities of TDF
  • Drug-drug interaction studies with drugs that inhibit renal tubular secretion such as trimethoprim (or cotrimoxazole) and probenecid; drugs that are excreted by the kidneys and are likely to be used concomitantly by some HIV-infected individuals, such as stavudine (d4T), certain antibiotics (including aminoglycosides, cephalosporins, and penicillins) narcotic analgesics (such as demerol and morphine) lithium and digoxin; and the studies which the sponsor has indicated that it plans to conduct with ddI EC, methadone, oral contraceptives and adefovir
  • Correlation of the IC50 or IC90 with plasma levels of TFV