More On PMPA

Parts of the following report were excerpted from the FDA Briefing Document submitted by Gilead to the FDA for this hearing.

Tenofovir is a novel nucleotide analog with activity against human immunodeficiency virus types 1 and 2 (HIV-1 and HIV-2) and hepatitis B virus. Tenofovir diphosphate (PMPApp), the active intracellular moeity, is a potent inhibitor of retroviral reverse transcriptase and acts as a DNA chain terminator. During preclinical evaluation, tenofovir demonstrated low oral bioavailability. An orally available prodrug of tenofovir, tenofovir disoproxil fumarate (DF), was selected for clinical development because of its advantageous pharmacokinetic profile, oral bioavailability, potent antiviral activity, and unique in vitro resistance profile. Clinical development of tenofovir DF was initiated in 1997, leading to submission of a New Drug Application (NDA) in May 2001. Tenofovir DF was submitted for accelerated approval based on surrogate efficacy as well as safety endpoints from 24-week data; along with safety data from extended dosing phases of the registrational studies, wherein patients have been treated for a mean of 58 weeks with some patients having received tenofovir DF for up to 143 weeks. The application is based on the overall evidence accumulated in adequate and well-controlled studies demonstrating the efficacy and safety of tenofovir DF for treatment-experienced HIV infected patients The NDA for tenofovir DF includes data from nearly 1,050 HIV-infected patients who have been enrolled and treated in clinical studies evaluating safety, pharmacokinetics, and antiviral activity. Clinical studies have been complemented by extensive genotypic and phenotypic assessment of clinical HIV isolates. The results demonstrate that tenofovir DF taken once daily has an excellent safety profile and significant anti-HIV activity, including activity against multi-drug resistant HIV. There was general agreement that the safety profile so far shows PMPA to be tolerable. In general, there did not appear to be much difference between patients receiving PMPA or placebo in the studies 902 and 907 regarding lab abnormalities and adverse events.

The FDA and several speakers and panelists complemented Gilead on the extensive resistance data accumulated and several other aspects of their drug development. A 96-week study (study 903) designed to support traditional approval is currently underway to evaluate the safety and efficacy of tenofovir DF in treatment-na´ve patients. Results from the initial 48 weeks of study 903 will be available in Spring 2002. A second confirmatory study (study 928) will be conducted in treatment-experienced pediatric patients. Expanded access programs are ongoing in several countries and have enrolled 3,880 patients as of 27 August 2001, including 2,214 in the U.S.

Anti-Hepatitis B (HBV) Activity

Tenofovir is a potent and selective inhibitor of HBV in vitro. Tenofovir inhibits HBV production in HepG2 2.2.15 and HB611 cells with IC50 values of 1.1 and 2.5 mM, respectively, and corresponding CC50 values of > 100 and 260 ÁM, respectively. As observed with anti-HIV activity, tenofovir DF showed increased in vitro potency against HBV in comparison with tenofovir. Tenofovir was also shown to be equally effective against both wild-type and lamivudine-resistant HBV in a cell culture assay. Tenofovir has also been shown to inhibit the replication of duck HBV (DHBV) in primary duck hepatocytes with an IC 50 of 0.11 ÁM.

Mitochondrial Toxicity

A variety of clinical symptoms observed in HIV patients treated with prolonged NRTI therapy may be linked to mitochondrial toxicity. These include myopathy and cardiomyopathy, polyneuropathy, lactic acidosis, pancreatitis, lipodystrophy and possibly others. Tenofovir DF was compared with nucleoside reverse transcriptase inhibitors (NRTIs) for effects on mitochondrial DNA (mtDNA) synthesis and lactic acid production. In HepG2 human liver cells, tenofovir DF (3-300 mM), lamivudine and abacavir had no effect on mitochondrial DNA content, zidovudine and stavudine caused 30-40% reduction, and ddC and ddI caused marked depletion of mtDNA.22 In normal human skeletal muscle cells (proliferating or quiescent), tenofovir DF (300 mM), lamivudine, abacavir and zidovudine had no effect on mtDNA levels, stavudine caused moderate reduction, and ddC and ddI showed marked depletion of mtDNA. Tenofovir DF and lamivudine did not increase the lactic acid production in HepG2 cells and skeletal muscle cells relative to the untreated control, whereas zidovudine produced a concentration-dependent increase in the lactate production in both cell types tested.22 Results of these in vitro studies suggest a low potential of tenofovir DF to interfere with mitochondrial functions. In vivo, no evidence of mitochondrial-related hepatic, hematologic, cardiac, pancreatic, or skeletal muscle toxicity was detected in chronic toxicity studies (42-week) in rats and dogs.

Absorption, Distribution, Metabolism, and Excretion

A small but statistically significant degree of CYP P450 induction (CYP 1A and 2B) was observed in livers from rats given tenofovir DF at doses of 400 mg/kg/day.38 Given the known differences in cytochrome P450 across species, the clinical relevance of this observation in humans is unknown. Extensive tissue distribution, suggested by the plasma pharmacokinetics of tenofovir, was confirmed in studies with C-labeled tenofovir in dogs and rats. Major sites of tissue uptake included the liver and kidney. Tenofovir was excreted (14-24% of plasma concentrations) but not concentrated in milk from lactating rats. Tenofovir was excreted unchanged in the urine of all animal species tested and renal excretion was identified as the primary route of elimination.

PMPA Response When Baseline Viral Loads are High

In both 902 and 907 studies the baseline viral loads were low and there were a small number of patients with high viral loads (>50,000 copies/ml). Several panelists said they would like to see more data on the response to PMPA when a patient╣s viral load was high. The ongoing 903 study in patients who are treatment-na´ve may offer this information. This was cited as a reason by several panelists in why they would like to see more data before recommending approval for PMPA in treatment-naives.

Genotypic Resistance: Cross-Study Virology Analyses

Further evaluation of the antiviral response in patients with specific thymidine analog mutations (M41L, D67N, K70R, L210W, T215 Y/F, and K219Q) was undertaken using combined data from studies 902 and 907. In these analyses, the presence of either M41L or L210W mutation in combination with 3 other thymidine analog mutations predicted a reduced response to therapy.

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