Discontinuation of Aplaviroc Trials due to Hepatotoxicity

Discontinuation of Aplaviroc Trials due to Hepatotoxicity

CCR5 is the major chemokine coreceptor that HIV uses toenter CD4+ T-cells. Its blocking is being explored as a newanti-HIV strategy. Three competitive inhibitors have enteredclinical trials: Maraviroc (UK-427,857; Pfizer), Vicriviroc (SCHD;Schering-Plough) and Aplaviroc (GSK-873140; GlaxoSmithKline).Aplaviroc is an orally bioavailable spirodiketopiperazinederivative that specifically blocks the binding of macrophageinflammatory protein 1-alpha (MIP-1α) to CCR5, potently inhibitingHIV-1 gp120 binding to CCR5, and preserves naturalligands RANTES and MIP-1β binding to CCR5. Althoughother CCR5 inhibitor binding sites are often found in thetransmembrane domain, Aplaviroc CCR5 binding sites appearclustered around the ECL2 interface. Limited variabilityin anti-HIV activity has been observed against different R5-tropic isolates in peripheral blood mononuclear cells (PBMC)from multiple donors.Aplaviroc shows substantial occupancy of CCR5 bindingsites at in vivo attainable concentrations and a longer bindingduration than the other CCR5 inhibitors currently under investigation.In vitro studies suggest that the drug has prolongedCCR5 coreceptor occupancy, with a half-life > 100 hours. Itexhibits > 97% CCR5 coreceptor occupancy in blood duringrepeat oral administration and sustains viral suppression for24 to 48 hours after therapy discontinuation. In a dose-rangingstudy, after therapy was stopped and plasma drug levelsbecame undetectable, CCR5 coreceptor occupancy remained> 50% for approximately five days.In a phase I/II, randomized, double-blind, placebo-controlled,dose-ranging study, Aplaviroc was given as monotherapyfor 10 days to HIV-infected antiretroviral-naive and-experienced patients at doses of 200 or 600 mg twice dailyand 200 or 400 mg once daily (eight receiving drug, two receiving placebo per arm). All doses were given with amoderate-fat meal. Antiretroviral-experienced patients abstainedfrom treatment for 12 weeks prior to entry. All patientshad a viral load of ≥ 5,000 copies/ml and a CD4 count nadir> 200 cells/mm3. All patients were infected with R5-tropicHIV. A > 1 log, dose-dependent, viral load decrease wasobserved in patients taking 400 mg once daily and 200 or600 mg twice daily. The greatest viral load reduction wasobserved between 24 and 36 hours after Aplaviroc discontinuation,suggesting a long CCR5 coreceptor occupancy.Evidence of viral tropism conversion to dual-tropic virus wasseen in one patient on day 10, but virus reverted back toR5-tropic virus on day 24.Aplaviroc appears safe and well tolerated when takenorally. The most common adverse effects noted in the 10-day,monotherapy, dose-ranging study were loose stools, diarrhea,abdominal pain, nausea, and flatulence. Headache,dizziness, and fatigue also occurred. Most adverse effectsresolved within the first three days. No serious Grade 3 or 4adverse effects were reported. No changes in laboratory orECG abnormalities were observed.The drug displays additive or synergistic activity whencombined with other antiretroviral agents. In PBMC exposedto R5-tropic HIV, Aplaviroc had synergistic effects when combinedwith zidovudine, nevirapine, indinavir, and enfuvirtide,and additive effects when combined with another investigationalCCR5 antagonist, SCH-C. Potent synergism was observedin PBMC exposed to dual-tropic HIV and treated withAplaviroc when combined with investigational CXCR4 inhibitorsAMD3100 or TE14011. No antagonistic effects or synergisticcellular toxicities were observed in vitro.Aplaviroc is a cytochrome P450-3A substrate in vitro, andtherefore ritonavir boosts plasma levels of the drug. In a trialconducted in eight HIV-uninfected adults, coadministrationof Aplaviroc with lopinavir/ritonavir 400/100 mg twice dailyresulted in significant increases of seven-fold in Cmin plasmaconcentrations of Aplaviroc. No changes in lopinavir levels,but small increases in ritonavir levels, were noticed.GlaxoSmithKline announced in mid-September 2005 thatit had halted safety and efficacy trials of Aplaviroc after twoof the 250 treatment-naive trial participants developed severeliver toxicity. However, studies of Aplaviroc are continuingamong treatment-experienced patients with drug-resistantviruses to currently approved treatments. Up this time nofurther information is available about the mechanisms involvedin these cases of liver toxicity. The results are eagerlyawaited.