By Liz Highleyman

Liver toxicity is a potential adverse event associated with many types of drugs, including some antiretroviral medications. Because CCR5 antagonists are a novel class of drugs that have never before been used, and because the natural function of the CCR5 co-receptor is not well understood, researchers are particularly alert for harmful side effects.

Development of 1 drug in this class, GlaxoSmithKline's aplaviroc (GW873140) was halted in 2005 after some patients in clinical trials experienced severe liver enzyme (ALT and/or AST) elevations, an indicator of hepatotoxicity.

Pfizer's CCR5 antagonist maraviroc (Selzentry) was approved by the U.S. Food and Drug Administration (FDA) this past August. Clinical trials that led to the drug's approval did not appear to show a problem with liver toxicity, but researchers conducted a thorough review of liver-related adverse events in these studies to be sure. Results were reported at the recent 11th European AIDS Conference (EACS) in Madrid, Spain (October 24-27, 2007).

The investigators analyzed hepatic safety data, including incidence of grade 3/4 (serious/severe) liver enzyme abnormalities and cases of hepatotoxicity in various studies:

• Preclinical studies;

• Early Phase 1/2a clinical trials including more than 700 participants;

• A4001029, a Phase 2b exploratory study of maraviroc versus placebo plus optimized background therapy in patients with dual/mixed tropic (non-CCR5-tropic) HIV;

• The ongoing Phase 2b/3 MOTIVATE 1 and 2 trials (A4001027 and A4001028), which include more than 1000 highly treatment-experienced patients with exclusively CCR5-tropic HIV randomized to receive once- or twice-daily maraviroc or placebo plus optimized background therapy;

• The Phase 3 MERIT study, looking at once- or twice-daily maraviroc versus efavirenz (Sustiva) in treatment-naive participants (the once-daily arm was discontinued).

Results

• Toxicology studies in rats identified increased liver enzymes and necrosis with a 1500 mg/kg dose, as well as bile duct and hepatocyte changes at 8 times the therapeutic dose.

• Sporadic cases of liver enzyme elevation were reported in Phase 1/2a clinical trials.

- 1 female patient experienced severe ALT/AST elevation in the once-daily maraviroc arm of a Phase 1 study.

• In A4001029, at 48 weeks, the number of patients who experienced grade 3/4 liver-related adverse events in the once-daily maraviroc, twice-daily maraviroc, and placebo arms was 3, 1, and 2, respectively.

- 1 patient in the once-daily maraviroc arm developed life-threatening hepatotoxicity necessitating a liver transplant.

- This individual began to experience rising liver enzymes before starting maraviroc and was also taking other drugs known to be hepatotoxic.

• In the MOTIVATE 1 and 2 trials, there was no excess incidence of liver enzyme abnormalities or bilirubin elevation in the maraviroc arms.
o In the combined trials, about one-third of patients developed mild-to-moderate (grade 1/2) liver enzyme elevation, but rates were similar in the maraviroc and placebo arms (ALT 26% vs 32%; AST 30% vs 38%; bilirubin 13% vs 18%).

- Grade 3/4 liver-related adverse events were uncommon: 1.5% for once-daily maraviroc, 2.6% for twice-daily maraviroc, and 1.5% for placebo.

- 1.4% of patients in all 3 arms discontinued due to hepatic adverse events (6 in each maraviroc dose arm and 3 in the placebo arm).

• Overall hepatotoxicity rates were also similar between study arms in the MERIT trial.

- 6 patients in the twice-daily maraviroc arm experienced grade 3/4 hepatic adverse events compared with 11 in the efavirenz arm.

- 3 patients in the maraviroc arms discontinued due to serious hepatic adverse events versus 4 in the efavirenz arm.

- 3 patients in the twice-daily maraviroc arm experienced grade 3 hyperbilirubinemia (elevated bilirubin), but this was not associated with ALT/AST elevation.

• The lack of excess liver toxicity in the maraviroc arms also held true for HIV-HCV and HIV-HBV coinfected patients (who are at greater risk for drug-induced liver toxicity).

• Patients taking maraviroc who included the protease inhibitor tipranavir (Aptivus) in their background regimen did not have a higher rate of liver toxicity.

• Few patients across the studies potentially met the biochemical criteria for Hy's Law -- a predictor of death due to drug-related liver injury (total bilirubin > 2 x ULN and AST and/or ALT > 3 x ULN) -- and these were evenly distributed across study arms.

Conclusion

In summary, the investigators concluded that while some sporadic liver enzyme abnormalities occured in Phase I/IIa clinical trials, there was no demonstrated dose relationship and no association with elevated bilirubin. Further, in the Phase IIb/III MOTIVATE studies, there was no evidence of more liver enzyme elevations in the maraviroc arms compared with the placebo arms over 48 weeks.

Based on these findings, they suggested that "hepatotoxicity may not be a CCR5-class safety issue."

This conclusion is also supported by the lack of greater liver toxicity in clinical trials to date of Schering-Plough's CCR5 antagonist candidate, vicriviroc.

University Hospital Utrecht, Netherlands; Pfizer Global Research and Development, Sandwich, UK; Pfizer Global Research and Development, New London, CT; Weill Medical College of Cornell University, New York, NY; Pfizer Clinical Research Unit, Erasme, Brussels, Belgium; Veterans Affairs Medical Center, Boise, ID.

11/09/07

Reference
IM Hoepelman, A Ayoub, J Heera, and others. The Incidence of Severe Liver Enzyme Abnormalities and Hepatic Adverse Events in the Maraviroc Clinical Development Programme. 11th European AIDS Conference (EACS). Madrid, Spain. October 24-27, 2007.