FDA Approval: Maraviroc

Background:

On August 6, 2007, the FDA granted accelerated approval for the CCR5 antagonist maraviroc, making it the first approved agent in this drug class.

Indications:

Maraviroc is indicated for treatment-experienced patients who have (1) detectable HIV RNA, (2) evidence of resistance to multiple antiretrovirals, and (3) infection with CCR5-tropic virus. This last criterion requires that patients undergo pretreatment testing with a viral tropism assay, which is currently offered by only one company (Monogram Biosciences). Although the test (Trofile) has been used previously in clinical trials of CCR5 antagonists, it did not become commercially available until maraviroc was approved. Approximately one half of all patients with highly drug-resistant virus are expected to have CCR5-tropic virus and, hence, will be candidates for maraviroc treatment.

Maraviroc’s approval was based primarily on favorable 24-week results from the MOTIVATE studies, which were presented initially at this year’s Retrovirus Conference (ACC Apr 2 2007). In these two identical studies, a total of 1076 triple-class–experienced patients with CCR5-tropic virus at screening received an optimized background regimen plus either placebo, once-daily maraviroc, or twice-daily maraviroc. At 24 weeks, approximately twice as many maraviroc recipients as placebo recipients had undetectable viral loads, and maraviroc treatment also induced a significantly greater mean CD4-cell response. No clinically important differences were observed in the safety and tolerability of maraviroc versus placebo; notably, malignancy incidence was similar in the study arms. Patients who experienced virologic failure during maraviroc treatment often had selection for CXCR4-tropic virus; however, such selection was not associated with any short-term adverse clinical or immunologic consequences.

Maraviroc is not approved for treatment-naive patients. However, as presented at this year’s IAS Conference on HIV Pathogenesis, Treatment and Prevention (Abstract WESS104), more than 700 treatment-naive patients have been randomized to receive AZT/3TC plus either maraviroc or efavirenz. At 48 weeks, 65% of the maraviroc arm and 69% of the efavirenz arm had viral loads <50 copies/mL. Although these virologic response rates were similar, noninferiority could not be established (the lower bound of the 97.5% confidence interval for a 4% difference was 10.9%, which crossed the study-specified threshold for noninferiority). However, maraviroc was associated with a significantly greater CD4-cell response than was efavirenz (mean, 170 vs. 143 cells/mm³).

Pharmacology and dosing:

Maraviroc is available as 150-mg and 300-mg tablets; it is given twice daily, with or without food. Because maraviroc is metabolized in the liver by cytochrome P450 3A (CYP3A), dosing will vary depending on coadministered drugs. Specifically, dosing should be provided as follows:

• 150 mg twice daily when given with CYP3A inhibitors (with or without a CYP3A inducer), such as PIs (except ritonavir-boosted tipranavir); delavirdine; ketoconazole, itraconazole, or clarithromycin; or other strong CYP3A inhibitors (e.g., nefazadone, telithromycin)

• 600 mg twice daily when given with potent CYP3A inducers (without a strong CYP3A inhibitor), including efavirenz, etravirine, rifampin, carbamazepine, phenobarbital, and phenytoin

• 300 mg twice daily when given with other concomitant medications, including ritonavir-boosted tipranavir, nevirapine, all NRTIs, and T-20

Importantly, as noted above, when maraviroc is given with both a potent inhibitor and an inducer — such as the combination of ritonavir-boosted darunavir plus etravirine — then the net effect is inhibition, and the proper dose is 150 mg twice daily.

Although metabolized by the cytochrome P450 system, maraviroc does not inhibit or induce the activity of these enzymes to any clinically relevant degree. According to the package insert, during drug-interaction studies, maraviroc had no clinically relevant effect on the pharmacokinetics of midazolam or of the oral contraceptives ethinylestradiol and levonorgestrel; it also had no effect on the urinary 6β-hydroxycortisol/cortisol ratio. Together, these findings suggest that the drug does not induce CYP3A in vivo.

Adverse effects:

As noted above, in the MOTIVATE studies, maraviroc had a comparable safety and tolerability profile to placebo. In the study of treatment-naive patients, the maraviroc groups had lower rates of discontinuations due to adverse effects than did the placebo group and also had more favorable lipid profiles.

Cost and availability:

According to Pfizer, maraviroc will be in pharmacies by mid-September 2007. The wholesale cost for either the 150-mg or the 300-mg twice-daily dose is US$29 daily or $870 monthly. The turnaround time for receiving results of the Trofile assay is likely to be similar to the time for receiving results of a resistance phenotype assay (approximately 3 weeks).