Selzentry (maraviroc)

Selzentry (maraviroc) is an entry inhibitor and works by blocking HIV from entering human cells. Specifically maraviroc is a selective, slowly reversible, small molecule antagonist of the interaction between human CCR5 and HIV-1 gp120. Blocking this interaction prevents CCR5-tropic HIV-1 entry into cells.

Selzentry is specifically indicated, in combination with other antiretroviral agents, for treatment experienced adult patients infected with only CCR5-tropic HIV-1 detectable, who have evidence of viral replication and HIV-1 strains resistant to multiple antiretroviral agents.

Selzentry is supplied as a film coated tablet designed for oral administration.

The recommended initial dose of this drug differs based on concomitant medications due to drug interactions. It must be given in combination with other antiretroviral medications.

Selzentry plus CYP3A inhibitors (with or without a CYP3A inducer)
These include:

• protease inhibitors (except tipranavir/ritonavir)
• delavirdine
• ketoconazole, itraconazole, clarithromycin
• other strong CYP3A inhibitors (e.g., nefazadone, telithromycin)

The recommended initial dose of Selzentry is 150 mg twice daily.

Selzentry plus other concomitant medications, including tipranavir/ritonavir, nevirapine, all NRTIs and enfuvirtide
The recommended dose is 300 mg twice daily.

Selzentry plus CYP3A inducers (without a strong CYP3A inhibitor)
These include:

• efavirenz
• rifampin
• carbamazepine, phenobarbital, and phenytoin

The recommended initial dose of Selzentry is 600 mg twice daily.

FDA Approval
FDA approval of Selzentry was based on the results of one completed clinical trial, A4001029, and two ongoing clinical trials, A4001027 (MOTIVATE-1) and A4001028 (MOTIVATE-2).

Study A4001029
This exploratory, randomized, double blind, multicenter trial was designed to determine the safety and efficacy of maraviroc in subjects infected with dual/mixed co-receptor tropic HIV-1. Subjects were randomized in a 1:1:1 ratio to Selzentry once daily, Selzentry twice daily, or placebo. Selzentry treatment was not associated with increased risk of infection or HIV disease progression nor was it associated with a significant decrease in HIV-1 RNA compared to placebo. In addition, no adverse effect was noted on CD4 cell count.

A4001027 (MOTIVATE-1) and A4001028 (MOTIVATE-2)
These ongoing, double-blind, randomized, placebo-controlled, multicenter studies enrolled approximately 1,000 subjects infected with CCR5-tropic HIV-1. All subjects received an optimized background therapy (OBT) of consisting of 3 to 6 antiretroviral agents (excluding low-dose ritonavir). They were then randomized 2:2:1 to maraviroc 300 mg once daily, maraviroc 300 mg twice daily, or placebo. Pooled analysis at 24 weeks revealed the percentage of subjects with a mean change from baseline to week 24 in HIV-1 RNA (log10 copies/mL) to <400 copies/mL was 60.8% in the Selzentry group versus 27.8% for placebo. The percentage of subjects with a mean change from baseline to week 24 in HIV-1 RNA (log10 copies/mL) to <50 copies/mL was 45.3% in the Selzentry arm compared to 23.0% in the placebo arm. The mean changes in plasma HIV-1 RNA from baseline to week 24 was -1.96 log10 copies/mL for subjects receiving maraviroc + OBT compared to -0.99 log10 copies/mL for subjects receiving OBT only. The mean increase in CD4+ counts was higher on maraviroc twice daily + OBT (106.3 cells/mm3) than on placebo + OBT (57.4 cells/mm3 ).

Ongoing Study Commitments

• Pfizer has agreed to submit week 48 reports and datasets for studies A4001027 and A4001028.
  Week 48 report submission: August 2007
• Pfizer has agreed to a deferred pediatric study under PREA for the treatment of HIV in pediatric subjects from 2 to 18 years of age. This study will determine the maraviroc exposure (pharmacokinetics profile) followed by 48 weeks of dosing, with efficacy based on viral load reduction through 48 weeks of dosing, and safety monitored over 96 weeks for pediatric subjects from 2 to 18 years of age to support maraviroc dose selection, safety and efficacy.
  Protocol Submission: December 2007
  Final Report Submission: December 2011
• Pfizer has agreed to a deferred pediatric study under PREA for the treatment of HIV in pediatric subjects from birth to = 2 years of age. This study will determine the maraviroc exposure (pharmacokinetic profile) followed by 48 weeks of dosing with efficacy based on viral load reduction through 48 weeks of dosing, and safety monitored over 96 weeks for pediatric subjects from birth to 2 years of age to support maraviroc dose selection, safety and efficacy.
  Protocol Submission: December 2007
  Final Report Submission: December 2015
• Pfizer has agreed to submit week 96 reports and datasets for Studies A4001027 and A4001028.
  Report Submission: July 2008
• Pfizer has agreed to conduct a five-year follow-up for subjects in Studies A4001027 and A4001028 for mortality, liver failure, malignancy, myocardial ischemia or infarction and rhabdomyolysis, as well as for infections reported as serious adverse events or qualify as a CDC Category C event.
  Final Report Submission: August 2011
• Pfizer has agreed to conduct and submit a final report for a non-randomized, controlled, observational study to provide additional safety data regarding the incidence of mortality, liver failure, malignancy, myocardial ischemia or infarction, and rhabdomyolysis, as well as for infections that qualify as a CDC Category C event. Follow-up of subjects will be at least every 6 months for a total of 5 years.
  Protocol Submission: December 2007
  Final Report Submission: June 2016
• Pfizer has agreed to conduct and submit a study in patients with HIV-1 who are co-infected with hepatitis C and/or B, including some subjects with a Child-Pugh score of C.
  Protocol Submission: April 2008
  Interim Report Submission: December 2011
  Final Report Submission: December 2013
• Pfizer has agreed to submit Week 48 and Week 96 reports for Study A4001026. Subjects in this study will also be followed for a total of 5 years for mortality, liver failure, malignancy, myocardial ischemia or infarction, rhabdomyolysis, as well as for infections reported as serious adverse events or qualify as a CDC Category C events.
  Week 48 interim report submission: October 2007
  Week 96 study report submission: November 2008
  Final Report Submission: October 2011
• Pfizer has agreed to perform cell culture combination activity of maraviroc with darunavir and tipranavir, and submit complete study report of these assessments.
  Final Report Submission: May 2008
• Pfizer has agreed to conduct a study to evaluate the effect of renal impairment on the pharmacokinetics of maraviroc. a) at a dose of 150 mg when combined with a boosted protease inhibitor (e.g., saquinavir/ritonavir) in subjects with mild and moderate renal impairment and subjects with End-Stage Renal Disease (ESRD) that require dialysis. b) at a dose of 300 mg alone in subjects with severe renal impairment and subjects with end stage renal disease who require dialysis.
  Protocol Submission: December 2007
  Final Report Submission: December 2008
• Pfizer has agreed to conduct a study to evaluate the potential for maraviroc metabolite(s) to inhibit CYP2D6 enzymes at a maraviroc dose of 600 mg.
  Protocol Submission: December 2007
  Final Report Submission: June 2008
• Pfizer has agreed to conduct a study to evaluate the potential of maraviroc to inhibit P-gp.
  Protocol Submission: December 2007
  Final Report Submission: June 2008
• Pfizer has agreed to conduct a study to investigate the potential for maraviroc to induce CP1A2.
  Protocol Submission: December 2007
  Final Report Submission: June 2008
• Pfizer has agreed to conduct and submit a clinical study to evaluate the potential for pharmacodynamic interaction between maraviroc and inhibitors of phosphodiesterase type 5 (PDE5).
  Protocol Submission: December 2007
  Final Report Submission: June 2008

Adverse events associated with the use of Selzentry may include, but are not limited to, the following:

• Cough
• Pyrexia
• Upper Respiratory Tract Infections
• Rash
• Musculoskeletal Symptoms
• Abdominal Pain
• Dizziness

Selzentry (maraviroc) is an entry inhibitor and works by blocking HIV from entering human cells. Specifically maraviroc is a selective, slowly reversible, small molecule antagonist of the interaction between human CCR5 and HIV-1 gp120. Maraviroc selectively binds to the human chemokine receptor CCR5 present on the membrane of CD4 cells (T-cells), preventing the interaction of HIV-1 gp120 and CCR5 necessary for CCR5-tropic HIV-1 to enter cells.

Rosario MC, Poland B, Sullivan J, Westby M, van der Ryst E A pharmacokinetic-pharmacodynamic model to optimize the phase IIa development program of maraviroc. Journal of Acquired Immune Deficiency Syndromes 2006 Jun;42(2):183-91

Dorr P, Westby M, Dobbs S, Griffin P, Irvine B, Macartney M, Mori J, Rickett G, Smith-Burchnell C, Napier C, Webster R, Armour D, Price D, Stammen B, Wood A, Perros M Maraviroc (UK-427,857), a potent, orally bioavailable, and selective small-molecule inhibitor of chemokine receptor CCR5 with broad-spectrum anti-human immunodeficiency virus type 1 activity. Antimicrobial Agents and Chemotherapy 2005 Nov;49(11):4721-32

Fätkenheuer G, Pozniak AL, Johnson MA, Plettenberg A, Staszewski S, Hoepelman AI, Saag MS, Goebel FD, Rockstroh JK, Dezube BJ, Jenkins TM, Medhurst C, Sullivan JF, Ridgway C, Abel S, James IT, Youle M, van der Ryst E Efficacy of short-term monotherapy with maraviroc, a new CCR5 antagonist, in patients infected with HIV-1. Nature Medicine 2005 Nov;11(11):1170-2. Epub 2005 Oct 5

Wood A, Armour D The discovery of the CCR5 receptor antagonist, UK-427,857, a new agent for the treatment of HIV infection and AIDS. Progress in Medicinal Chemistry 2005;43:239-71

Walker DK, Abel S, Comby P, Muirhead GJ, Nedderman AN, Smith DA Species differences in the disposition of the CCR5 antagonist, UK-427,857, a new potential treatment for HIV. Drug Metabolism and Disposition: The Biological Fate of Chemicals 2005 Apr;33(4):587-95

For additional information regarding Selzentry or HIV, please visit the Selzentry web page.