ViiV Healthcare Announces FDA Approval of SELZENTRY® (maraviroc) for Use in Children and Adolescents Living With HIV

SELZENTRY can be used with other antiretroviral medicines to treat only CCR5-tropic HIV-1 infection in patients 2 years of age and older weighing at least 10 kg

Research Triangle Park, NC — On November 4, 2016, ViiV Healthcare received approval from the U.S. Food and Drug Administration (FDA) to market SELZENTRY for the treatment of only CCR5-tropic HIV-1 infection, in combination with other antiretroviral agents, in pediatric patients 2 years of age or older who weigh at least 10 kilograms (kg).1 SELZENTRY is a first-in-class CCR5 co-receptor antagonist designed to inhibit entry into the immune system’s CD4+ T-cells by CCR5-tropic HIV-1. SELZENTRY is not recommended in patients with dual/mixed- or CXCR4-tropic HIV-1.

In addition to the 150 milligram (mg) and 300 mg SELZENTRY tablets currently available, new 25 mg and 75 mg tablets and a 20 mg per milliliter (mL) oral solution will be available in January 2017. The dose of SELZENTRY in pediatric patients 2 years of age and older should be based on the patient’s body weight and the drug interaction potential for other medications the patient is currently taking.

This approval is based on results of an open-label trial (Trial A4001031) in which 103 treatment-experienced pediatric patients infected with only CCR5-tropic HIV-1, who were 2 to 18 years of age and weighed at least 10 kg, received SELZENTRY twice daily in combination with optimized background therapy (OBT). At 48 weeks, 48 percent of patients treated with SELZENTRY and OBT achieved plasma HIV-1 RNA less than 48 copies per mL and 65 percent of patients achieved plasma HIV-1 RNA less than 400 copies per mL. The mean CD4+ T-cell count increase from baseline to Week 48 was 247 cells per cubic millimeter.

In the study, each patient’s dose of SELZENTRY was based on body surface area and whether he or she was receiving potent cytochrome P450 3A inhibitors and/or inducers.The median duration of therapy with SELZENTRY was 131 weeks with 72 percent of patients receiving study treatment for more than 48 weeks and 62 percent receiving maraviroc for 96 weeks.

Results of the study showed that among the 103 pediatric patients included, the safety profile of SELZENTRY through 96 weeks was similar to that for adults. Most of the reported adverse events (AEs) were mild to moderate; severe adverse events occurred in 2 percent of subjects. The most common AEs reported with twice-daily therapy with SELZENTRY were vomiting (12 percent), abdominal pain (4 percent), diarrhea (4 percent), nausea (4 percent) and dizziness (3 percent). Through 48 weeks, SELZENTRY-related gastrointestinal AEs, including nausea, vomiting, diarrhea, constipation and abdominal pain/cramps, were observed more commonly in patients who received the SELZENTRY oral solution (21 percent) compared with those who received SELZENTRY tablets (16 percent). Three patients (3 percent) discontinued due to AEs.

“Children and adolescents continue to need new options in HIV therapy, which we at ViiV Healthcare are committed to addressing,” said Bill Collier, head of ViiV Healthcare, North America. “We recognize that HIV disproportionately impacts certain populations, including youth. ViiV Healthcare is dedicated to reducing disparities and helping improve the lives of all people living with HIV. We want to ensure no one is left behind.”

According to estimates in the U.S., 2,037 people 19 years of age and younger became infected with HIV in 2014, and 8,952 in this age group were living with HIV in 2013.2

About ViiV Healthcare

ViiV Healthcare is a global specialist HIV company established in November 2009 by GlaxoSmithKline (LSE: GSK) and Pfizer (NYSE: PFE) dedicated to delivering advances in treatment and care for people living with HIV. Shionogi joined in October 2012. The company’s aim is to take a deeper and broader interest in HIV/AIDS than any company has done before and take a new approach to deliver effective and new HIV medicines as well as support communities affected by HIV. For more information on the company and its management, portfolio, pipeline and commitment, please visit www.viivhealthcare.com.

About SELZENTRY

SELZENTRY (maraviroc) is an oral CCR5 coreceptor antagonist. It is approved in the U.S. for the treatment of only CCR5-tropic HIV-1 infection, in combination with other antiretroviral agents, in adults and pediatric patients 2 years of age and older who weigh at least 10 kg. SELZENTRY is not recommended in patients with dual/mixed- or CXCR4-tropic HIV-1. SELZENTRY is known as Celsentri® outside of the U.S.

INDICATION AND USAGE

SELZENTRY is indicated in combination with other antiretroviral agents for the treatment of only CCR5‐tropic human immunodeficiency virus type 1 (HIV‐1) infection in patients 2 years of age and older and weighing ≥10 kg.

Limitations of Use: SELZENTRY is not recommended in patients with dual/mixed‐ or CXCR4‐ tropic HIV‐1.

IMPORTANT SAFETY INFORMATION for SELZENTRY® (maraviroc)

BOXED WARNING: Hepatotoxicity has been reported, which may be preceded by severe rash or other features of a systemic allergic reaction (eg, fever, eosinophilia, or elevated IgE). Immediately evaluate patients with signs or symptoms of hepatitis or allergic reaction.

CONTRAINDICATION

SELZENTRY is contraindicated in patients with severe renal impairment (CrCl <30 mL/min) or end‐stage renal disease (ESRD) who are taking potent cytochrome P450 (CYP) 3A inhibitors or inducers.

ADDITIONAL WARNINGS AND PRECAUTIONS

Hepatotoxicity: Hepatotoxicity accompanied by severe rash or systemic allergic reaction, including life‐threatening events, has been reported in clinical trials and postmarketing. These events occurred approximately 1 month after patients started treatment. Among reported cases of hepatitis, some were observed in the absence of allergic features or with no pre-existing hepatic disease.

Hepatic laboratory parameters, including alanine aminotransferase (ALT), aspartate aminotransferase (AST), and bilirubin should be obtained prior to starting SELZENTRY and at other time points during treatment as clinically indicated. Discontinuation of SELZENTRY should be considered in any patient with signs or symptoms of hepatitis, or with increased liver transaminases combined with rash or other systemic symptoms.

When administering SELZENTRY to patients with pre‐existing liver dysfunction or who are coinfected with hepatitis B and/or C virus, additional monitoring may be warranted. The safety and efficacy of SELZENTRY have not been specifically studied in patients with significant underlying liver disorders.

Severe Skin and Hypersensitivity Reactions: Severe, potentially life‐threatening skin and hypersensitivity reactions have been reported in patients taking SELZENTRY, in most cases concomitantly with other drugs associated with these reactions. These include cases of Stevens‐Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), and drug rash with eosinophilia and systemic symptoms (DRESS). The cases were characterized by features including rash, constitutional findings, and sometimes organ dysfunction, including hepatic failure. Discontinue SELZENTRY and other suspected agents immediately if signs or symptoms of severe skin or hypersensitivity reactions develop. Delay in stopping treatment with SELZENTRY or other suspect drugs after the onset of rash may result in a life‐threatening reaction. Clinical status, including liver aminotransferases, should be monitored and appropriate therapy initiated.

Cardiovascular Events: More cardiovascular events, including myocardial ischemia and/or infarction, were observed in treatment‐experienced adult patients who received SELZENTRY compared to placebo. In treatment‐naïve adult patients, the incidence of such events was lower with SELZENTRY than with efavirenz.

Patients with cardiovascular comorbidities, risk factors for postural hypotension, or receiving concomitant medication known to lower blood pressure, could be at increased risk of cardiovascular adverse events triggered by postural hypotension. Additional monitoring may be warranted. Patients should be advised that if they experience dizziness while receiving SELZENTRY, they should avoid driving or operating machinery.

Postural Hypotension in Patients with Renal Impairment: SELZENTRY is contraindicated in patients with severe renal impairment (CrCl <30 mL/min) or end‐stage renal disease (ESRD) who are taking potent CYP3A inhibitors with or without a potent CYP3A inducer due to an increased risk of postural hypotension as a result of increased systemic exposure to SELZENTRY.

SELZENTRY should be used in patients with severe renal impairment or ESRD only if they are not receiving a concomitant potent CYP3A inhibitor or inducer and no alternative treatment options are available. If adult patients with severe renal impairment or ESRD, not receiving a concomitant potent CYP3A inhibitor or inducer, experience any symptoms of postural hypotension while taking SELZENTRY 300 mg twice daily, the dose should be reduced to 150 mg twice daily.

Immune Reconstitution Syndrome, including the occurrence of autoimmune disorders with variable time to onset, has been reported.

Potential Risk of Infection: SELZENTRY antagonizes the CCR5 coreceptor located on some immune cells, and therefore could potentially increase the risk of developing infections. Patients should be monitored closely for evidence of infection while receiving SELZENTRY.

Potential Risk of Malignancy: While no increase in malignancy has been observed with

SELZENTRY, due to this drug’s mechanism of action, it could affect immune surveillance and lead to an increased risk of malignancy. Long‐term follow‐up is needed to more fully assess this risk.

ADVERSE REACTIONS

• The most common adverse events in treatment‐experienced adult patients through 48 weeks (>8%) which occurred at a higher frequency compared with placebo were upper respiratory tract infections, cough, pyrexia, rash, and dizziness.
• The most common adverse events in treatment‐naive adult patients through 96 weeks (>8%) which occurred at a higher frequency than the comparator arm were upper respiratory tract infections, bronchitis, flatulence, bloating and distention, upper respiratory tract signs and symptoms, and gastrointestinal atonic and hypomotility disorders.
• The most common adverse reactions in treatment‐experienced pediatric patients (≥3%) were vomiting, abdominal pain, diarrhea, nausea, and dizziness.

DRUG INTERACTIONS

SELZENTRY is a substrate of CYP3A and P‐glycoprotein (P‐gp). Coadministration with potent CYP3A inhibitors, including delavirdine or protease inhibitors (except tipranavir/ritonavir), will increase the concentration of SELZENTRY. Coadministration with potent CYP3A inducers, including efavirenz, may decrease the concentration of SELZENTRY. Healthcare providers should ensure that an appropriate dose adjustment of SELZENTRY is made when SELZENTRY is coadministered with potent CYP3A inhibitors and/or potent CYP3A inducers since concentrations, therapeutic effects, and the safety of SELZENTRY may be affected.

Concomitant use of SELZENTRY and St. John's wort (Hypericum perforatum) or products containing St. John's wort is not recommended.

SELZENTRY is not recommended in pediatric patients 2 years of age or older and weighing ≥10 kg receiving potent CYP3A inducers without a potent CYP3A inhibitor. Additionally, there are insufficient data to make a dosing recommendation for use of SELZENTRY in pediatric patients concomitantly receiving non‐interacting medications and weighing <30 kg.

USE IN SPECIFIC PATIENT POPULATIONS

Pregnancy: The Antiretroviral Pregnancy Registry monitors outcomes in women exposed to SELZENTRY during pregnancy. The limited data available on the use of SELZENTRY during pregnancy are not sufficient to assess any potential drug‐associated risk of birth defects and miscarriage.

Lactation: Breastfeeding is not recommended due to the potential for HIV transmission and the potential for serious adverse reactions in nursing infants.

Pediatric Patients: SELZENTRY is not recommended in patients younger than 2 years of age because the pharmacokinetics, safety, and efficacy of this drug have not been established in this patient population.

Renal Impairment in Pediatric Patients: There are no data to recommend specific doses of SELZENTRY in pediatric patients with mild to moderate renal impairment.

Hepatic Impairment: SELZENTRY is principally metabolized by the liver. Therefore, concentrations of SELZENTRY may be increased in patients with hepatic impairment. SELZENTRY has not been studied in patients with severe hepatic impairment or in pediatric patients with any degree of hepatic impairment.

HOW SUPPLIED: SELZENTRY is available in 25‐mg, 75‐mg, 150‐mg, and 300‐mg tablets, and a 20‐mg/mL oral solution.

Full US Prescribing Information for SELZENTRY is available: here

REFERENCES

1. SELZENTRY® (maraviroc) U.S. prescribing information. Available: here

2. Centers for Disease Control and Prevention. HIV Surveillance Report, 2014; vol. 26. Published November 2015. Accessed November 4, 2016. Available at: https://www.cdc.gov/hiv/pdf/library/reports/surveillance/cdc-hiv-surveillance-report-2020-updated-vol-33.pdf.