U.S. FDA approves Gilead Sciences’ Complera™

Gilead Sciences, Inc. (Nasdaq:GILD) today announced that the U.S. Food and Drug Administration (FDA) has approved Complera(TM) (emtricitabine/rilpivirine/tenofovir disoproxil fumarate), a complete single-tablet regimen for the treatment of HIV-1 infection in treatment-naïve adults. Complera combines three antiretroviral medications in one daily tablet – Gilead’s Truvada(R), which is a fixed-dose combination of the two nucleoside reverse transcriptase inhibitors emtricitabine and tenofovir disoproxil fumarate, and Tibotec Pharmaceuticals’ non-nucleoside reverse transcriptase inhibitor, rilpivirine (marketed as Edurant(TM) in the United States by Janssen Therapeutics, Division of Janssen Products, LP). Truvada and rilpivirine were approved by the FDA in August 2004 and May 2011, respectively, for use as part of HIV combination therapy.

“In the 30 years since the first AIDS cases were reported, we’ve made incredible strides in the treatment of this disease,” said Tony Mills, MD, Director of Medical Research, Anthony Mills MD, Inc. and a participating investigator in ongoing Complera studies. “The concept of a single-tablet regimen has become a goal in HIV drug development, and the standard of care in medical practice in the United States. However, no one therapy is appropriate for all patients. Given its efficacy, safety and convenience, the availability of Complera represents an exciting milestone in addressing the individual needs of patients new to HIV therapy.”

The approval of Complera is supported by 48-week data from two Phase 3 double-blind, active controlled, randomized studies (ECHO and THRIVE) conducted by Tibotec that evaluated the safety and efficacy of rilpivirine compared to efavirenz among treatment-naïve HIV-1 infected adults. Both arms of the study were administered with a background regimen, in which the majority of patients in the rilpivirine arm received Truvada. A bioequivalence study, conducted by Gilead, demonstrated that the co-formulated single-tablet regimen achieved the same levels of medication in the blood as emtricitabine plus rilpivirine plus tenofovir disoproxil fumarate.

“Complera is the second complete single-tablet regimen that Gilead has introduced, and it represents a collaboration between two organizations that share a vision of simplifying HIV therapy for patients,” said John C. Martin, PhD, Chairman and Chief Executive Officer, Gilead Sciences. “Tremendous progress has been made in the field of HIV, but we recognize new therapies are still needed, and we continue to work to advance options that address the needs of patients.”

Complera is the second complete antiretroviral treatment regimen for HIV-1 available to treatment-naïve patients in a single once-daily pill. The first, Atripla(R) (efavirenz 600 mg/emtricitabine 200 mg/tenofovir disoproxil fumarate 300 mg), is marketed by Gilead and Bristol-Myers Squibb. Complera does not cure HIV-1 infection or help prevent the transmission of HIV to others. Complera has Boxed Warnings including lactic acidosis/severe hepatomegaly with steatosis and post treatment acute exacerbation of hepatitis B; see below for additional important safety information. The following points should be considered when initiating therapy with Complera:

• More rilpivirine-treated subjects with HIV-1 RNA greater than 100,000 copies/mL at the start of therapy experienced virologic failure compared to subjects with HIV-1 RNA less than 100,000 copies/mL at the start of therapy.
• The observed virologic failure rate in rilpivirine-treated subjects conferred a higher rate of overall treatment resistance and cross-resistance to the NNRTI class compared to efavirenz.
• More subjects treated with rilpivirine developed lamivudine/emtricitabine associated resistance compared to efavirenz.
• Complera is not recommended for patients less than 18 years of age.

Gilead first entered into a license and collaboration agreement with Tibotec for the development and commercialization of Complera in July 2009. Under the terms of the agreement, Gilead will assume the lead role in the manufacturing, registration, distribution and commercialization of Complera in the United States, Canada, Brazil, the European Union, Australia and New Zealand. Tibotec will be responsible for the commercialization of rilpivirine as a stand-alone product and will hold rights to co-detail Complera in these territories. A marketing application for the emtricitabine/rilpivirine/tenofovir disoproxil fumarate single-tablet regimen is currently pending in the European Union.

The companies also have finalized an agreement for the development and commercialization of the single-tablet regimen for the rest of world, including the developing world. Gilead will be responsible for the registration, distribution and commercialization of the single-tablet regimen in certain European countries, Latin America and the Caribbean. Tibotec will be responsible for all countries outside of the Gilead territories, the most significant of which include Asia Pacific, including Japan, the Middle East, Eastern Europe and all of Africa.

Important Product Safety Information About Complera, Including Boxed Warnings

BOXED WARNINGS: LACTIC ACIDOSIS/SEVERE HEPATOMEGALY WITH STEATOSIS and POST TREATMENT ACUTE EXACERBATION OF HEPATITIS B

Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been reported with the use of nucleoside analogs, including tenofovir disoproxil fumarate, a component of Complera, in combination with other antiretrovirals.

Complera is not approved for the treatment of chronic hepatitis B virus (HBV) infection and the safety and efficacy of Complera have not been established in patients coinfected with HBV and HIV-1.Severe acute exacerbations of hepatitis B have been reported in patients who are coinfected with HBV and HIV-1 and have discontinued Emtriva or Viread, which are components of Complera.Hepatic function should be monitored closely with both clinical and laboratory follow-up for at least several months in patients who are coinfected with HIV-1 and HBV and discontinue Complera.If appropriate, initiation of anti-hepatitis B therapy may be warranted.

CONTRAINDICATIONS

Complera should not be co-administered with the following drugs, as significant decreases in rilpivirine plasma concentrations may occur due to CYP3A enzyme induction or gastric pH increase, which may result in loss of virologic response and possible resistance to Complera or to the class of NNRTIs:

• the anticonvulsants carbamazepine, oxcarbazepine, phenobarbital, phenytoin
• the antimycobacterials rifabutin, rifampin, rifapentine
• proton pump inhibitors, such as esomeprazole, lansoprazole, omeprazole, pantoprazole, rabeprazole
• the glucocorticoid systemic dexamethasone (more than a single dose)
• St John’s wort (Hypericum perforatum)

WARNINGS AND PRECAUTIONS

• New onset or worsening renal impairment
  Renal impairment, including cases of acute renal failure and Fanconi syndrome (renal tubular injury with severe hypophosphatemia), has been reported with the use of tenofovir disoproxil fumarate. Assess creatinine clearance (CrCl) before initiating treatment with Complera. Monitor CrCl and serum phosphorus in patients at risk for renal impairment, including patients who have previously experienced renal events while receiving Hepsera(R) (adefovir dipivoxil). Avoid administering Complera with concurrent or recent use of nephrotoxic drugs. Patients with CrCl below 50 mL per minute should not receive Complera.
• Drug Interactions
  Complera should be used with caution when given with drugs that may reduce the exposure of rilpivirine.
  Complera should be used with caution when co-administered with a drug with a known risk of Torsade de Pointes.
• Depressive Disorders
  The adverse reaction depressive disorders (depressed mood, depression, dysphoria, major depression, mood altered, negative thoughts, suicide attempt, suicidal ideation) has been reported with rilpivirine. During the Phase 3 trials (N = 1,368), the incidence of depressive disorders (regardless of causality, severity) reported among rilpivirine (N = 686) or efavirenz (N = 682) was 8% and 6%, respectively. Most events were mild or moderate in severity. The incidence of Grade 3 and 4 depressive disorders (regardless of causality) was 1% for both rilpivirine and efavirenz. The incidence of discontinuation due to depressive disorders among rilpivirine or efavirenz was 1% in each arm. Suicide attempt was reported in 2 subjects in the rilpivirine arm while suicide ideation was reported in 1 subject in the rilpivirine arm and in 3 subjects in the efavirenz arm. Patients with severe depressive symptoms should seek immediate medical evaluation to assess the possibility that the symptoms are related to Complera, and if so, to determine whether the risks of continued therapy outweigh the benefits.
• Decreases in bone mineral density
  Bone mineral density (BMD) monitoring should be considered for patients who have a history of pathologic bone fracture or other risk factors for osteoporosis or bone loss. Cases of osteomalacia (associated with proximal renal tubulopathy and which may contribute to fractures) have been reported in association with the use of tenofovir disoproxil fumarate.
• Co-administration with other products
  Complera should not be administered concurrently with other medicinal products containing any of the same active components, emtricitabine, rilpivirine, or tenofovir disoproxil fumarate (Emtriva, Edurant, Viread, Truvada, Atripla), with medicinal products containing lamivudine (Epivir, Epivir-HBV, Epzicom, Combivir, Trizivir), or with adefovir dipivoxil (Hepsera).
• Fat redistribution
  Redistribution/accumulation of body fat has been observed in patients receiving antiretroviral therapy.
• Immune reconstitution syndrome
  Immune reconstitution syndrome has been reported in patients treated with combination antiretroviral therapy, including the components of Complera. Further evaluation and treatment may be necessary.

ADVERSE REACTIONS

The most common adverse drug reactions to rilpivirine (incidence greater than or equal to 2%, Grades 2-4) were insomnia and headache.

The most common adverse drug reactions to emtricitabine and tenofovir disoproxil fumarate (incidence greater-than or equal to 10%) were diarrhea, nausea, fatigue, headache, dizziness, depression, insomnia, abnormal dreams, and rash.

DRUG INTERACTIONS

• Complera should not be used with drugs where significant decreases in rilpivirine plasma concentrations may occur (See CONTRAINDICATIONS).
• Complera is a complete regimen for the treatment of HIV-1 infection; therefore Complera should not be administered with other antiretroviral medications for the treatment of HIV-1 infection.
• Drugs inducing or inhibiting CYP3A enzymes: Rilpivirine is primarily metabolized by cytochrome P450 (CYP) 3A, and drugs that induce or inhibit CYP3A may thus affect the clearance of rilpivirine. Coadministration of rilpivirine and drugs that induce CYP3A may result in decreased plasma concentrations of rilpivirine and loss of virologic response and possible resistance to rilpivirine or to the class of NNRTIs. Coadministration of rilpivirine and drugs that inhibit CYP3A may result in increased plasma concentrations of rilpivirine.
• Drugs increasing gastric PH: Coadministration of rilpivirine with drugs that increase gastric pH may decrease plasma concentrations of rilpivirine and loss of virologic response and possible resistance to rilpivirine or to the class of NNRTIs.
• Drugs affecting renal function: Since emtricitabine and tenofovir are primarily eliminated by the kidneys, coadministration of Complera with drugs that reduce renal function or compete for active tubular secretion may increase serum concentrations of emtricitabine, tenofovir, and/or other renally eliminated drugs. Some examples include, but are not limited to, acyclovir, adefovir dipivoxil, cidofovir, ganciclovir, valacyclovir and valganciclovir.
• QT prolonging drugs: There is limited information available on the potential for a pharmacodynamic interaction between rilpivirine and drugs that prolong the QTc interval of the electrocardiogram. In a study of healthy subjects, supratherapeutic doses of rilpivirine (75 mg once daily and 300 mg once daily) have been shown to prolong the QTc interval of the electrocardiogram. Complera should be used with caution when coadministered with a drug with a known risk of Torsade de Pointes.

DOSAGE AND ADMINISTRATION

Adults: The recommended dose of Complera is one tablet taken orally once daily with a meal.

Renal Impairment: Because Complera is a fixed-dose combination, it should not be prescribed for patients requiring dose adjustment such as those with moderate or severe renal impairment (creatinine clearance below 50 mL per minute).

Important Safety Product Information About Truvada, Including Boxed Warnings

Truvada, a combination of Emtriva (emtricitabine) and Viread (tenofovir disoproxil fumarate [DF]), is indicated in combination with other antiretroviral agents (such as non nucleoside reverse transcriptase inhibitors or protease inhibitors) for the treatment of HIV-1 infection.

The following points should be considered when initiating therapy with Truvada for the treatment of HIV-1 infection:

• It is not recommended that Truvada be used as a component of a triple nucleoside regimen.
• Truvada should not be coadministered with Atripla (efavirenz/emtricitabine/tenofovir DF), Emtriva, Viread, or lamivudine-containing products.
• In treatment-experienced patients, the use of Truvada should be guided by laboratory testing and treatment history.

WARNINGS: LACTIC ACIDOSIS/SEVERE HEPATOMEGALY WITH STEATOSIS and POST TREATMENT ACUTE EXACERBATION OF HEPATITIS B

Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been reported with the use of nucleoside analogs, including Viread, a component of Truvada, in combination with other antiretrovirals.

Truvada is not approved for the treatment of chronic hepatitis B virus (HBV) infection, and the safety and efficacy of Truvada have not been established in patients coinfected with HBV and HIV-1. Severe acute exacerbations of hepatitis B have been reported in patients who are coinfected with HBV and HIV-1 and have discontinued Truvada. Hepatic function should be monitored closely with both clinical and laboratory follow-up for at least several months in patients who are coinfected with HIV-1 and HBV and discontinue Truvada. If appropriate, initiation of anti-hepatitis B therapy may be warranted.

WARNINGS AND PRECAUTIONS

New Onset or Worsening Renal Impairment

• Emtricitabine and tenofovir are principally eliminated by the kidney. Renal impairment, including acute renal failure and Fanconi syndrome (renal tubular injury with severe hypophosphatemia), has been reported with the use of tenofovir DF.
• Assess CrCl before initiating treatment with Truvada. Routinely monitor CrCl and serum phosphorus in patients at risk for renal impairment, including patients who have previously experienced renal events while receiving Hepsera (adefovir dipivoxil).
• Dosing interval adjustment of Truvada and close monitoring of renal function are recommended in all patients with CrCl 30-49 mL/min. No safety or efficacy data are available in patients with renal impairment who received Truvada using these dosing guidelines, so the potential benefit of Truvada therapy should be assessed against the potential risk of renal toxicity. Truvada should not be administered in patients with CrCl <30 mL/min or patients requiring hemodialysis.
• Avoid administering Truvada with concurrent or recent use of nephrotoxic drugs.

Coadministration With Other Products

• Since Truvada contains emtricitabine and tenofovir DF, Truvada should not be coadministered with Atripla, Emtriva or Viread. Due to similarities between emtricitabine and lamivudine, Truvada should not be coadministered with other drugs containing lamivudine, including Combivir (zidovudine/lamivudine) Epivir or Epivir-HBV (lamivudine), Epzicom (abacavir sulfate/lamivudine), or Trizivir (abacavir sulfate/lamivudine/zidovudine).
• Truvada should not be administered with Hepsera.

Bone Mineral Density

• Decreases in bone mineral density (BMD): BMD monitoring should be considered for HIV-1 infected patients who have a history of pathologic bone fracture or who are at risk for osteopenia. Cases of osteomalacia (associated with proximal renal tubulopathy and which may contribute to fractures) have been reported in association with the use of Viread.

Fat Redistribution

• Redistribution/accumulation of body fat including central obesity, dorsocervical fat enlargement (buffalo hump), peripheral wasting, facial wasting, breast enlargement and “cushingoid appearance” have been observed in patients receiving antiretroviral therapy. The mechanism and long-term consequences of these events are currently unknown. A causal relationship has not been established.

Immune Reconstitution

• Immune reconstitution syndrome has been reported in patients treated with combination antiretroviral therapy, including Truvada, which may necessitate further evaluation and treatment.

Early Virologic Failure

• Triple nucleoside-only regimens: Early virologic failure has been reported in HIV-infected patients on regimens containing only 3 nucleoside reverse transcriptase inhibitors (NRTIs). Monitor carefully and consider treatment modification.

ADVERSE REACTIONS

• The most common (incidence greater-than or equal to 10%, any severity) and/or treatment-emergent (Grade 2-4, occurring in greater-than or equal to 5% of subjects) adverse reactions occurring in subjects treated with efavirenz, emtricitabine and tenofovir DF in Study 934 through 144 weeks include diarrhea, nausea, fatigue, sinusitis, upper respiratory tract infections, nasopharyngitis, headache, dizziness, depression, insomnia, abnormal dreams and rash.

DRUG INTERACTIONS

• Didanosine (ddI): tenofovir disoproxil fumarate increases ddI concentrations. Use with caution and monitor for evidence of ddI toxicity (eg, pancreatitis, neuropathy) when coadministered. The ddI dose should be reduced to 250 mg for patients weighing >60 kg. Data are not available to recommend a dose adjustment of ddI for patients weighing <60 kg. Coadministration of didanosine buffered tablet formulation with Truvada should be under fasted conditions.
• Atazanavir (ATV): coadministration decreases ATV concentrations and increases tenofovir concentrations. ATV 300 mg should be boosted with ritonavir 100 mg only and taken with food when administered with Truvada. Monitor for evidence of tenofovir-associated adverse reactions and discontinue Truvada if appropriate. ATV without ritonavir should not be coadministered with Truvada.
• Lopinavir/ritonavir (LPV/r): coadministration increases tenofovir concentrations. Patients receiving LPV/r and Truvada should be monitored for tenofovir-associated adverse reactions and discontinue Truvada if appropriate.

DOSAGE AND ADMINISTRATION

• Recommended dose: one tablet (containing 200 mg of emtricitabine and 300 mg of tenofovir disoproxil fumarate) once daily taken orally with or without food in adults and pediatric patients 12 years of age and older with body weight greater than or equal to 35 kg (greater than or equal to 77 lb.).

Renal dosing guidelines

Creatinine clearance (mL/min) a greater-than or equal to 50 30-49 <30

(including patients requiring hemodialysis)

Recommended dosing

Every 24 hours Every 48 hours Truvada should not be administered

aCalculated using ideal (lean) body weight.

• The safety and effectiveness of these dosing interval adjustment recommendations have not been clinically evaluated in patients with moderate renal impairment; clinical response to treatment and renal function should be closely monitored in these patients.

Please see full Prescribing Information for Complera and Truvada (including BOXED WARNINGS).