European Commission (EC) Approves Bristol-Myers Squibb’s Evotaz (Atazanavir And Cobicistat Fixed-Dose Combination) For The Treatment Of HIV-1 Infection In Adults

The European Commission approval is based upon Phase III clinical trial - Reyataz®(atazanavir) and cobicistat combination demonstrated virologic failure rates as low as 6% at 48 weeks and 8% at 144 weeks [HIV-1 RNA =50 copies/mL: 6% Reyataz/cobicistat arm and 4% Reyataz/ritonavir arm at 48 weeks; 8% Reyataz/cobicistat arm and 5% Reyataz/ritonavir arm at 144 weeks]

Reyataz/cobicistat safety was demonstrated through 144 weeks in clinical trials

PRINCETON, N.J.--(BUSINESS WIRE)--Bristol-Myers Squibb Company (NYSE:BMY) announced today that the European Commission has approved Evotaz (atazanavir 300 mg and cobicistat 150 mg) tablets in combination with other antiretroviral agents for the treatment of HIV-1 infected adults without known mutations associated with resistance to atazanavir. Coformulated to be one pill, once-daily, Evotaz combines the protease inhibitor atazanavir, which is marketed as Reyataz (atazanavir) capsules, and cobicistat, a pharmacokinetic enhancer marketed as Tybost^® by Gilead Sciences, Inc. Today’s approval allows for the marketing of Evotaz in all 28 Member States of the European Union (EU) and offers patients living with HIV an innovative treatment option that delivers proven suppression through 144 weeks. The marketing authorization follows a positive opinion by the Committee for Medicinal Products for Human Use (CHMP) in May 2015. The U.S. Food and Drug Administration (FDA) approved Evotaz in the United States in January 2015.

“The clinical efficacy demonstrated by Reyataz/cobicistat – in one pill rather than two as with ritonavir-boosted Reyataz – is significant for protecting against drug resistance and helping to increase the potential for virologic suppression”

Evotaz is contraindicated in patients with previously demonstrated clinically significant hypersensitivity to the active substances or to any of the excipients of Evotaz, in combination with certain drugs, and in patients with moderate to severe hepatic impairment. Evotaz and Reyataz do not cure HIV-1 infection or AIDS.

There are 2.2 million people living with HIV in the European region, according to recent estimates from UNAIDS and WHO, and between 2004 and 2013, more than 300,000 people were newly infected. Only one-third of diagnosed patients (35%) in the eastern European region were receiving antiretroviral therapy in 2012, a number that is significantly below the 80% coverage goal set by WHO for 2015. Virologic suppression, or the reduction of HIV viral load to undetectable amounts in the blood, is the goal of antiretroviral treatment in all patients.

“HIV remains a significant public health concern throughout the world, and the increase in new infections in recent years in Europe means that it is more important than ever to continue to deliver new treatment options to help patients achieve virologic suppression,” said Murdo Gordon, Head of Worldwide Markets, Bristol-Myers Squibb. “By combining reduced pill burden with a low rate of virologic failure and no protease inhibitor mutations, Evotaz increases the possibility of suppressing HIV, and we are pleased to bring it to physicians and patients in the EU.”

Study Design

Evotaz is the first and only fixed-dose combination (FDC) of a protease inhibitor pharmacoenhanced by cobicistat that is supported by comparative Phase III trial data. The European Commission’s approval is based on data from Gilead’s Study 114, a randomized, double-blind clinical trial (N=692) evaluating the safety and efficacy of Reyataz 300 mg with cobicistat 150 mg (the components of Evotaz) (n=344) versus Reyataz 300 mg with ritonavir 100 mg (Reyataz/ritonavir) (n=348), another pharmacokinetic enhancing agent, in combination with emtricitabine/tenofovir disoproxil fumarate in treatment-naive adults. At 48 weeks, 85% of patients in the Reyataz/cobicistat arm achieved virologic success (HIV-1 RNA levels of <50 copies/mL) compared to 87% of patients in the Reyataz/ritonavir arm. Low rates of virologic failure (HIV-1 RNA =50 copies/mL: 6% Reyataz/cobicistat arm; 4% Reyataz/ritonavir arm) were also observed at 48 weeks. The long-term data at week 144 also confirmed these results, with virologic success and failure rates of 72% and 8%, respectively, in the Reyataz/cobicistat arm, and 74% and 5%, respectively, in the Reyataz/ritonavir arm. Virologic failure, which occurs when therapies are unable to completely suppress HIV, may be caused in part by drug resistance. Limited data are available on the development of resistance to Reyataz/cobicistat. However, in the clinical trial, no patients taking Reyataz/cobicistat who had virologic failure developed protease inhibitor resistance through 48 weeks. Specifically, zero patients developed tenofovir-associated resistance K65R, and two patients developed emtricitabine resistance M184V. In the Reyataz/ritonavir arm, zero resistance was observed.

“The clinical efficacy demonstrated by Reyataz/cobicistat – in one pill rather than two as with ritonavir-boosted Reyataz – is significant for protecting against drug resistance and helping to increase the potential for virologic suppression,” said Douglas Manion, M.D., Head of Specialty Development, Bristol-Myers Squibb. “Preventing resistance is a paramount consideration for management of HIV, and a critical success factor in suppressing the disease.”

Reyataz/cobicistat also demonstrated a safety profile comparable to Reyataz/ritonavir. The most common moderate to severe adverse events (AEs) in both treatment arms were jaundice, ocular iterus, and nausea. There were similar low rates of discontinuation due to AEs with Reyataz/cobicistat as compared to Reyataz/ritonavir at 48 weeks (6% and 7%, respectively). The Summary of Product Characteristics will be available at www.ema.europa.eu.

In October 2011, Bristol-Myers Squibb announced a licensing agreement with Gilead for the development and commercialization of a once-daily, fixed-dose combination product of atazanavir and cobicistat, now named Evotaz. Under the terms of the agreement, Bristol-Myers Squibb and its affiliates are responsible for the formulation, manufacturing, registration, distribution and commercialization of the Evotaz fixed-dose combination product worldwide. Gilead retains sole rights for the manufacture, development and commercialization of cobicistat as a stand-alone product and for use in combination with other agents.

About Reyataz (atazanavir)

Reyataz, co-administered with low dose ritonavir, is indicated in the EU for the treatment of HIV-infected adults and pediatric patients 6 years of age and older in combination with other antiretroviral medicinal products. Use of Reyataz in treatment-experienced patients should be based on individual viral resistance testing and the patient’s treatment history. For more information, please see the Reyataz Summary of Product Characteristics at www.ema.europa.eu.

About Bristol-Myers Squibb in HIV

For more than 20 years, Bristol-Myers Squibb has focused on delivering innovative medicines to help meet the needs of patients living with HIV-1. Our goal is to help individuals living with HIV to live longer and healthier lives by achieving and maintaining viral suppression and addressing the challenges of treatment resistance. We are investigating new ways to attack the HIV virus, and studies are ongoing for innovative treatments including an HIV-1 attachment inhibitor (BMS-663068) and an HIV-1 maturation inhibitor (BMS-955176).

Important Safety Information (ISI) for Evotaz and Reyataz in the U.S.

The following ISI is based on information from U.S. Prescribing Information for Evotaz and Reyataz. Please consult the full Prescribing Information for all labeled safety information.

INDICATIONS for Evotaz^TM (atazanavir and cobicistat) and Reyataz^® (atazanavir)

EVOTAZ is a fixed dose combination of atazanavir and cobicistat, and is indicated for use with other antiretroviral agents for the treatment of HIV-1 infection in adults.

REYATAZ is indicated in combination with other antiretroviral agents for the treatment of HIV-1 infection in adults, and for patients 3 months and older weighing at least 10 kg.

LIMITATIONS OF USE

• Use of EVOTAZ or REYATAZ/ritonavir in treatment-experienced patients should be guided by the number of baseline primary protease inhibitor resistance substitutions
• REYATAZ is not recommended for use in pediatric patients less than 3 months due to the risk of kernicterus

IMPORTANT SAFETY INFORMATION for EVOTAZ and REYATAZ

CONTRAINDICATIONS

EVOTAZ and REYATAZ are contraindicated:

• In patients with previously demonstrated clinically significant hypersensitivity (e.g., Stevens-Johnson syndrome, erythema multiforme, or toxic skin eruptions) to any of the product components
• When coadministered with drugs highly dependent on CYP3A or UGT1A1 for clearance and for which elevated plasma concentrations of the interacting drugs are associated with serious and/or life-threatening events. The following are contraindicated with EVOTAZ and REYATAZ: alfuzosin, rifampin, irinotecan, triazolam, orally administered midazolam, dihydroergotamine, ergotamine, methylergonovine, cisapride, St. John’s wort (Hypericum perforatum), lovastatin, simvastatin, pimozide, sildenafil when used for pulmonary arterial hypertension, indinavir, nevirapine. Additionally, EVOTAZ is contraindicated with: dronedarone, ranolazine, lurasidone, colchicine in patients with renal and/or hepatic impairment. Additionally, REYATAZ is contraindicated with ergonovine
• When coadministered with drugs that strongly induce CYP3A [e.g., rifampin, St. John’s wort (Hypericum perforatum), nevirapine] and may lead to lower exposure and loss of efficacy of EVOTAZ and REYATAZ

WARNINGS AND PRECAUTIONS

The following Warnings and Precautions are associated with EVOTAZ (atazanavir and cobicistat) and REYATAZ (atazanavir):

• Cardiac Conduction Abnormalities: PR interval prolongation may occur in some patients. Atrioventricular (AV) conduction abnormalities were asymptomatic and generally limited to first-degree AV block. There have been reports of second-degree AV block and other conduction abnormalities. There is limited clinical experience in patients with preexisting conduction system disease such as marked first degree AV block or second or third degree AV block. Consider ECG monitoring in these patients
• Rash: Cases of Stevens-Johnson syndrome, erythema multiforme, and toxic skin eruptions, including drug rash, eosinophilia, and systemic symptoms (DRESS) syndrome, have been reported in patients receiving atazanavir. Discontinue if severe rash develops. Mild-to-moderate maculopapular skin eruptions have also been reported, and generally did not require discontinuation of treatment
• Nephrolithiasis and cholelithiasis have been reported during postmarketing surveillance in HIV-infected patients receiving atazanavir. Some patients required hospitalization and some had complications. If signs or symptoms of nephrolithiasis and/or cholelithiasis occur, consider temporary interruption or discontinuation of therapy
• Hepatotoxicity: Patients with hepatitis B or C viral infections or marked elevations in transaminases are at risk of further transaminase elevations or hepatic decompensation. In these patients, hepatic laboratory testing should be performed before and during therapy
  • EVOTAZ is not recommended in patients with hepatic impairment
  • REYATAZ/ritonavir is not recommended in patients with any degree of hepatic impairment
  • REYATAZ is not recommended for patients with severe hepatic impairment
• Risk of Serious Adverse Reactions or Loss of Virologic Response Due to Drug Interactions: In patients initiating or already receiving EVOTAZ or REYATAZ with ritonavir, receiving medications metabolized by CYP3A or initiation of medications metabolized by CYP3A, may increase plasma concentrations of medications metabolized by CYP3A. In addition, initiation of medications that inhibit or induce CYP3A may increase or decrease concentrations of EVOTAZ or REYATAZ with ritonavir, respectively. These interactions may lead to clinically significant adverse reactions, potentially leading to severe, life threatening, or fatal events from greater exposures of concomitant medications, clinically significant adverse reactions from greater exposures of EVOTAZ or REYATAZ with ritonavir, or loss of therapeutic effect of EVOTAZ or REYATAZ with ritonavir and possible development of resistance
• Hyperbilirubinemia: Reversible, asymptomatic elevations in indirect (unconjugated) bilirubin occurred in most patients treated with atazanavir. There are no long-term safety data for patients with persistent elevations in total bilirubin >5 times upper limit of normal. Alternative antiretroviral therapy may be considered if jaundice or scleral icterus present cosmetic concerns
• Immune reconstitution syndrome has been reported in patients treated with combination antiretroviral therapy, including atazanavir. Autoimmune disorders (such as Graves’ disease, polymyositis, and Guillain-Barré syndrome) have also been reported to occur in the setting of immune reconstitution; however, the time to onset is more variable, and can occur many months after initiation of treatment
• Diabetes mellitus/hyperglycemia: New onset of diabetes, exacerbation of preexisting diabetes, and hyperglycemia have been reported in postmarketing surveillance in HIV-infected patients treated with protease inhibitor therapy. A causal relationship has not been established
• Fat Redistribution or accumulation of body fat including central obesity, dorsocervical fat enlargement (buffalo hump), peripheral wasting, breast enlargement, and “cushingoid appearance” have been seen in patients receiving antiretroviral therapy. A causal relationship has not been established
• Hemophilia: Increased bleeding has been reported in patients with hemophilia type A and B treated with protease inhibitors. A causal relationship has not been established

EVOTAZ (atazanavir and cobicistat): ADDITIONAL WARNINGS AND PRECAUTIONS

• Effects on Serum Creatinine: Cobicistat decreases estimated creatinine clearance (CrCl) by inhibiting the tubular secretion of creatinine without affecting actual renal glomerular function. This effect should be considered when interpreting changes in estimated CrCl in patients initiating EVOTAZ, particularly in patients with medical conditions or receiving drugs needing monitoring with estimated CrCl
  Prior to initiating therapy with EVOTAZ, assess estimated CrCl. Dosage recommendations are not available for drugs that require dosage adjustment in cobicistat-treated patients with renal impairment. Consider alternative medications that do not require dosage adjustments in patients with renal impairment. Patients who experience a confirmed increase in serum creatinine of greater than 0.4 mg/dL from baseline should be closely monitored for renal safety

• New onset or worsening renal impairment when used with tenofovir disoproxil fumarate: Renal impairment, including cases of acute renal failure and Fanconi syndrome, has been reported when cobicistat was used with tenofovir disoproxil fumarate (tenofovir DF)
  • Coadministration of EVOTAZ and tenofovir DF is not recommended in patients who have an estimated creatinine clearance below 70 mL/min
  • When EVOTAZ is used with tenofovir DF, evaluate baseline and perform routine monitoring of estimated CrCl, urine glucose, and urine protein. Measure serum phosphorus in patients at risk for renal impairment
  • Coadministration of EVOTAZ and tenofovir DF in combination with concomitant or recent use of a nephrotoxic agent is not recommended
• Antiretrovirals that are Not Recommended: EVOTAZ is not recommended in combination with other antiretroviral drugs that require CYP3A inhibition to achieve adequate exposures (e.g., other HIV protease inhibitors or elvitegravir) because dosing for such combinations has not been established; coadministration may lead to loss of therapeutic effect and development of resistance
  EVOTAZ is not recommended in combination with products containing the individual components of EVOTAZ (atazanavir or cobicistat) or in combination with ritonavir containing products

REYATAZ: ADDITIONAL WARNINGS AND PRECAUTIONS

• Patients with Phenylketonuria: Phenylalanine can be harmful to patients with phenylketonuria (PKU). REYATAZ oral powder contains phenylalanine (a component of aspartame). REYATAZ capsules do not contain phenylalanine
• Resistance/cross resistance in various degrees have been observed among protease inhibitors

MOST COMMON MODERATE OR SEVERE ADVERSE REACTIONS

EVOTAZ (atazanavir and cobicistat):

• In treatment-naive adults (=2%): nausea (2%), ocular icterus (3%), jaundice (5%), rash (5%)

REYATAZ (atazanavir), regardless of causality:

• In treatment-naive adults (=2%): nausea (4-14%), jaundice/scleral icterus (5-7%), rash (3- 7%), headache (1-6%), abdominal pain (4%), vomiting (3-4%), peripheral neurologic symptoms (<1-4%), diarrhea (1-3%), insomnia (<1-3%), and dizziness (<1-2%)
• In treatment-experienced adults (=2%): jaundice/scleral icterus (9%), myalgia (4%), diarrhea (3%), nausea (3%), depression (2%), and fever (2%)
• In pediatric patients taking the capsule formulation (=5%): cough (21%), fever (18%), jaundice/scleral icterus (15%), rash (14%), vomiting (12%), diarrhea (9%), headache (8%), peripheral edema (7%), extremity pain (6%), nasal congestion (6%), oropharyngeal pain (6%), wheezing (6%), and rhinorrhea (6%)
• In pediatric patients taking the oral powder formulation: The adverse reactions were generally similar to that observed in clinical studies of REYATAZ in pediatric patients taking the capsule formulation

DRUG INTERACTIONS

EVOTAZ: Coadministration of EVOTAZ and the following drugs is not recommended

• efavirenz, etravirine, ritonavir, boceprevir, telaprevir, simeprevir, apixaban, rivaroxaban, dabigatran etexilate (in specific renal impairment groups), voriconazole, salmeterol, avanafil, inhaled or nasal corticosteroids that are metabolized by CYP3A
• when EVOTAZ is coadministered with tenofovir DF and an H2-receptor antagonist in treatment-experienced patients
• proton pump inhibitors in treatment-experienced patients

REYATAZ: Coadministration of REYATAZ and the following drugs is not recommended

• salmeterol
• when REYATAZ is coadministered with ritonavir: boceprevir, other HIV protease inhibitors, voriconazole
• when REYATAZ is coadministered without ritonavir: carbamazepine, phenytoin, phenobarbital, bosentan, buprenorphine
• in treatment-experienced patients: proton pump inhibitors or efavirenz
• in patients with renal or hepatic impairment: colchicine

See Table 5 of the EVOTAZ Full Prescribing Information, and Table 16 of the REYATAZ Full Prescribing Information for additional established and potentially significant Drug Interactions, and related dose modification recommendations.

EVOTAZ and REYATAZ: Use in Renal Impairment

• EVOTAZ and REYATAZ should not be used in treatment-experienced patients with end-stage renal disease managed with hemodialysis

Please click here for the EVOTAZ full prescribing information

Please click here for the REYATAZ full prescribing information

*From U.S. Prescribing Information. EU SmPC may differ.

About Bristol-Myers Squibb

Bristol-Myers Squibb is a global biopharmaceutical company whose mission is to discover, develop and deliver innovative medicines that help patients prevail over serious diseases. For more information, please visit http://www.bms.com or follow us on Twitter at http://twitter.com/bmsnews.

Bristol-Myers Squibb Forward Looking Statement

This press release contains "forward-looking statements" as that term is defined in the Private Securities Litigation Reform Act of 1995 regarding the research, development and commercialization of pharmaceutical products. Such forward-looking statements are based on current expectations and involve inherent risks and uncertainties, including factors that could delay, divert or change any of them, and could cause actual outcomes and results to differ materially from current expectations. No forward-looking statement can be guaranteed. Among other risks, there can be no guarantee that Evotaz will become a commercially successful product. Forward-looking statements in this press release should be evaluated together with the many uncertainties that affect Bristol-Myers Squibb's business, particularly those identified in the cautionary factors discussion in Bristol-Myers Squibb's Annual Report on Form 10-K for the year ended December 31, 2014 in our Quarterly Reports on Form 10-Q and our Current Reports on Form 8-K. Bristol-Myers Squibb undertakes no obligation to publicly update any forward-looking statement, whether as a result of new information, future events or otherwise.

Tybost^® is a registered trademark of Gilead Sciences, Inc.