Gilead's Once-Daily Single Tablet Regimen Complera® Maintains HIV Suppression Among Patients Switching From Protease Inhibitor-Based Regimens

– SPIRIT Study Meets 24-Week Primary Endpoint of Non-Inferiority –

WASHINGTON--(BUSINESS WIRE)--Jul 24, 2012 - Gilead Sciences, Inc. (Nasdaq: GILD) today announced 24-week data from a Phase 3 clinical trial, SPIRIT (Switching boosted PI to Rilpivirine In Combination with Truvada as a Single Tablet Regimen), which evaluated virologically suppressed treatment-experienced HIV patients switching from a multi-pill regimen containing a ritonavir-boosted protease inhibitor to the once-daily single tablet regimen Complera® (emtricitabine/rilpivirine/tenofovir disoproxil fumarate). The study met its 24-week primary endpoint, which found that switching to Complera was non-inferior to remaining on a ritonavir-boosted protease inhibitor regimen. These findings will be presented today in an oral session (Abstract #TUAB0104) at the 19th International AIDS Conference (AIDS 2012) in Washington, D.C.

“Since its approval last year for patients new to HIV therapy, the daily single tablet regimen of Complera has become an important addition to the list of treatment options available for these patients,” said Frank J. Palella Jr., MD, Professor of Medicine at the Northwestern University Feinberg School of Medicine and Principal Investigator of the SPIRIT study. “In this current study, data demonstrate Complera has the potential to help a broader range of HIV-infected patients.”

Complera was approved by the U.S. Food and Drug Administration (FDA) in August 2011 for treatment-naïve patients, and is the latest complete HIV regimen available in a once-daily single tablet. The product combines Gilead's Truvada® (emtricitabine and tenofovir disoproxil fumarate), which itself is a fixed-dose combination of two HIV medicines, with Janssen R&D Ireland's rilpivirine (marketed as Edurant®).

At 24 weeks of treatment, 94 percent of patients (n=297/317) who switched to Complera maintained HIV RNA (viral load) levels less than 50 copies/mL compared to 90 percent of patients (n=143/159) who remained on a regimen containing a ritonavir-boosted protease inhibitor-based regimen (FDA snapshot algorithm; 95 percent CI for the difference: -1.6 percent to +9.1 percent; predefined criterion for non-inferiority was the lower bound of a two sided 95 percent CI of -12 percent). Fewer patients taking Complera experienced virologic failure compared to those taking a protease-based regimen (0.9 percent versus 5 percent, respectively). Additionally, patients in the Complera arm demonstrated statistically significant improvements in total cholesterol levels. The ratio of total cholesterol to HDL (high-density lipoprotein or “good” cholesterol) declined by an average of 0.27 in the Complera arm, compared to an increase of 0.08 in the protease inhibitor arm (p<0.001).

In addition to SPIRIT, Gilead is evaluating Complera in two post-marketing studies - an open-label Phase 3b head-to-head trial comparing Complera to Atripla® (efavirenz 600 mg/emtricitabine 200 mg/tenofovir disoproxil fumarate 300 mg) among patients who are new to therapy (Study 110), and a Phase 2b open-label pilot study evaluating the efficacy and safety of switching virologically suppressed Atripla patients to Complera (Study 111). Twenty-four week data from Study 111 were presented at the 18th Annual Conference of the British HIV Association (BHIVA) in April 2012, and 48-week data will be presented at an upcoming medical meeting.

SPIRIT Study

SPIRIT (Study 106) is a randomized (2:1), open-label Phase 3 study of switching virologically suppressed HIV patients from a regimen consisting of a ritonavir-boosted protease inhibitor and two nucleoside reverse transcriptase inhibitors (n=159) to Complera (n=317). The primary objective of the study is to evaluate the non-inferiority, at a 12 percent margin, of Complera compared to a protease-based regimen in maintaining HIV RNA levels less than 50 copies/mL through 24 weeks of therapy, based on the FDA snapshot algorithm. Secondary endpoints include changes in serum lipid levels, change in CD4 cell count, and safety and tolerability through 48 weeks of therapy. Patients randomized to the protease-based regimens rolled over to Complera after week 24.

At baseline, patients in the Complera switch arm had mean CD4 cell counts of 576 cells/mm3 compared to 600 cells/mm3 in the protease arm. Mean fasting lipids levels at baseline for the Complera and protease arms, respectively, were 192 and 194 mg/dL in total cholesterol, 121 and 124 mg/dL in LDL, 53 and 50 mg/dL in HDL, and 163 and 173 mg/dL in triglycerides. Mean ratios of total cholesterol to HDL at baseline were 3.86 for the Complera arm and 4.08 for the protease arm.

Virologic Outcome at 24 Weeks (FDA Snapshot Algorithm)

 

    Complera n=317

 

  Protease-Based
Regimen

n=159

 

Virologic response   94%   90%
Virologic failure   0.9%   5.0%
No 24-week data   5.4%   5.0%
Discontinued due to adverse events   1.9%   0
Discontinued due to other reasons   3.5%   3.1%
Missing data during 24-week window but on study drug

 

  0   1.9%
Changes in CD4 cell counts at 24 weeks of therapy were +20 cells/mm3 for the Complera arm and +32 cells/mm3 for the protease-based regimen (p=0.28). Five percent (n=16) and 6.9 percent (n=11) of patients in the Complera and protease-based regimen arms, respectively, experienced a Grade 3 or 4 adverse event.

At 24 weeks Complera patients had greater mean changes in fasting total cholesterol (-25 vs. -1 mg/dL), LDL (-16 vs. 0 mg/dL) and triglycerides (-53 vs. +3 mg/dL) compared to those who remained on protease-based regimens (p<0.001 for all comparisons between treatment groups). Patients in both arms had similar changes in HDL (-4 vs. -1 mg/dL for Complera and protease-based regimen, respectively; p<0.001). Switching to Complera resulted in greater improvements in the 10-year Framingham Risk Score, a measure of cardiovascular risk, at week 24 compared to a protease-based regimen (p=0.001).

The mean change in estimated glomerular filtration rate (GFR) by Cockcroft-Gault at week 24 was -4.4 mL/min for the Complera arm and 0.1 mL/min for the protease-based regimen (p<0.001). Resistance mutations were observed in two patients in the Complera switch arm and one in the protease inhibitor arm.

Complera Important Product Safety Information and Indication

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® (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 ‰¥ 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).

INDICATION

Complera is indicated for use as a complete regimen for the treatment of HIV-1 infection in antiretroviral treatment-naïve adults. This indication is based on Week 48 safety and efficacy analyses from 2 randomized, double-blind, active controlled, Phase 3 trials in treatment-naïve subjects comparing rilpivirine to efavirenz.

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.

About Gilead Sciences

Gilead Sciences is a biopharmaceutical company that discovers, develops and commercializes innovative therapeutics in areas of unmet medical need. The company's mission is to advance the care of patients suffering from life-threatening diseases worldwide. Headquartered in Foster City, California, Gilead has operations in North America, Europe and Asia Pacific.

Forward-Looking Statement

This press release includes forward-looking statements, within the meaning of the Private Securities Litigation Reform Act of 1995, that are subject to risks, uncertainties and other factors, including the risk that healthcare providers may not recognize the benefits of switching their patients from protease inhibitor-based regimens to Complera. In addition, as Complera is used over longer periods of time by many patients with underlying health problems taking numerous other medicines, Gilead may find new issues such as safety, resistance or drug interaction issues, which may require it to provide additional warnings or contraindications on the label or narrow Complera's approved indication, each of which could reduce the market acceptance of Complera. These risks, uncertainties and other factors could cause actual results to differ materially from those referred to in the forward-looking statements. The reader is cautioned not to rely on these forward-looking statements. These and other risks are described in detail in Gilead's Quarterly Report on Form 10-Q for the quarter ended March 31, 2012, as filed with the U.S. Securities and Exchange Commission. All forward-looking statements are based on information currently available to Gilead, and Gilead assumes no obligation to update any such forward-looking statements.

U.S. full prescribing information for Complera is available at www.Complera.com.

Complera and Truvada are registered trademarks of Gilead Sciences, Inc.

Atripla is a registered trademark of Bristol-Myers Squibb & Gilead Sciences, LLC.

Edurant is a registered trademark of Janssen R&D Ireland.

For more information on Gilead Sciences, please visit the company's website at www.gilead.com, follow Gilead on Twitter (@GileadSciences) or call Gilead Public Affairs at 1-800-GILEAD-5 or 1-650-574-3000.

 

Contact: Gilead Sciences, Inc.
Patrick O'Brien, 650-522-1936 (Investors)
Erin Rau, 650-522-5635 (Media)

 

 

Posted: July 2012

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