FOSTER CITY, Calif.--(BUSINESS WIRE)--Gilead Sciences, Inc. (Nasdaq: GILD) announced today that it has submitted a supplemental New Drug Application (sNDA) to the U.S. Food and Drug Administration (FDA) for the approval of once-daily Truvada® (emtricitabine/tenofovir disoproxil fumarate) for pre-exposure prophylaxis (PrEP) to reduce the risk of HIV-1 infection among uninfected adults. Truvada was approved by the FDA in 2004 for the treatment of HIV-1 infection and is currently the most-prescribed antiretroviral treatment in the United States.
If the sNDA is approved, Truvada would be the first agent indicated for uninfected individuals to reduce the risk of acquiring HIV through sex, a prevention approach called PrEP. The sNDA is based on the results of two large placebo-controlled trials of Truvada as PrEP, sponsored by the U.S. National Institutes of Health (NIH) and the University of Washington. Several other clinical studies support the use of Truvada for HIV risk reduction.
“The data from these large-scale clinical trials suggest that Truvada may have a role to play in meeting the urgent public health need to reduce new HIV infections,” said John C. Martin, PhD, Chairman and Chief Executive Officer of Gilead Sciences. “Gilead is proud to have played a part in helping to define the use of Truvada as a potential new prevention tool and we commend the many institutions, investigators and study volunteers for their commitment to advancing this important area of research.”
According to current Centers for Disease Control and Prevention (CDC) data, each year some 50,000 people are newly infected with HIV in the United States. Despite extensive efforts to prevent infections using existing interventions, the HIV incidence rate has remained steady for many years. More than half of new infections (61 percent) occur among men who have sex with men, and nearly a quarter (23 percent) occur among women.
Truvada is not currently indicated to reduce the risk of HIV infection.
The first trial providing data to support the Truvada sNDA is a Phase 3 randomized, double-blind, placebo-controlled trial known as the Pre-Exposure Prophylaxis Initiative (iPrEx), which was sponsored by the NIH and conducted among 2,499 high-risk HIV-negative adult men who have sex with men in the United States and countries in Africa, Asia and South America. Results from the trial, published in The New England Journal of Medicine in November 2010, showed that once-daily use of Truvada for PrEP reduced the risk of acquiring HIV overall by 44 percent compared with placebo and by up to 73 percent among men who reported taking the drug consistently (defined as at least 90 percent of days). Among men who took the drug consistently enough to have detectable drug in their body, the risk was reduced by more than 90 percent.
“It is clear that new prevention strategies are urgently needed to tackle the unacceptably high number of new HIV infections in the United States,” said Robert M. Grant, MD, MPH, Betty Jean and Hiro Ogawa Endowed Investigator, Gladstone Institute of Virology and Immunology, University of California, San Francisco and lead investigator of the iPrEx trial. “It is exciting to consider the prospect of a new intervention that, when offered with condoms and other preventative measures, can help to further reduce the individual risk of HIV acquisition and the community impact of the disease.”
The Truvada sNDA submission is also supported by data from Partners PrEP, a Phase 3 randomized, double-blind, placebo-controlled trial conducted among 4,758 heterosexual couples in Kenya and Uganda in which one partner was infected with HIV and the other was not. Partners PrEP, sponsored by the University of Washington, released initial results in advance of the 6th International AIDS Society Conference on HIV Pathogenesis, Treatment and Prevention, held in July 2011. Once-daily use of oral Truvada by the HIV-negative participants reduced their risk of acquiring HIV by 73 percent compared with placebo.
“This year marked the 30-year milestone of the AIDS pandemic and the loss of an estimated 30 million lives, but it has also been a year of hope with several significant new advances in antiretroviral-based HIV prevention,” said Connie Celum, MD, MPH, Professor of Global Health and Medicine at the University of Washington and lead investigator of the Partners PrEP trial. “To turn the tide in this epidemic, we need to use the prevention strategies that work, including the effective treatment of people already infected with HIV, and pre-exposure prophylaxis for persons at high risk of acquiring HIV. The efficacy results observed in the Partners PrEP trial indicate that PrEP may be an important new tool for HIV prevention among heterosexuals in serodiscordant relationships, who account for a large proportion of new HIV cases worldwide.”
Additional supportive data come from two studies sponsored by CDC. The first trial, known as TDF2, was a Phase 3 randomized, double-blind, placebo-controlled trial conducted in Botswana among 1,200 HIV-negative heterosexual men and women. Participants taking once-daily oral Truvada for PrEP had 63 percent fewer HIV infections compared with those receiving placebo. The second trial, known as CDC 4323, was a Phase 2 randomized, placebo-controlled, double-blind study of men who have sex with men in the United States designed primarily to assess the safety, adherence and acceptability of PrEP.
Although full details are not yet available, another separate Phase 3 study of Truvada for PrEP known as FEM-PrEP was stopped in April 2011 based on a recommendation by the study’s Independent Data Monitoring Committee that the trial would not be able to establish the efficacy of Truvada among HIV-negative women in sub-Saharan Africa. The reason for this outcome is not yet understood and a complete detailed analysis of the data is currently underway.
In all studies, side effects included nausea, weight loss and serum creatinine elevations. The incidence of side effects was consistent with Truvada’s safety and tolerability profile when used as HIV treatment, which is supported by more than 1.8 million years of patient use. Overall, there have been more than 4.4 million patient years of experience with tenofovir-containing regimens. Three cases of resistance to emtricitabine were reported in the iPrEx trial among participants who tested negative for HIV infection by serology at enrollment, but were later found to have been infected with HIV prior to enrollment using a different assay. Two of these cases occurred in the active drug arm, and one case occurred in the placebo arm.
Based on the iPrEx trial results, in January 2011 CDC issued interim guidance on Truvada as PrEP among high-risk adult men who have sex with men. Both study investigators and CDC have emphasized the need for HIV testing and clinical screening before initiation of PrEP to ensure that anyone starting PrEP is not already HIV infected; close monitoring for viral-like symptoms among PrEP patients that could be an indication of acute HIV infection; and discontinuation of PrEP if HIV infection does occur.
CDC guidance also stresses that effectiveness is highly dependent on medication adherence; the importance of confirming that patients who take Truvada for PrEP are at substantial ongoing risk for HIV infection; the need to provide counseling on the importance of adhering closely to the prescribed regimen and using other HIV prevention methods; and the importance of regularly testing for HIV infection.
CDC is currently developing formal U.S. Public Health Service guidelines for the use of PrEP. Among the topics that will be addressed by the formal guidelines are procedures for initial HIV testing and health screening, as well as ongoing monitoring for side effects, clinical toxicities, HIV infection and possible drug resistance among those who become infected despite taking PrEP.
Gilead donated drug and placebo tablets for iPrEx, Partners PrEP, TDF2 and CDC 4323, as well as for other ongoing trials of PrEP for HIV prevention being conducted worldwide among multiple high-risk populations.
Important Safety Product Information About Truvada, Including Boxed Warnings
Truvada, a combination of Emtriva(R) (emtricitabine) and Viread(R) (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(R) (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(R) (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 (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 Truvada (including BOXED WARNINGS).
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 the FDA may not approve Truvada for HIV risk reduction, and any approval, if granted, may have significant limitations on its use. Additionally, even if approved, physicians may be reluctant to prescribe the product for HIV risk reduction, and payers may be reluctant to approve or provide reimbursement for the product for HIV risk reduction. As a result, there may not be significant use of Truvada as a risk reduction tool. 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 September 30, 2011, 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 Truvada is available at www.Truvada.com .
Truvada, Viread, Emtriva and Hepsera are registered trademarks of Gilead Sciences, Inc. Atripla is a registered trademark of Bristol-Myers Squibb & Gilead Sciences, LLC.
For more information on Gilead Sciences, please visit the company’s website at www.gilead.com or call Gilead Public Affairs at 1-800-GILEAD-5 or 1-650-574-3000.
SOURCE: Gilead Sciences, Inc.
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