Gilead’s Once-Daily Novel Prodrug for the Treatment of HIV Meets 24-Week
Primary Objective in Phase 2 Study
-- Data Support Tenofovir Alafenamide Fumarate as Component of Future Single
Tablet HIV Regimens --
FOSTER CITY, Calif. -- October 31, 2012
Gilead Sciences, Inc. (Nasdaq: GILD) today announced that a Phase 2 clinical
trial evaluating tenofovir alafenamide fumarate (TAF; formerly referred to as
GS-7340), an investigational novel prodrug of tenofovir for the treatment of
HIV-1 infection, met its primary objective. The ongoing study compares a
once-daily single tablet regimen containing TAF 10 mg/elvitegravir 150
mg/cobicistat 150 mg/emtricitabine 200 mg with Stribild^TM (elvitegravir 150
mg/cobicistat 150 mg/emtricitabine 200 mg/tenofovir disoproxil fumarate 300
mg) among treatment-naïve adults. The TAF-based regimen achieved a similar
virologic response to Stribild based on the proportion of patients with HIV
RNA levels (viral load) of less than 50 copies/mL at 24 weeks of therapy (87
percent versus 90 percent, respectively).
Compared to Stribild, the TAF-based regimen demonstrated statistically
significantly smaller reductions from baseline to week 24 in bone mineral
density at the lumbar spine and hip (p<0.005). In addition, small,
statistically significant differences were seen in serum creatinine and in
calculated creatinine clearance between the two arms in favor of the
TAF-containing regimen (p<0.02). No patient discontinued study drug for renal
adverse events. There were no statistically significant differences in the
frequency of laboratory abnormalities and the frequency and nature of adverse
events were generally similar between the two arms. Both regimens were
generally well tolerated. Gilead plans to submit these data for presentation
at a scientific conference next year.
“These interim findings are encouraging and warrant advancing this
TAF-containing single tablet regimen into Phase 3 development,” said Norbert
Bischofberger, PhD, Executive Vice President, Research and Development and
Chief Scientific Officer, Gilead Sciences.
TAF is also being studied in a second ongoing Phase 2 trial evaluating a
single tablet regimen containing TAF, Janssen R&D Ireland’s protease inhibitor
Prezista^® (darunavir), cobicistat and emtricitabine compared to Truvada^®
(emtricitabine and tenofovir disoproxil fumarate) plus Prezista and
cobicistat, dosed as individual components. The study is fully enrolled and
24-week results will be available in the first half of 2013.
About the Study
The Phase 2 study is a randomized, double-blind 48-week clinical trial among
HIV-1 infected adults with HIV RNA levels (viral load) greater than or equal
to 5,000 copies/mL and CD4 cell counts greater than 50 cells/mm^3. A total of
170 patients were randomized (2:1) to receive a once-daily tablet containing
TAF 10 mg/elvitegravir 150 mg/cobicistat 150 mg/emtricitabine 200 mg (n=112)
or Stribild (n=58). Bone mineral density was assessed in all patients by DEXA
scans at baseline and at week 24.
The study is ongoing. Secondary endpoints will include the proportion of
patients who achieve viral load of less than 50 copies/mL at 48 weeks of
therapy, and changes in HIV-1 RNA and in CD4 cell count from baseline to Weeks
24 and 48. After week 48, patients will continue to take their blinded study
drug until treatment assignments have been unblinded, at which point all will
be given the option to participate in an open-label rollover extension and
receive the TAF-based single tablet regimen.
Additional information about the study can be found at www.clinicaltrials.gov.
About Tenofovir Alafenamide Fumarate
Tenofovir alafenamide fumarate (TAF) is a nucleotide reverse transcriptase
inhibitor and a novel prodrug of tenofovir, the active agent in Viread^®
(tenofovir disoproxil fumarate). Phase 1b dose-ranging studies identified a
dose of TAF that is ten times lower than Viread and provides greater antiviral
efficacy. The smaller milligram size of TAF may enable the development of new
fixed-dose combinations and single tablet regimens for HIV therapy that are
not feasible with Viread.
As an integrase inhibitor, elvitegravir interferes with HIV replication by
blocking the ability of the virus to integrate into the genetic material of
human cells. Elvitegravir was licensed by Gilead from Japan Tobacco Inc. (JT)
in March 2005. Under the terms of Gilead’s agreement with JT, Gilead has
exclusive rights to develop and commercialize elvitegravir in all countries of
the world, excluding Japan, where JT retains rights. Gilead submitted a New
Drug Application (NDA) to FDA for elvitegravir on June 27, 2012, and the
agency has set a target action date under the Prescription Drug User Fee Act
(PDUFA) of April 27, 2013.
Cobicistat is Gilead’s proprietary potent mechanism-based inhibitor of
cytochrome P450 3A (CYP3A), an enzyme that metabolizes drugs in the body.
Unlike ritonavir, cobicistat acts only as a pharmacoenhancing or “boosting”
agent and has no antiviral activity. Gilead submitted an NDA to FDA for
cobicistat on June 28, 2012, and a PDUFA date of April 28, 2013 has been set.
TAF, elvitegravir and cobicistat are investigational products and their safety
and efficacy have not yet been established.
Important Safety Information about Stribild
Stribild contains four Gilead compounds in a complete once-daily, single
tablet regimen: elvitegravir 150 mg; cobicistat 150 mg; emtricitabine 200 mg;
and tenofovir disoproxil fumarate 300 mg. Stribild is indicated as a complete
regimen for the treatment of HIV-1 infection in adults who are antiretroviral
treatment-naïve. Stribild does not cure HIV-1 infection.
BOXED WARNING: 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 (“tenofovir DF”), a component of Stribild,
in combination with other antiretrovirals.
*Stribild is not approved for the treatment of chronic hepatitis B virus
(HBV) infection and the safety and efficacy of Stribild 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 Stribild. 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
Stribild. If appropriate, initiation of anti-hepatitis B therapy may be
*Coadministration: Do not use with drugs highly dependent on CYP3A for
clearance and for which elevated plasma concentrations are associated with
serious and/or life-threatening events. Do not use with drugs that
strongly induce CYP3A as this may lead to a loss of virologic response and
possible resistance to Stribild. Use with the following drugs is
contraindicated: alfuzosin, rifampin, dihydroergotamine, ergotamine,
methylergonovine, cisapride, lovastatin, simvastatin, pimozide, sildenafil
for pulmonary arterial hypertension, triazolam, oral midazolam, and St.
Warnings and Precautions
*New onset or worsening renal impairment: Cases of acute renal failure and
Fanconi syndrome have been reported with the use of tenofovir DF and
Stribild. Monitor estimated creatinine clearance (CrCl), urine glucose,
and urine protein in all patients prior to initiating and during therapy;
additionally monitor serum phosphorus in patients with or at risk for
renal impairment. Cobicistat may cause modest increases in serum
creatinine and modest declines in CrCl without affecting renal glomerular
function; patients with an increase in serum creatinine greater than 0.4
mg/dL from baseline should be closely monitored for renal safety. Do not
initiate Stribild in patients with CrCl below 70 mL/min. Discontinue
Stribild if CrCl declines below 50 mL/min. Avoid concurrent or recent use
with a nephrotoxic agent.
*Use with other antiretroviral products: Stribild should not be
coadministered with products containing any of the same active components;
with products containing lamivudine; with adefovir dipivoxil; or with
products containing ritonavir.
*Decreases in bone mineral density (BMD) and cases of osteomalacia have
been seen in patients treated with tenofovir DF. Consider monitoring BMD
in patients with a history of pathologic fracture or risk factors for bone
*Fat redistribution and accumulation have been observed in patients
receiving antiretroviral therapy.
*Immune reconstitution syndrome, including the occurrence of autoimmune
disorders with variable time to onset, has been reported.
*Common adverse drug reactions in clinical studies (incidence greater than
or equal to 5%; all grades) were nausea, diarrhea, abnormal dreams,
headache and fatigue.
*CYP3A substrates: Stribild can alter the concentration of drugs
metabolized by CYP3A or CYP2D6.
Do not use with drugs highly dependent on these factors for clearance and for
which elevated plasma concentrations are associated with serious and/or
life-threatening adverse events.
*CYP3A inducers: Drugs that induce CYP3A can decrease the concentrations of
components of Stribild. Do not use with drugs that strongly induce CYP3A
as this may lead to loss of virologic response and possible resistance to
*Antacids: Separate Stribild and antacid administration by at least 2
*Prescribing information: Consult the full prescribing information for
Stribild for more information on potentially significant drug
interactions, including clinical comments.
Dosage and Administration
*Adult dosage: One tablet taken orally once daily with food.
*Renal impairment: Do not initiate in patients with CrCl below 70 mL/min.
Discontinue in patients with CrCl below 50 mL/min.
*Hepatic impairment: Not recommended in patients with severe hepatic
Pregnancy and Breastfeeding
*Pregnancy Category B: There are no adequate and well-controlled studies in
pregnant women. Use during pregnancy only if the potential benefit
justifies the potential risk. An Antiretroviral Pregnancy Registry has
*Breastfeeding: Emtricitabine and tenofovir have been detected in human
milk. Because of both the potential for HIV transmission and the potential
for serious adverse reactions in nursing infants, mothers should be
instructed not to breastfeed.
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.
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 risks related to the
possibility of unfavorable 48-week results from this or other clinical trials
involving TAF, including the trial evaluating the single tablet regimen of
TAF, darunavir, cobicistat and emtricitabine. Further, Gilead may be unable to
obtain clinical trial results in the timelines currently anticipated and may
need to modify or delay the clinical trials or to perform additional trials.
Further, Gilead may make a strategic decision to discontinue development of
TAF if, for example, Gilead believes commercialization will be difficult
relative to other opportunities in its pipeline. There is also risk of failing
to obtain approvals from regulatory authorities for TAF, alone or in
combination with other products, and the New Drug Applications for
elvitegravir and cobicistat may not be approved by the U.S. Food and Drug
Administration or other regulatory agencies in the timelines anticipated or at
all. As a result, these product candidates as standalone agents or as part of
single tablet regimens may never be successfully commercialized. 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 June 30, 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 Stribild is available at
U.S. full prescribing information for Truvada is available at www.Truvada.com.
Stribild, Truvada and Viread are trademarks or registered trademarks of Gilead
Prezista 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.
Gilead Sciences, Inc.
Patrick O’Brien, 650-522-1936 (Investors)
Cara Miller, 650-522-1616 (Media)
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