Gilead’s Tenofovir Alafenamide (TAF)-Based Single Tablet HIV Regimen
Maintains High Viral Suppression Through 48 Weeks in Phase 2 Study
-- Efficacy Similar to Stribild^®, with Favorable Safety Profile --
DENVER -- September 12, 2013
Gilead Sciences, Inc. (Nasdaq: GILD) today announced 48-week results from a
Phase 2 study (Study 102) evaluating an investigational once-daily single
tablet regimen containing tenofovir alafenamide (TAF) for the treatment of
HIV-1 infection. At 48 weeks, a regimen of elvitegravir 150 mg/cobicistat 150
mg/emtricitabine 200 mg/TAF 10 mg was found to be similar to Stribild^®
(elvitegravir 150 mg/cobicistat 150 mg/emtricitabine 200 mg/tenofovir
disoproxil fumarate 300 mg) based on the percentage of patients with HIV RNA
levels less than 50 copies/mL, and was associated with more favorable renal
and bone safety markers. These findings were presented today in a latebreaker
session (Abstract #H-1464d) at the 53^rd Interscience Conference on
Antimicrobial Agents and Chemotherapy (ICAAC 2013) taking place in Denver.
“These results suggest that TAF has the potential to be an important advance
for people living with HIV,” said Paul Sax, MD, Clinical Director of the
Division of Infectious Diseases at Brigham and Women’s Hospital, Boston,
Professor of Medicine at Harvard Medical School, and an investigator for Study
102. “In this study, the TAF-based regimen matched Stribild’s high viral
suppression and demonstrated a favorable safety profile with respect to renal
and bone changes.”
In Study 102, 170 HIV-positive treatment-naïve adult patients were randomized
(2:1) to receive the investigational TAF-based regimen or Stribild. At 48
weeks, 88.4 percent (n=99/112) of patients taking TAF and 87.9 percent
(n=51/58) of patients taking Stribild achieved HIV RNA (viral load) less than
50 copies/mL, based on the FDA snapshot algorithm (intent-to-treat analysis;
stratum-adjusted difference between TAF and Stribild: -1.0 percent, p=0.84, 95
percent CI for the difference: -12.1 percent, 10.0 percent). No drug
resistance was observed in patients receiving the TAF-based regimen.
Both regimens were generally well tolerated. There were no treatment-related
serious adverse events. There were numeric differences in laboratory
abnormalities of renal and bone markers, which favored the TAF-based regimen.
There was a statistically significant difference in the median change in
estimated glomerular filtration rate (eGFR) from baseline to week 48, with
eGFR decreasing by -5.5 mL/min in the TAF arm compared to a decline of -10.0
mL/min in the Stribild arm (p=0.041). Additionally, there was a significantly
smaller median percentage decrease in bone mineral density from baseline to
week 48 for the TAF-based regimen compared to Stribild (-1.00 vs. -3.37
(p<0.001) for the lumbar spine and -0.62 vs. -2.39 (p<0.001) for the hip).
There were no pathological bone fractures in either arm of the study.
“Based on these positive results, we believe that TAF has the potential to
become a key component of next-generation single tablet regimens in HIV
therapy,” said Norbert W. Bischofberger, PhD, Gilead’s Executive Vice
President, Research and Development and Chief Scientific Officer. “We are now
completing enrollment of two Phase 3 clinical trials comparing a TAF-based
regimen to Stribild in patients new to HIV treatment, and look forward to
sharing initial results from these large-scale studies by the end of 2014.”
About Study 102
Study 102 is a randomized, double-blind 48-week clinical trial evaluating the
efficacy and safety of a once-daily single tablet regimen containing
elvitegravir 150 mg/cobicistat 150 mg/emtricitabine 200 mg/TAF 10 mg (n=112)
compared to Stribild (elvitegravir 150 mg/cobicistat 150 mg/emtricitabine 200
mg/tenofovir disoproxil fumarate 300 mg) (n=58) among HIV-1 infected
treatment-naïve adults with HIV RNA levels greater than or equal to 5,000
copies/mL, CD4 cell counts greater than 50 cells/mm^3 and estimated creatinine
clearance of at least 70 mL/min. Bone mineral density was assessed in all
patients by DEXA scans at baseline and at 24 and 48 weeks of treatment. The
primary endpoint of the study is the percentage of patients with HIV RNA
levels less than 50 copies/mL at week 24, per the FDA snapshot algorithm.
Secondary endpoints include the proportion of patients who achieve viral load
of less than 50 copies/mL at week 48, and changes in HIV-1 RNA and in CD4 cell
count from baseline to weeks 24 and 48.
At baseline, patients receiving the TAF-based regimen had a median HIV RNA of
4.55 log copies/mL and median CD4 cell count of 385 cells/mm^3. Patients
receiving Stribild had a median HIV RNA of 4.58 log copies/mL and median
CD4 cell count of 397 cells/mm^3. At week 48, mean CD4 cell count increases
from baseline were 177 cells/mm^3 in the TAF arm and 204 cells/mm^3 for
Discontinuations due to adverse events were similar in both treatment arms
(3.6 percent for TAF vs. 0 percent for Stribild), and the frequency and nature
of adverse events was also similar. The most common adverse events occurring
in at least 10 percent of TAF patients were nausea (21 percent for TAF vs. 12
percent for Stribild), diarrhea (16 percent vs. 16 percent), upper respiratory
tract infection (15 percent vs. 21 percent), fatigue (14 percent vs. 9
percent), headache (10 percent vs. 14 percent) and cough (10 percent vs. 10
The incidence of laboratory abnormalities (Grades 3-4) was 25 percent in the
TAF arm and 17 percent for Stribild. Grades 3-4 laboratory abnormalities
occurring in at least 5 percent of patients in either treatment arm were LDL
(low-density lipoprotein or “bad” cholesterol), elevated creatine
phosphokinase and neutropenia.
There were no discontinuations due to renal events and no cases of proximal
renal tubulopathy in either arm. Additional exploratory markers of proximal
renal tubulopathy, measuring impaired absorption and secretion of proteins
caused by damage to the proximal tubule, favored the TAF-based regimen. At 48
weeks of treatment, the change from baseline in the ratio of urine retinol
binding protein to creatinine for the TAF-based regimen was -0.1 µg/g compared
to +20.7 µg/g for Stribild (p=0.001), and the change from baseline in the
ratio of urine β-2 microglobulin to creatinine for the TAF-based regimen and
Stribild was -33.6 µg/g and +0.4 µg/g, respectively (p=0.008).
Additional information about the study can be found at www.clinicaltrials.gov.
About Tenofovir Alafenamide
Tenofovir alafenamide (TAF) is a nucleotide reverse transcriptase inhibitor
(NtRTI). It is a novel prodrug of tenofovir. Phase 1b dose-ranging studies
identified a dose of TAF that is ten times lower than Viread^® (tenofovir
disoproxil fumarate) and provided greater reduction in viral load. The smaller
milligram dose of TAF may enable the development of new fixed-dose
combinations and single tablet regimens for HIV therapy that are not feasible
Elvitegravir is a member of the integrase inhibitor class of antiretroviral
compounds. Integrase inhibitors interfere 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.
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.
Elvitegravir/cobicistat/emtricitabine/TAF and elvitegravir and cobicistat as
single agents are investigational products and their safety and efficacy have
not yet been established.
Indication and 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^®
(emtricitabine) 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 warranted.
*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 results from other clinical trials involving the
single tablet regimen containing TAF, including Phase 3 studies. In addition,
Gilead may be unable to complete enrollment of patients in the Phase 3 studies
or obtain trial results in the timelines currently anticipated and may need to
modify or delay the clinical trials or to perform additional trials. In
addition, Gilead may make a strategic decision to discontinue development of
the single tablet regimen containing TAF if, for example, Gilead believes
commercialization will be difficult relative to other opportunities in its
pipeline. Further, Gilead may be unable to obtain approvals from regulatory
authorities for the TAF-based single tablet regimen, or for elvitegravir or
cobicistat as single agents. If marketing approval is granted for any of these
products, there may be significant limitations on their use. As a result, the
TAF-based single tablet regimen 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, 2013, 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 and Viread is available at
Stribild and Viread are registered trademarks of Gilead Sciences, Inc.
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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