Gilead Announces Full 24-Week Phase 2 Results for Once-Daily Single Tablet
HIV Regimen Containing Novel Prodrug Tenofovir Alafenamide (TAF)
-- TAF-Based Regimen Now in Phase 3 Development --
ATLANTA -- March 5, 2013
Gilead Sciences, Inc. (Nasdaq: GILD) today announced detailed 24-week results
from a Phase 2 study (Study 102) evaluating a once-daily single tablet regimen
containing tenofovir alafenamide (TAF) for the treatment of HIV-1 infection. A
regimen of TAF 10 mg/elvitegravir 150 mg/cobicistat 150 mg/emtricitabine 200
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 at 24 weeks
of treatment. These findings were presented today in a latebreaker session
(Abstract #99LB) at the 20th Conference on Retroviruses and Opportunistic
Infections (CROI 2013) taking place in Atlanta.
“Given that HIV is now a chronic disease that can be managed with life-long
therapy, there remains a need for new treatment options that are well
tolerated,” said Andrew Zolopa, MD, Professor of Medicine, Infectious
Diseases, Stanford University School of Medicine and an investigator for Study
102. “In this study, a TAF-based single tablet regimen achieved comparable
viral suppression to Stribild while demonstrating improvement in renal and
bone safety indicators.”
In Study 102, HIV-positive treatment-naïve adult patients were randomized
(2:1) to receive the investigational TAF-based regimen or Stribild. At 24
weeks, 87 percent (n=97/112) of patients taking TAF and 90 percent (n=52/58)
of patients taking Stribild achieved HIV RNA (viral load) less than 50
copies/mL, based on the FDA snapshot algorithm (95 percent CI for the
difference: -15.7 percent to 5.9 percent for TAF vs. Stribild; p=0.36). There
were no statistically significant differences in the frequency and nature of
Grades 3-4 laboratory abnormalities, and the frequency and nature of adverse
events were similar between the two arms. Both regimens were generally well
“We are pleased with these positive Phase 2 data, which we believe demonstrate
that TAF-based single tablet regimens have the potential to play an important
role in HIV therapy,” said Norbert W. Bischofberger, PhD, Gilead’s Executive
Vice President, Research and Development and Chief Scientific Officer. “Our
Phase 3 program for TAF is enrolling rapidly, and we look forward to sharing
initial results from the first pivotal study in 2014.”
In January 2013, Gilead announced the initiation of two Phase 3 trials,
Studies 104 and 111, which are examining
TAF/elvitegravir/cobicistat/emtricitabine compared to Stribild among HIV
patients new to therapy.
Topline results from Study 102 were announced in October 2012.
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 TAF 10
mg/elvitegravir 150 mg/cobicistat 150 mg/emtricitabine 200 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 and CD4 cell counts greater than 50 cells/mm^3. Bone mineral density
was assessed in all patients by DEXA scans at baseline and at 24 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 24, mean CD4 cell count increases from baseline were 163 cells/mm^3 in
the TAF arm and 177 cells/mm^3 for Stribild (p=0.76).
Both regimens were generally well tolerated, and discontinuations due to
adverse events were similar in both treatment arms (3.6 percent for TAF vs. 0
percent for Stribild).
The frequency of adverse events was similar in both treatment arms, and more
than 90 percent of adverse events were Grades 1-2. The most common adverse
events occurring in at least 5 percent of TAF patients were nausea (18 percent
for TAF vs. 12 percent for Stribild), diarrhea (12 percent in both study
arms), fatigue (12 percent for TAF vs. 9 percent for Stribild), headache (10
percent in both arms), upper respiratory tract infection (7 percent for TAF
vs. 12 percent for Stribild) and flatulence (5 percent for TAF vs. 3 percent
for Stribild). There were no treatment-related serious adverse events in
either treatment arm.
There was a similarly low incidence of laboratory abnormalities (Grades 3-4)
in both arms of the study. 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), neutropenia and elevated creatine
phosphokinase. No proximal renal tubulopathy cases and no discontinuations due
to renal events occurred in either treatment arm.
Median changes from baseline in total cholesterol, HDL (high-density
lipoprotein or “good” cholesterol) and LDL at 24 weeks were, respectively,
+31, +6 and +17 mg/dL for TAF and +15, +2 and +4 mg/dL for Stribild (total
cholesterol, p<0.001; HDL, p=0.007; LDL, p=0.001). The median change in total
cholesterol/HDL ratio at week 24 was 0.1 in both arms (p=0.47). The median
change in triglycerides was +24 mg/dL for TAF and +21 mg/dL for Stribild
Additionally, at 24 weeks of treatment there were numeric differences in renal
laboratory abnormalities favoring the TAF-based regimen. The median change in
serum creatinine from baseline to week 24 was 0.07 mg/dL for the TAF-based
regimen compared to 0.12 mg/dL for Stribild (p=0.02). The median change in the
estimated glomerular filtration rate (eGFR) from baseline to week 24 was -4.9
mL/min compared to -11.8 mL/min for the TAF and Stribild arms, respectively
(p=0.04). The mean percentage decrease in bone mineral density from baseline
to week 24 for the TAF-based regimen compared to Stribild was -0.8 vs. -2.5
(p=0.002) for the lumbar spine and -0.3 vs. -2.0 (p<0.001) for the hip.
The study is ongoing. 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
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 and provides
greater antiviral efficacy. 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 with Viread.
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. Gilead submitted a New Drug
Application (NDA) to the U.S. Food and Drug Administration (FDA) for
elvitegravir as a standalone agent on June 27, 2012, and the agency has set a
target action date under the Prescription Drug User Fee Act (PDUFA) of April
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 as a standalone agent on June 28, 2012, and a PDUFA date of April
28, 2013 has been set.
TAF/elvitegravir/cobicistat/emtricitabine 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 for 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 H8IV 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 also be unable to enroll 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 table
regiment 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
elvitegravir and/or cobicistat, alone or in combination with other products.
If marketing approval is granted for any of these products, there may be
significant limitations on their use. 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 Annual Report on Form 10-K for the year ended December 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 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)
Erin Rau, 650-522-5635 (Media)
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