|[September 12, 2013]
Gilead's Tenofovir Alafenamide (TAF)-Based Single Tablet HIV Regimen Maintains High Viral Suppression Through 48 Weeks in Phase 2 Study
DENVER --(Business Wire)--
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 53rd 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-na�ve 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-na�ve adults with HIV RNA
levels greater than or equal to 5,000 copies/mL, CD4 cell counts greater
than 50 cells/mm3 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 log10 copies/mL and median CD4 cell count of 385
cells/mm3. Patients receiving Stribild had a median HIV RNA
of 4.58 log10 copies/mL and median CD4 cell count of 397
cells/mm3. At week 48, mean CD4 cell count increases from
baseline were 177 cells/mm3 in the TAF arm and 204 cells/mm3
for Stribild (p=0.41).
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 percent).
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 absorpton 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 �g/g compared to +20.7 �g/g for Stribild
(p=0.001), and the change from baseline in the ratio of urine �-2
microglobulin to creatinine for the TAF-based regimen and Stribild was
-33.6 �g/g and +0.4 �g/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 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.
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
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-na�ve. Stribild does not cure HIV-1
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
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. John's wort.
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
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 loss.
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 Stribild.
Antacids: Separate Stribild and antacid administration by at
least 2 hours.
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
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 been established.
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
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 www.gilead.com.
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 (News - Alert) (@GileadSciences) or call Gilead Public Affairs
at 1-800-GILEAD-5 or 1-650-574-3000.
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