– Descovy (FTC/TAF)-based Regimens
Demonstrate Comparable Efficacy and Improved Renal and Bone
Laboratory Parameters Compared to Truvada (FTC/TDF)-based Regimens
–
Gilead Sciences, Inc. (Nasdaq:GILD) today announced two-year
(96-week) data from a Phase 3 study and 48-week data from two Phase
3b studies evaluating the safety and efficacy of switching
virologically suppressed HIV-1 infected patients from regimens
containing Truvada® (emtricitabine and tenofovir disoproxil
fumarate 200mg/300mg; FTC/TDF) to regimens containing Descovy®
(emtricitabine and tenofovir alafenamide 200mg/25mg; FTC/TAF).
Results demonstrated regimens containing Descovy to be
statistically non-inferior to regimens containing Truvada, with
improvements in certain renal and bone laboratory parameters among
patients receiving Descovy (FTC/TAF)-based regimens. The data were
presented in an oral session (Treatment Strategies) at the 2016 HIV
Glasgow conference in Glasgow, Scotland, UK.
Descovy is indicated for use in combination with other
antiretroviral agents for the treatment of HIV-1 infection in
patients 12 years of age and older. Descovy should not be used as
pre-exposure prophylaxis (PrEP) to reduce the risk of acquiring
HIV-1 infection. Descovy has a boxed warning in its product label
regarding the risks of lactic acidosis/severe hepatomegaly with
steatosis, and post treatment acute exacerbation of hepatitis B.
See below for important safety information.
“As people are living longer with HIV, several studies show that
patients who switch from regimens containing Truvada to regimens
containing Descovy are able to maintain viral suppression while
improving renal and bone laboratory markers, which may help address
long-term health needs,” said Dr. Chloe Orkin, Consultant, Barts
Health NHS Trust, London. “Along with its favorable safety profile,
Descovy offers patients and physicians a versatile treatment
backbone that can be paired with a range of third agents.”
In Study 1089, 663 virologically suppressed, HIV infected adults
were randomized to switch to regimens containing Descovy or
continue on regimens containing Truvada, while remaining on the
same third agents. At Week 96, virologic suppression (HIV-1 RNA
<50 c/mL) was maintained in 89 percent of participants in both
groups (difference in percentages: -0.5 percent; 95 percent CI:
-5.3 percent to 4.4 percent). Drug-related serious adverse events
were rare (Descovy (FTC/TAF)-based regimens, 0 percent; Truvada
(FTC/TDF)-based regimens, 0.3 percent) and drug discontinuation due
to adverse events was low for both treatment groups (Descovy
(FTC/TAF)-based regimens, 2.4 percent; Truvada (FTC/TDF)-based
regimens, 1.2 percent). The most commonly reported adverse events
included upper respiratory tract infection, diarrhea and
nasopharyngitis.
In the same study, the effect of the two regimens on laboratory
parameters of kidney and bone health was investigated.
Statistically significant differences were observed in mean changes
from baseline to Week 96 in bone mineral density (BMD) between
patients receiving Descovy (FTC/TAF)-based regimens compared to
patients receiving Truvada (FTC/TDF)-based regimens (spine: 2.15
percent vs. -0.17 percent; hip: 1.85 percent vs. -0.33 percent;
p<0.05 for both). Additionally, more patients receiving Descovy
(FTC/TAF)-based regimens experienced a greater than three percent
improvement in BMD from baseline to Week 96, compared with those
receiving Truvada (FTC/TDF)-based regimens (spine: 40 percent vs.
18 percent; hip: 29 percent vs. 11 percent; p<0.05 for
both).
Differences favoring regimens containing Descovy were also
observed in multiple tests of renal laboratory parameters which
included median changes from baseline to Week 96 in estimated
glomerular filtration rate (eGFR; +10.00 mL/min vs. +4.00 mL/min;
p<0.05) and median percent changes in: urine
protein-to-creatinine ratio (-26.0 percent vs. +2.7 percent;
p<0.05); urine albumin-to-creatinine ratio (+3.4 percent vs.
+27.0 percent; p<0.05); urine retinol binding
protein-to-creatinine ratio; (-4.1 percent vs. +42.6 percent;
p<0.05); and urine beta-2 microglobulin-to-creatinine ratio
(-29.7 percent vs. +46.8 percent; p<0.05). There were no cases
of Fanconi syndrome. Additionally, there were no cases of proximal
renal tubulopathy in the Descovy (FTC/TAF)-based regimens group,
and one case in the Truvada (FTC/TDF)-based regimens group through
Week 96.
Odefsey® (rilpivirine 25mg/emtricitabine 200mg/tenofovir
alafenamide 25mg tablets; RPV/FTC/TAF) is a FTC/TAF-based single
tablet regimen indicated as a complete regimen for the treatment of
HIV-1 infection in patients 12 years of age and older who have no
antiretroviral treatment history and HIV-1 RNA levels ≤100,000
c/mL. Odefsey is also indicated to replace a stable antiretroviral
regimen in those who are virologically suppressed (HIV-1 RNA <50
c/mL) for at least six months with no history of treatment failure
and no known resistance to the individual components of Odefsey.
Odefsey also has a boxed warning in its product label regarding the
risks of lactic acidosis/severe hepatomegaly with steatosis, and
post treatment acute exacerbation of hepatitis B. See below for
important safety information.
In Study 1216, 630 virologically suppressed, HIV infected adults
were randomized to switch to Odefsey or to continue on Complera®
(rilpivirine 25mg/emtricitabine 200mg/tenofovir disoproxil fumarate
300mg tablets; RPV/FTC/TDF). At Week 48, similar rates of virologic
suppression (HIV-1 RNA <50 c/mL) were maintained in both
treatment groups (Odefsey, 94 percent; Complera, 94 percent;
difference in percentages: −0.3 percent; 95 percent CI: −4.2
percent to +3.7 percent). Drug-related serious adverse events and
drug discontinuation due to adverse events were low across both
treatment groups (0.1 percent in both). The most commonly reported
adverse events included upper respiratory tract infection, diarrhea
and nasopharyngitis.
Statistically significant improvements favoring Odefsey were
observed from baseline to Week 48 in mean BMD at the hip and spine
compared to patients in the Complera group (spine: +1.61 percent
vs. +0.08 percent; hip: +1.04 percent vs. -0.25 percent; p<0.001
for both). Additionally, improvements favoring Odefsey were
observed in multiple tests of renal laboratory parameters,
including median changes in eGFR from baseline to Week 48 (Odefsey,
+4.5mL/min; Complera, +0.7 mL/min; p=0.002) and median percent
changes in: urine protein-to-creatinine ratio (-18.0 percent vs.
+21.5 percent; p<0.001); urine albumin-to-creatinine ratio (-7.8
percent vs. +16.8 percent; p<0.001); urine retinol binding
protein-to-creatinine ratio; (-18.8 percent vs. +7.3 percent;
p<0.001); and urine beta-2 microglobulin-to-creatinine ratio
(-29.0 percent vs. +12.0 percent; p<0.001). No cases of Fanconi
syndrome or proximal renal tubulopathy were reported through Week
48.
In Study 1160, 875 virologically suppressed, HIV infected adults
were randomized to switch to Odefsey, or to continue on Atripla®
(efavirenz 600mg/emtricitabine 200mg/tenofovir disoproxil fumarate
300mg tablets; EFV/FTC/TDF). At Week 48, high rates of virologic
suppression (HIV-1 RNA <50 c/mL) were maintained in both
treatment groups (Odefsey, 90 percent; Atripla, 92 percent;
difference in percentages: -2.0 percent; 95 percent CI: -5.9% to
+1.8%) and general safety was similar between the arms. The most
commonly reported adverse events included upper respiratory tract
infection, nasopharyngitis and cough.
Statistically significant improvements favoring Odefsey were
observed from baseline to Week 48 in mean BMD at the hip and spine
compared to patients in the Atripla group (spine: +1.65 percent vs.
+0.05 percent; hip: +1.28 percent vs. -0.13 percent; p<0.001 for
both). A larger percentage of patients receiving Odefsey showed
improvements in their osteopenia or osteoporosis at either hip
(p=0.004) or spine (p<0.001). Additionally, improvements
favoring Odefsey were observed in multiple tests of renal
laboratory parameters, demonstrated by changes in total and tubular
proteinuria (p<0.001) and percent changes in: urine
protein-to-creatinine ratio (-30.0 percent vs. -2.0 percent;
p<0.001); urine albumin-to-creatinine ratio (-13.5 percent vs.
+12.2 percent; p<0.001); urine retinol binding protein
creatinine ratio (-27.6 percent vs. +29.1 percent; p<0.001);
urine beta-2-microglobulin creatinine ratio (-41.0 percent vs.
+17.1 percent; p<0.001). No cases of Fanconi syndrome or
proximal renal tubulopathy were reported through Week 48.
“Results from the studies presented at HIV Glasgow further
support the efficacy, as well as the renal and bone safety profile,
of regimens containing Descovy as treatment options for appropriate
virologically suppressed patients,” said Norbert W. Bischofberger,
PhD, Gilead’s Executive Vice President, Research and Development
and Chief Scientific Officer. “These data also demonstrate Gilead’s
ongoing commitment to developing treatments that may improve health
as people grow older with HIV while we continue to search for a
cure for the virus.”
Odefsey combines Gilead’s emtricitabine and tenofovir
alafenamide with rilpivirine, marketed by Janssen Sciences Ireland
UC, one of the Janssen Pharmaceutical Companies of Johnson &
Johnson. Gilead is responsible for the manufacturing, registration,
distribution and commercialization of Odefsey in most countries,
while Janssen will distribute it in approximately 18 markets and
have co-detailing rights in several key markets, including the
United States. The original agreement was established for the
development and commercialization of Complera®, marketed as
Eviplera® in the EU, and was expanded in 2014 to include
Odefsey.
Additional Study
Information
Study 1089 is a Phase 3, 96-week randomized, multi-center,
double blind, active controlled study of 663 virologically
suppressed HIV-1 infected adult patients receiving Truvada
(FTC/TDF)-based regimens. The study was designed to evaluate the
efficacy and safety of switching from Truvada to Descovy, versus
continuing Truvada while remaining on the same third agent. The
primary endpoint was virologic success (HIV-1 RNA <50 c/mL) at
Week 48. The median age of participants was 49 years, and females
comprised 15 percent of the study population. Inclusion criteria
required an estimated glomerular filtration rate eGFR ≥ 50 mL/min,
according to the Cockcroft-Gault formula for creatinine clearance.
The median estimated eGFR at study initiation was 100 mL/min.
Dosing of Descovy was dependent on the third agent: 200/10mg with
ritonavir-boosted protease inhibitors (darunvair, atazanavir and
lopinavir) and 200/25mg with unboosted third agents (raltegravir,
dolutegravir, nevirapine, efavirenz, rilpivirine and maraviroc). In
the United States, only one dose of Descovy (200/25mg) is approved
for use with any third agent. Approximately 46 percent of patients
enrolled were treated with a boosted protease inhibitor, 28 percent
were treated with an integrase inhibitor and 25 percent were
treated with a non-nucleoside reverse transcriptase inhibitor.
Study 1216 is a Phase 3b, 96-week randomized, double blind,
multicenter study among 630 virologically suppressed adults (HIV-1
RNA levels ˂50 copies/mL) on a stable regimen of Complera for ≥ six
months. The study was designed to evaluate the efficacy and safety
of switching from Complera to Odefsey versus remaining on Complera.
The primary endpoint was virologic success (HIV-1 RNA <50 c/mL)
at Week 48. The median age of participants was 45 years, with 10
percent female and 19 percent black participants. Inclusion
criteria required an eGFR ≥ 50 mL/min, according to the
Cockcroft-Gault formula for creatinine clearance.
Study 1160 is a Phase 3b, 96-week randomized, double blind,
multicenter study of 875 virologically suppressed adults (HIV-1 RNA
levels ˂50 copies/mL) on a stable regimen of Atripla for ≥ six
months. The study was designed to evaluate the efficacy and safety
of switching from Atripla to Odefsey versus remaining on Atripla.
The primary endpoint was virologic success (HIV-1 RNA <50 c/mL)
at Week 48. The median age of participants was 49 years, and
females comprised 13 percent of the study population. Inclusion
criteria required an eGFR ≥ 50 mL/min, according to the
Cockcroft-Gault formula for creatinine clearance.
Additional information about the studies can be found at
www.clinicaltrials.gov.
Important U.S. Safety Information For
Descovy And Odefsey
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 in combination with
other antiretrovirals.
- Descovy and Odefsey are not approved
for the treatment of chronic hepatitis B virus (HBV) infection and
the safety and efficacy have not been established in patients
coinfected with HIV-1 and HBV. Severe acute exacerbations of
hepatitis B have been reported in patients who are coinfected with
HIV-1 and HBV and have discontinued products containing
emtricitabine (FTC) and/or tenofovir disoproxil fumarate (TDF), and
may occur with discontinuation of Descovy or Odefsey. After
discontinuation, 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. If appropriate,
initiation of anti-hepatitis B therapy may be warranted.
Contraindications
Contraindications for Descovy:
Contraindications for Odefsey:
- Coadministration. Do not use
with drugs that induce CYP3A or increase gastric pH as this may
lead to loss of efficacy and possible resistance to Odefsey or the
NNRTI class. Do not use with carbamazepine, oxcarbazepine,
phenobarbital, phenytoin, rifampin, rifapentine, proton pump
inhibitors (e.g., dexlansoprazole, esomeprazole, lansoprazole,
omeprazole, pantoprazole, rabeprazole), systemic dexamethasone
(>1 dose) and St. John’s wort.
Warnings and precautions
Warnings and precautions for Descovy and Odefsey:
- Fat redistribution or
accumulation has been observed in patients receiving antiretroviral
therapy.
- Immune reconstitution syndrome,
including the occurrence of autoimmune disorders with variable time
to onset, has been reported.
- New onset or worsening renal
impairment: Cases of acute renal failure and Fanconi syndrome
have been reported with the use of tenofovir prodrugs. In clinical
trials of emtricitabine and tenofovir alafenamide (TAF) with
elvitegravir and cobicistat, there have been no cases of Fanconi
syndrome or proximal renal tubulopathy (PRT). Do not initiate in
patients with estimated creatinine clearance (CrCl) <30 mL/min.
Patients with impaired renal function and/or taking nephrotoxic
agents (including NSAIDs) are at increased risk of renal-related
adverse reactions. Discontinue in patients who develop clinically
significant decreases in renal function or evidence of Fanconi
syndrome. Renal monitoring: In all patients, monitor CrCl, urine
glucose, and urine protein prior to initiating and during therapy.
In patients with chronic kidney disease, additionally monitor serum
phosphorus.
- Bone loss and mineralization
defects: Decreases in bone mineral density (BMD) have been
reported with the use of tenofovir prodrugs. Consider monitoring
BMD in patients with a history of pathologic fracture or risk
factors for bone loss. Mineralization defects, including
osteomalacia associated with PRT, have been reported with the use
of TDF-containing products.
Additional warnings and precautions for Odefsey:
- Skin and hypersensitivity
reactions: Severe skin and hypersensitivity reactions have been
reported with the use of rilpivirine-containing regimens, including
cases of Drug Reaction with Eosinophilia and Systemic Symptoms
(DRESS). In rilpivirine clinical trials, most rashes were Grades
1-2 and occurred in the first 4-6 weeks of treatment; Grades 2-4
rash occurred in 1% of subjects. Discontinue Odefsey immediately if
severe skin or hypersensitivity reactions occur, including severe
rash or rash accompanied by fever, blisters, mucosal involvement,
conjunctivitis, facial edema, angioedema, hepatitis or
eosinophilia. Monitor clinical status including laboratory
parameters and initiate appropriate therapy.
- Loss of virologic response due to
drug interactions: See Contraindications and Drug Interactions
sections. Consider the potential for drug interactions prior to and
during Odefsey therapy and monitor for adverse reactions.
- Prolongation of QTc interval:
Rilpivirine doses 3 and 12 times higher than the recommended dose
can prolong the QTc interval. Consider alternatives to Odefsey in
patients at higher risk for Torsade de Pointes or when
coadministered with a drug with known risk of Torsade de
Pointes.
- Depressive disorders: Evaluate
patients with severe depressive symptoms to assess if symptoms are
due to Odefsey and if the risks of continued treatment outweigh the
benefits. In rilpivirine adult clinical trials (N=686), the
incidence of depressive disorders was 9%, Grades 3-4 depressive
disorders was 1%, discontinuation due to depressive disorders was
1%, and suicidal ideation and suicide attempt was reported in 4 and
2 subjects, respectively. In a rilpivirine adolescent clinical
trial (N=36), the incidence of depressive disorders was 19%, Grades
3-4 depressive disorders was 6%, and suicidal ideation and suicide
attempt were reported in 1 subject.
- Hepatotoxicity: Hepatic adverse
events have been reported, including cases of hepatic toxicity, in
patients without pre-existing hepatic disease or other identifiable
risk factors. In patients with hepatic abnormalities (e.g.,
hepatitis, elevated liver-associated tests), order laboratory tests
before starting treatment and monitor for hepatotoxicity during
treatment; consider testing and monitoring in all patients.
Adverse reactions
Adverse reactions for Descovy and Odefsey:
- Common adverse reactions
(incidence ≥5%; all Grades) in clinical studies of FTC/TAF in
combination with other antiretroviral agents were nausea (10%),
diarrhea (7%), headache (6%), and fatigue (5%).
Additional adverse reactions for Odefsey:
- Most common adverse reactions
(incidence ≥2%, Grades 2-4) in clinical studies of rilpivirine in
combination with other antiretroviral agents were depressive
disorders (2%), insomnia (2%) and headache (2%).
Drug interactions
Drug interactions for Descovy and Odefsey:
- Prescribing information: Consult
the full prescribing information for more information on
potentially significant drug interactions, including clinical
comments.
- Drugs affecting renal function:
Coadministration with drugs that reduce renal function or compete
for active tubular secretion may increase concentrations of FTC and
tenofovir and the risk of adverse reactions.
Additional drug interactions for Descovy:
- Metabolism: Drugs that inhibit
P-gp can increase the concentrations of components of Descovy.
Drugs that induce P-gp can decrease the concentrations of
components of Descovy, which may lead to loss of efficacy and
development of resistance.
Additional drug interactions for Odefsey:
- Metabolism: Drugs that induce
CYP3A or P-gp and drugs that increase gastric pH can decrease the
concentrations of components of Odefsey. Drugs that inhibit CYP3A
or P-gp can increase the concentrations of components of
Odefsey.
- QT prolonging drugs: Consider
alternatives to Odefsey in patients taking a drug with known risk
of Torsade de Pointes.
Dosage and administration
Information for Descovy and Odefsey:
- Dosage for patients 12 years and
older (≥35 kg): 1 tablet taken orally once daily.
- Descovy: take with or without
food, in combination with other antiretroviral agents.
- Odefsey: take with a meal, as a
single-tablet regimen.
- Renal impairment: Not
recommended in patients with CrCl <30 mL/min.
- Testing prior to initiation:
Test patients for HBV infection and assess CrCl, urine glucose and
urine protein.
Additional information for Odefsey:
- Testing after initiation: In
virologically-suppressed patients, additional monitoring of HIV-1
RNA and regimen tolerability is recommended.
Pregnancy and lactation
Information for Descovy and Odefsey:
- Pregnancy: There are
insufficient data on use during pregnancy. In animal studies, no
adverse developmental effects were observed. An Antiretroviral
Pregnancy Registry has been established.
- Lactation: Women infected with
HIV-1 should be instructed not to breastfeed, due to the potential
for HIV-1 transmission.
About Gilead
Gilead Sciences is a biopharmaceutical company that discovers,
develops and commercialises innovative therapeutics in areas of
unmet medical need. The company’s mission is to advance the care of
patients suffering from life-threatening diseases. Gilead has
operations in more than 30 countries worldwide, with headquarters
in Foster City, California.
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 physicians may not see benefits of
switching patients from regimens containing Truvada to regimens
containing Descovy. Further, there is a possibility of unfavorable
results from other clinical trials involving Descovy
(FTC/TAF)-based regimens. 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, 2016, 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 Atripla,
Complera, Descovy, Odefsey, and Truvada, including BOXED
WARNINGS, are available at www.gilead.com.
Complera, Descovy, Eviplera, Odefsey, and
Truvada are registered trademarks of Gilead Sciences, Inc., or its
related companies. 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, follow Gilead on
Twitter (@GileadSciences) or call Gilead Public Affairs at
1-800-GILEAD-5
or 1-650-574-3000.
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