Gilead’s Odefsey® (Emtricitabine, Rilpivirine, Tenofovir Alafenamide) Meets Primary 48-Week Objective in Two Phase 3b Stud...
July 21 2016 - 04:30PM
Business Wire
Gilead Sciences, Inc. (Nasdaq:GILD) today announced that two
Phase 3b switch studies evaluating Odefsey® (emtricitabine
200mg/rilpivirine 25mg/tenofovir alafenamide 25mg) for the
treatment of HIV-1 infection met their primary objectives. The
ongoing studies were designed to explore the efficacy and safety of
Odefsey among virologically suppressed adult patients switching
from the tenofovir disoproxil fumarate (TDF)-based regimens
Complera® (emtricitabine 200mg/rilpivirine 25mg/tenofovir
disoproxil fumarate 300mg) (Study 1216) or Atripla® (efavirenz
600mg/emtricitabine 200mg/tenofovir disoproxil fumarate 300mg)
(Study 1160). 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.
Odefsey maintained similar rates of virologic suppression as the
TDF-based regimens in both studies based on the proportion of
patients with HIV-1 RNA levels (viral load) <50 copies/mL. At
Week 48, virologic suppression was maintained in 94 percent of
patients taking Odefsey and in 94 percent of patients taking
Complera in Study 1216 (difference: -0.3 percent; 95 percent CI:
-4.2 percent to +3.7 percent), and in 90 percent of patients taking
Odefsey versus 92 percent of patients taking Atripla in Study 1160
(difference: -2.0 percent; 95 percent CI: -5.9 percent to +1.8
percent).
Compared to the TDF-based regimens, Odefsey demonstrated
statistically significant improvements in bone mineral density
(BMD) at the hip and spine (p<0.001) in both studies.
Additionally, improvements in total and tubular proteinuria
statistically favored Odefsey in both studies (p<0.001). Study
regimens were generally well tolerated, and general safety and
discontinuation rates due to adverse events were comparable in the
two studies. The most commonly reported adverse events for Odefsey
included upper respiratory tract infection, diarrhea,
nasopharyngitis, cough and headache. Gilead plans to submit these
data for presentation at scientific conferences in 2016.
“As people are living longer with HIV, there is an increasing
need for safe and tolerable treatment options to help address the
long-term health needs of people living with HIV,” said Norbert
Bischofberger, PhD, Executive Vice President, Research and
Development and Chief Scientific Officer, Gilead Sciences. “Results
from these two studies support the efficacy, as well as the renal
and bone safety profile, of Odefsey as a new treatment option for
virologically suppressed patients.”
Odefsey was approved in the United States on March 1, 2016, and
is 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
copies/mL. Odefsey is also indicated as replacement for a stable
antiretroviral regimen in those who are virologically suppressed
(HIV-1 RNA <50 copies/mL) for at least six months with no
history of treatment failure and no known resistance to the
individual components of Odefsey. No dosage adjustment of Odefsey
is required in patients with estimated creatinine clearance ≥30 mL
per minute.
Odefsey 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.
About Studies 1216 and
1160
Study 1216 is a Phase 3b, 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
consecutive months. Patients were randomized 1:1 to either maintain
their Complera regimen or switch to Odefsey. Study 1160 is a Phase
3b, randomized, double-blind, multicenter study among 875
virologically suppressed adults (HIV-1 RNA levels <50 copies/mL)
on a stable regimen of Atripla for ≥ six consecutive months.
Patients were randomized 1:1 to either maintain their Atripla
regimen or switch to Odefsey. The studies will follow patients for
96 weeks after randomization.
The studies are ongoing. The primary objective of each study is
to evaluate the efficacy of switching from Complera or Atripla to
Odefsey in HIV-1 positive subjects who are virologically suppressed
as determined by the proportion of subjects with HIV-1 RNA <50
copies/mL at Week 48 as defined by the FDA snapshot algorithm. The
secondary objectives are to evaluate the bone safety of the
regimens by the percent change from baseline in hip and spine BMD
at Week 48 and Week 96, to evaluate the safety and tolerability of
the treatment arms through Week 48 and to evaluate the efficacy,
safety and tolerability of the treatment arms through Week 96.
Additional information about the studies can be found at
www.clinicaltrials.gov.
Important U.S. Safety Information for
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.
- Odefsey is not approved for the
treatment of chronic hepatitis B virus (HBV) infection, and the
safety and efficacy of Odefsey 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 and/or tenofovir disoproxil fumarate (TDF), and may
occur with discontinuation of Odefsey. 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 Odefsey. If appropriate, initiation of
anti-hepatitis B therapy may be warranted.
Contraindications
- 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
- 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.
- 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 with elvitegravir
and cobicistat, there have been no cases of Fanconi syndrome or
proximal renal tubulopathy (PRT). Do not initiate Odefsey 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 Odefsey 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.
Adverse reactions
- Most common adverse reactions
with rilpivirine (incidence ≥2%, Grades 2-4) are depressive
disorders (2%), insomnia (2%) and headache (2%); and with
emtricitabine and tenofovir alafenamide (incidence ≥10%, all
grades) is nausea (10%).
Drug interactions
- Prescribing information: Consult
the full prescribing information for Odefsey for more information
on Contraindications, Warnings, and potentially significant drug
interactions, including clinical comments.
- 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.
- Drugs affecting renal function:
Coadministration of Odefsey with drugs that reduce renal function
or compete for active tubular secretion may increase concentrations
of emtricitabine and tenofovir and the risk of adverse
reactions.
Dosage and administration
- Dosage: Patients 12 years and
older (≥35 kg): 1 tablet taken orally once daily with a meal.
- 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.
- Testing after initiation: In
virologically-suppressed patients, additional monitoring of HIV-1
RNA and regimen tolerability is recommended.
Pregnancy and lactation
- Pregnancy: There are
insufficient data on the use of Odefsey during pregnancy. In animal
studies, no adverse developmental effects were observed with the
components of Odefsey. 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 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. 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 the benefits of
prescribing Odefsey. 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 March 31, 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, including
BOXED WARNINGS, for Atripla, Complera and Odefseyare
available at www.gilead.com.
Atripla, Complera and Odefsey are registered
trademarks of Gilead Sciences, Inc., or its related companies.
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-5or 1-650-574-3000.
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