Gilead Sciences, Inc. (NASDAQ: GILD) today presented additional
results from the DISCOVER trial evaluating an investigational use
of Descovy (emtricitabine 200 mg and tenofovir alafenamide 25 mg
tablets; F/TAF) for HIV pre-exposure prophylaxis (PrEP). In a
sub-analysis of the DISCOVER trial, Descovy reached intracellular
drug concentration levels above the estimated protective threshold
significantly more quickly than Truvada (emtricitabine 200 mg and
tenofovir disoproxil fumarate 300 mg tablets; F/TDF), and
additional pharmacokinetic data confirm that these drug
concentration levels persist longer than Truvada. The results were
presented at the 10th International AIDS Society Conference on HIV
Science (IAS 2019) being held in Mexico City.
“Gilead is committed to driving advances in HIV prevention and
supporting broader public health initiatives that are designed to
reduce HIV infections,” said Diana Brainard, MD, Senior Vice
President, HIV and Emerging Viruses, Gilead Sciences. “These
results presented at IAS provide further evidence supporting the
potential for Descovy for PrEP™ to offer an important new
prevention option for people at risk of acquiring HIV.”
In April, Gilead submitted a supplemental New Drug Application
(sNDA) to the U.S. Food and Drug Administration (FDA) for
once-daily Descovy for PrEP. A Priority Review voucher was
submitted with the filing, leading to an anticipated review time of
six months. Descovy was approved in the United States in 2016 for
the treatment of HIV-1 infection in combination with other
antiretroviral agents, and the use of Descovy for a PrEP indication
is investigational. Descovy and Truvada have a Boxed Warning in
their U.S. product label regarding the risk of post-treatment acute
exacerbation of hepatitis B; Truvada for PrEP also includes a Boxed
Warning regarding the risk of drug resistance with use of Truvada
for PrEP in undiagnosed early HIV infection. See below for
Indications and Important Safety Information.
These results were based on a sub-analysis of the DISCOVER
trial, a two-year Phase 3 randomized, controlled, double-blind
study evaluating the safety and efficacy of the investigational use
of once-daily Descovy for PrEP compared with Truvada for PrEP. The
study enrolled adult men and transgender women who have sex with
men who were both at substantial and sustained risk for sexually
acquired HIV infection. DISCOVER trial sites included STI clinics,
LGBTQ health centers, and other clinical practices that are located
in areas with high background rates of HIV and that serve
populations with among the highest risk of HIV infection.
The primary endpoint of the DISCOVER trial was the incidence of
documented HIV infection per 100 person-years, with a minimum
follow-up of 48 weeks and at least 50 percent of participants
having 96 weeks of follow-up. Descovy met the primary endpoint of
non-inferiority. The most common treatment-emergent adverse events
(≥25 percent; all grades) were bacterial sexually transmitted
infections, including anal chlamydia infection, oropharyngeal
gonococcal infection and rectal gonorrhea. Common study
drug-related side effects (≥ 1 percent; all grades) included
diarrhea, nausea, headache and fatigue.
There were no differences in HIV risk factors, acquired STIs or
adherence between the two study drug arms in DISCOVER. Overall,
study participants randomized to Descovy for PrEP had a
significantly reduced time to achieve a 90 percent effective
concentration (EC90) of tenofovir diphosphate (TFV-DP) in
peripheral blood mononuclear cells (PBMCs), as compared with
participants taking Truvada. At Week 4, levels of TFV-DP in PBMCs
were 6.3-fold higher with Descovy compared with Truvada, resulting
in 98 percent of participants receiving Descovy had drug levels
above the EC90 compared with 68 percent of participants taking
Truvada. Pharmacokinetic data from separate PK studies demonstrate
that after using drugs for 14-28 days, F/TAF users who stop drug
still maintain TFV-DP concentrations above the EC90 for at least 60
percent longer than F/TDF users.
“Low tenofovir diphosphate concentrations in PBMCs were
associated with an increased risk of HIV acquisition,” said
Christoph Spinner, School of Medicine at Technical University of
Munich and lead study author. “These results provide valuable new
information about the profile of Descovy for its potential use as
PrEP.”
Additionally, at IAS, Gilead presented data assessing renal
adverse events in people at risk for HIV acquisition taking Truvada
for PrEP. These results of an analysis of multi-national Truvada
for PrEP utilization data in MSM are summarized in Poster
#TUPEC393.
The use of Descovy for the prevention of HIV is investigational
and has not been determined to be safe or efficacious and is not
approved anywhere globally.
IMPORTANT U.S. SAFETY INFORMATION AND INDICATION FOR THE USE
OF DESCOVY FOR HIV TREATMENT
BOXED WARNING: POST TREATMENT ACUTE EXACERBATION OF HEPATITIS
B
- Descovy is not approved for the treatment of chronic
hepatitis B virus (HBV) infection and the safety and efficacy of
Descovy 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. 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 Descovy. If appropriate, initiation of
anti-hepatitis B therapy may be warranted.
Warnings and precautions
- 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 FTC and tenofovir
alafenamide with elvitegravir and cobicistat, there have been no
cases of Fanconi syndrome or proximal renal tubulopathy (PRT). Do
not initiate Descovy 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
Descovy 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.
- Lactic acidosis and severe hepatomegaly with steatosis: Fatal
cases have been reported with the use of nucleoside analogs,
including FTC and TDF. Discontinue Descovy if clinical or
laboratory findings suggestive of lactic acidosis or pronounced
hepatotoxicity develop, including hepatomegaly and steatosis in the
absence of marked transaminase elevations.
Adverse reactions
- Most common adverse reaction (incidence ≥10%; all grades) in
clinical studies was nausea (10%).
Drug interactions
- Prescribing information: Consult the full prescribing
information for Descovy for more information on potentially
significant drug interactions, including clinical comments.
- 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.
- Drugs affecting renal function: Coadministration of Descovy
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 who weigh ≥25 kg: 1 tablet taken orally once
daily with or without food.
- 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.
- Pediatrics: The safety and effectiveness of Descovy
coadministered with an HIV-1 protease inhibitor that is
administered with either ritonavir or cobicistat have not been
established in pediatric subjects weighing less than 35 kg.
Pregnancy and lactation
- Pregnancy: There is insufficient human data on the use of
Descovy during pregnancy. An Antiretroviral Pregnancy Registry
(APR) has been established; available data from the APR for FTC
shows no difference in the rates of birth defects compared with a
U.S. reference population.
- Lactation: Women infected with HIV-1 should be instructed not
to breastfeed, due to the potential for HIV-1 transmission.
INDICATION
Descovy is indicated in combination with other antiretroviral
(ARV) agents for the treatment of HIV-1 infection in patients
weighing at least 35 kg.
Descovy is also indicated, in combination with other
antiretroviral agents other than protease inhibitors that require a
CYP3A inhibitor, for the treatment of HIV-1 infection in pediatric
patients weighing at least 25 kg and less than 35 kg.
Limitations of Use:
Descovy is not indicated for use as pre-exposure prophylaxis
(PrEP) to reduce the risk of acquiring HIV-1 infection.
IMPORTANT U.S. SAFETY INFORMATION AND INDICATION FOR TRUVADA
FOR PREP
BOXED WARNING: RISK OF DRUG RESISTANCE WITH USE OF TRUVADA
FOR PrEP IN UNDIAGNOSED EARLY HIV-1 INFECTION and POST TREATMENT
ACUTE EXACERBATION OF HEPATITIS B
- Truvada for PrEP must only be prescribed to individuals
confirmed to be HIV-negative immediately prior to initiation and at
least every 3 months during use. Drug-resistant HIV-1 variants have
been identified with use of Truvada for PrEP following undetected
acute HIV-1 infection. Do not initiate if signs or symptoms of
acute HIV-1 infection are present unless HIV-negative status is
confirmed
- Severe acute exacerbations of hepatitis B have been reported
in HBV-infected patients who discontinued Truvada. Hepatic function
should be monitored closely with both clinical and laboratory
follow-up for at least several months in patients with HBV after
discontinuing Truvada. If appropriate, initiation of anti-hepatitis
B therapy may be warranted
Contraindications
- Do not use Truvada for PrEP in individuals with unknown or
positive HIV status
Warnings and precautions: Comprehensive risk reduction
strategies
- Reduce HIV-1 risk: Truvada for PrEP is not always
effective in preventing HIV-1. Use only as part of a comprehensive
prevention strategy that includes safer sex practices, regular
testing for HIV-1 and other STIs, and counseling on reducing sexual
risk behaviors
- Reduce potential for drug resistance: Truvada for PrEP
should only be used in individuals confirmed to be HIV-negative
immediately prior to initiation, at least every 3 months while
taking Truvada, and upon an STI diagnosis. HIV-1 resistance
substitutions may emerge in individuals with undetected HIV-1
infection who are taking only Truvada. Truvada alone is not a
complete regimen for treating HIV-1
- HIV antibody tests may not detect acute HIV infection. If
recent exposures are suspected or symptoms of acute HIV infection
are present (e.g., fever, fatigue, myalgia, skin rash), delay
initiating (≥1 month) or discontinue use and confirm HIV-negative
status with a test approved by U.S. Food and Drug Administration
(FDA) for the diagnosis of acute HIV infection
- If a screening test indicates possible HIV-1 infection, convert
the HIV-1 PrEP regimen to an HIV treatment regimen until
HIV-negative status is confirmed.
- Counsel on adherence: Counsel individuals to strictly
adhere to their dosing schedule, as efficacy is strongly correlated
with adherence. Some individuals, such as adolescents, may benefit
from more frequent visits and counseling.
Warnings and precautions
- New onset or worsening renal impairment: Cases of acute
renal impairment and Fanconi syndrome have been reported with the
use of tenofovir disoproxil fumarate (TDF). Truvada is not
recommended in individuals with estimated creatinine clearance
(CrCl) <60 mL/min. Avoid concurrent or recent use with a
nephrotoxic agent. Acute renal failure has been reported after
initiation of high dose or multiple NSAIDs in patients at risk for
renal dysfunction; consider alternatives to NSAIDs in these
patients. Monitor renal function in all patients – See Dosage and
Administration
- Bone effects: Decreases in bone mineral density (BMD)
and mineralization defects, including osteomalacia associated with
proximal renal tubulopathy, have been reported with the use of TDF
Consider monitoring BMD in patients with a history of pathologic
fracture or risk factors for bone loss
- Lactic acidosis and severe hepatomegaly with steatosis:
Fatal cases have been reported with the use of nucleoside analogs,
including Truvada. Discontinue use if clinical or laboratory
findings suggestive of lactic acidosis or pronounced hepatotoxicity
develop, including hepatomegaly and steatosis in the absence of
marked transaminase elevations
- Drug interactions: See Drug Interactions section.
Consider the potential for drug interactions prior to and during
use of Truvada and monitor for adverse reactions
Adverse reactions
- Common adverse reactions (>2% and more frequently
than placebo) of Truvada for PrEP in clinical trials were headache,
abdominal pain, and weight loss
Drug interactions
- Prescribing information: Consult the full Prescribing
Information for Truvada for more information, warnings, and
potentially significant drug interactions, including clinical
comments
- Hepatitis C antivirals: Coadministration with
ledipasvir/sofosbuvir, sofosbuvir/velpatasvir, or
sofosbuvir/velpatasvir/voxilaprevir increases TDF exposure; monitor
for adverse reactions
- Drugs affecting renal function: Coadministration of
Truvada with drugs that reduce renal function or compete for active
tubular secretion may increase concentrations of emtricitabine
and/or tenofovir
Pregnancy and lactation
- Pregnancy: An Antiretroviral Pregnancy Registry (APR)
has been established. Available data from observational studies and
the APR show no increase in the rate of major birth defects for
Truvada compared with a US reference population. Consider HIV
prevention methods, including Truvada for PrEP in at-risk women due
to the potential increased risk of HIV-1 infection during pregnancy
and mother to child transmission during acute HIV-1 infection
- Lactation: Emtricitabine and tenofovir have been
detected in human milk. Evaluate the benefits and risks of Truvada
for PrEP in breastfeeding women, including the risk of HIV-1
acquisition due to nonadherence, and subsequent mother to child
transmission. Health benefits of breastfeeding should be considered
along with potential adverse effects of Truvada on the child, which
are unknown
Dosage and administration
- Dosage: One tablet once daily with or without food
- HIV screening: Test for HIV-1 infection prior to
initiating and at least every 3 months during treatment
- HBV screening: Test for HBV infection prior to or when
initiating treatment
- Renal impairment and monitoring: Not recommended in
individuals with CrCl <60 mL/min. In all patients, assess serum
creatinine, estimated creatinine clearance, urine glucose, and
urine protein on a clinically appropriate schedule. In patients
with chronic kidney disease, also assess serum phosphorus
INDICATION
Truvada for PrEP (pre-exposure prophylaxis) is indicated to
reduce the risk of sexually acquired HIV-1 in adults and
adolescents (≥35 kg) who are at risk for HIV, when used in
combination with safer sex practices. HIV-negative status must be
confirmed immediately prior to initiation
- If clinical symptoms of acute HIV-1 infection are present and
recent exposures (<1 month) are suspected, delay initiation for
at least 1 month until HIV-negative status is reconfirmed.
Alternatively, confirm HIV-negative status with a test cleared by
FDA to aid in the diagnosis of acute HIV-1 infection
Individuals at risk for sexually acquired HIV-1 may include
those:
- With HIV-1 infected partner(s), or
- Who engage in sexual activity in a high prevalence area or
social network and have additional risk factors, such as:
inconsistent or no condom use, diagnosis of sexually transmitted
infections (STIs), exchange of sex for commodities, use of illicit
drugs or alcohol dependence, incarceration, or sexual partners of
unknown HIV status with any of these risk factors
About Gilead Sciences
Gilead Sciences, Inc. is a research-based biopharmaceutical
company that discovers, develops and commercializes innovative
medicines in areas of unmet medical need. The company strives to
transform and simplify care for people with life-threatening
illnesses around the world. Gilead has operations in more than 35
countries worldwide, with headquarters in Foster City,
California.
For nearly 30 years, Gilead has been a leading innovator in the
field of HIV, driving advances in treatment, prevention, testing
and linkage to care, and cure research. Today, it’s estimated that
more than 12 million people living with HIV globally receive
antiretroviral therapy provided by Gilead or one of the company’s
manufacturing partners.
For more information on Gilead Sciences, please visit the
company’s website at www.gilead.com.
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 FDA and other regulatory agencies may not
approve Descovy for PrEP in the currently anticipated timelines or
at all, and any marketing approvals, if granted, may have
significant limitations on its use. As a result, Descovy for PrEP
may never be successfully commercialized. There is also the
possibility of unfavorable results from additional studies
involving Descovy and Truvada for PrEP. All statements other than
statements of historical fact are statements that could be deemed
forward-looking statements. 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, 2019, 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 Descovy
and Truvada, including BOXED WARNINGS, is available at
www.gilead.com
Descovy, Descovy for PrEP, Truvada, Truvada for
PrEP and Gilead are 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-5 or 1-650-574-3000.
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