Gilead Submits Supplemental New Drug Application to U.S. Food and Drug Administration for Once-Daily Descovy for HIV Pre-Exposure Prophylaxis
Business Wire 5-Apr-2019 8:30 AM
- Filing Supported by Data Demonstrating Non-inferiority Compared
to Truvada® Coupled with Bone and Renal
Safety Advantages in People at Risk of Sexually Acquired HIV Infection -
Gilead Sciences, Inc. (NASDAQ:GILD) announced today that the company
has submitted a supplemental New Drug Application (sNDA) to the U.S.
Food and Drug Administration (FDA) for Descovy® (emtricitabine
200 mg and tenofovir alafenamide 25 mg tablets) for pre-exposure
prophylaxis (PrEP) to reduce the risk of sexually acquired HIV-1
infection among individuals who are HIV-negative and at risk for HIV. A
Priority Review voucher was submitted with the filing, leading to an
anticipated review time of six months.
The filing is based on the results of the Phase 3 DISCOVER trial which
evaluated the safety and efficacy of Descovy compared to Truvada in men
and transgender women who have sex with men at high-risk for sexually
acquired HIV infection. Truvada® (emtricitabine 200 mg and
tenofovir disoproxil fumarate 300 mg tablets) for PrEP is currently the
only FDA approved product indicated to reduce the risk of sexually
acquired HIV-1 in individuals (=35 kg) who are HIV-negative and at risk
for HIV.
Results from the DISCOVER trial, presented at the 2019 Conference on
Retroviruses and Opportunistic Infections, demonstrated that Descovy
achieved non-inferiority to Truvada in study participants who were at
substantial and sustained risk of HIV acquisition. Additionally,
statistically significant improvements in renal and bone laboratory
parameters were observed for participants receiving Descovy versus those
receiving Truvada.
"Data have shown that when used in combination with other agents for HIV
treatment, Descovy offers high efficacy and additional benefits with
respect to renal and bone safety compared with Truvada. Now, the results
from the DISCOVER trial suggest that Descovy may offer those same
benefits for HIV prevention, which are important considerations for the
potential long-term use of PrEP," said John McHutchison, AO, MD, Chief
Scientific Officer and Head of Research and Development, Gilead
Sciences. "We look forward to working with the FDA to help evaluate
bringing this option to people at risk of acquiring HIV infection."
In the United States, Descovy is approved in combination with other
antiretroviral agents for the treatment of HIV infection in patients
weighing =25 kg and is not indicated for PrEP. Truvada is indicated in
combination with safer sex practices for HIV PrEP to reduce the risk of
sexually acquired HIV in at-risk individuals who are HIV-negative and
weigh =35 kg. Descovy and Truvada each have a Boxed Warning in their
respective product labels regarding the risk of post-treatment acute
exacerbation of hepatitis B; the Truvada label also carries a Boxed
Warning for the risk of drug resistance with PrEP in undiagnosed early
HIV infection. See below for Important Safety Information and complete
Indications.
"Studies, including DISCOVER, have shown that adherence to a once-daily
PrEP regimen can decrease the risk of HIV acquisition," said Edwin
DeJesus, MD, FACP, FIDSA, Medical Director, Orlando Immunology Center.
"If approved, Descovy may help equip health care providers with an
additional preventive option thereby potentially expanding the impact of
PrEP."
Among DISCOVER trial participants, Descovy and Truvada were well
tolerated and had low discontinuation rates due to adverse events of 1.3
percent and 1.8 percent, respectively. The most common (=5 percent in
the Descovy group) drug-related adverse event was diarrhea.
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 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 coadminstered 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 11.5
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. 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, 2018, 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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