– Data Demonstrate Sofosbuvir-Based Regimens Achieve High Cure
Rates in Hepatitis C Patient Populations with Unmet Need –
– Early Data from Gilead’s Functional Hepatitis B Cure Program
Suggest Activation of Immune Cells Crucial to Viral Clearance –
“Our scientific leadership has helped transform the treatment of
patients with chronic hepatitis C infection and we remain committed to
ensuring effective and well-tolerated treatment options for a broad
range of patient populations.” said John McHutchison , AO, MD, Chief
Scientific Officer, Head of Research and Development, Gilead Sciences .
“For patients with chronic hepatitis B infection, we are intensifying
our efforts to advance research and development toward a functional
cure.”
Further Progress in the Treatment of Hepatitis C
Results from an open-label Phase 2 study demonstrated that treatment
with the once-daily single-tablet regimen of Epclusa for 12 weeks in
patients with genotype 1, 2, 3, 4 or 6 HCV and severe renal impairment
undergoing dialysis resulted in cure rates (SVR12, or undetectable viral
load 12 weeks after completion of therapy) of 95 percent (n=56/59) with
only two patients experiencing virologic failure. The most common
adverse events (AEs) (>10 percent) were headache, fatigue, nausea,
vomiting and insomnia. No patients discontinued therapy due to an
adverse event.
In another open-label Phase 2 study, children aged three to five years
old with genotype 1 or 4 HCV infection received weight-based oral dosing
of ledipasvir/sofosbuvir granules 33.75 mg/150 mg if < 17 kg or 45 mg/
200 mg if ≥ 17 kg) once-daily for 12 weeks. Overall, 97 percent
(n=33/34) of the patients were cured, and none experienced virologic
failure. The most common AEs (>10 percent) were vomiting, cough,
pyrexia, rhinorrhea and streptococcal pharyngitis. One patient
discontinued treatment due to an adverse event of abnormal drug taste.
The use of Epclusa and Harvoni, including granules formulation, in the
aforementioned patient populations is investigational; their safety and
efficacy have not been established. The granule formulation is not
approved. Epclusa and Harvoni are both indicated in the US for the
treatment of chronic HCV infection in patients with no cirrhosis or
compensated cirrhosis: Epclusa for adults with genotypes 1-6; and
Harvoni for patients 12 years and older (or ≥35 kg) with genotypes 1, 4,
5 and 6. The US product labels for Epclusa and Harvoni each contain a
Boxed Warning for the risk of hepatitis B reactivation in HCV/HBV
co-infected patients. See below for US Important Safety Information.
Gilead is presenting data on GS-9688, an investigational, oral selective
toll-like receptor 8 (TLR8) agonist, one of several compounds under
investigation as part of Gilead’s HBV cure program. The data support
continued development of GS-9688 as a potential therapeutic approach for
achieving a functional cure for patients with chronic HBV infection.
In the first-in-human, healthy volunteer safety study, GS-9688 was
well-tolerated at single ascending doses up to 5mg and resulted in
pharmacodynamic activity as demonstrated by the production of the
systemic cytokines IL-1RA and IL-12p40 and by the activation of key
relevant immune cells including natural killer (NK) cells and
mucosal-associated invariant T (MAIT) cells. The most commonly reported
AEs among people receiving doses up to and including 5 mg were nausea
and vomiting. There were no reports of Grade 3 or higher AEs, laboratory
AEs or serious adverse events (SAEs) and no discontinuations or deaths.
In a Phase 1b safety and tolerability study of GS-9688 in HBV
chronically infected patients, dose-dependent activation of the
cytokines IL-12p40 and IL-1RA was demonstrated with once weekly dosing
for up to 4 weeks in viremic and virally-suppressed patients. There were
no reports of SAEs; the most common AEs were headache and nausea. Based
on these data, GS-9688 is currently being evaluated in Phase 2 studies
in patients with chronic hepatitis B.
GS-9688 is an investigational agent and not approved; its safety and
efficacy have not been established.
Presentations on Vemlidy® (tenofovir alafenamide 25mg, TAF)
add further evidence to its established safety and efficacy profile in
adults with chronic HBV and compensated liver disease, including longer
term data on the safety of Vemlidy in virologically suppressed HBV
patients. Through three years of treatment, patients originally
randomized to receive TAF continued to show an improved bone and renal
safety profile compared to treatment with tenofovir disoproxil fumarate
300mg (TDF) with maintained viral suppression. In a separate study in
post-liver transplant patients virally suppressed on TDF-based regimens,
switching to TAF maintained viral suppression in all TAF-treated
patients with improvements in renal function and bone mineral density,
after 48 weeks of treatment.
The use of Vemlidy in post-liver transplant patients is investigational;
its safety and efficacy have not been established. Vemlidy is indicated
in the US for the treatment of chronic HBV infection in adults with
compensated liver disease. The US Prescribing Information for VEMLIDY
contains a Boxed Warning regarding the risk of post treatment severe
acute exacerbation of hepatitis B; see below for Important Safety
Information.
US Important Safety Information About Epclusa
and Harvoni
BOXED WARNING: RISK OF HEPATITIS B VIRUS REACTIVATION IN HCV/HBV
COINFECTED PATIENTS
Test all patients for evidence of current or prior hepatitis B virus
(HBV) infection before initiating treatment with EPCLUSA or HARVONI. HBV
reactivation has been reported in HCV/HBV coinfected patients who were
undergoing or had completed treatment with HCV direct acting antivirals
(DAAs) and were not receiving HBV antiviral therapy. Some cases have
resulted in fulminant hepatitis, hepatic failure, and death. Cases have
been reported in patients who are HBsAg positive, in patients with
serologic evidence of resolved HBV, and also in patients receiving
certain immunosuppressant or chemotherapeutic agents; the risk of HBV
reactivation associated with treatment with HCV DAAs may be increased in
patients taking these other agents. Monitor HCV/HBV coinfected patients
for hepatitis flare or HBV reactivation during HCV treatment and
post-treatment follow-up. Initiate appropriate patient management for
HBV infection as clinically indicated.
Warnings and Precautions
Serious Symptomatic Bradycardia When Coadministered with Amiodarone:
Amiodarone is not recommended for use with EPCLUSA or HARVONI due to the
risk of symptomatic bradycardia, particularly in patients also taking
beta blockers or with underlying cardiac comorbidities and/or with
advanced liver disease. A fatal cardiac arrest was reported in a patient
taking amiodarone who was coadministered a sofosbuvir containing
regimen. In patients without alternative, viable treatment options,
cardiac monitoring is recommended. Patients should seek immediate
medical evaluation if they develop signs or symptoms of bradycardia.
Risk of Reduced Therapeutic Effect Due to Use with P-gp Inducers
and/or Moderate to Potent Inducers of CYP: Rifampin, St. John’s wort
and carbamazepine are not recommended for use with EPCLUSA or with
HARVONI. P-gp inducers may significantly decrease ledipasvir, sofosbuvir
and/or velpatasvir plasma concentrations. Moderate to potent inducers of
CYP2B6, CYP2C8 or CYP3A4 may significantly decrease sofosbuvir and/or
velpatasvir plasma concentrations.
Adverse Reactions
The most common adverse reactions (≥10%, all grades) with EPCLUSA were
headache and fatigue.
The most common adverse reactions (≥10%, all grades) with HARVONI were
fatigue, headache, and asthenia.
Drug Interactions
EPCLUSA: Coadministration is not recommended with topotecan due
to increased concentrations of topotecan; or with proton-pump
inhibitors, oxcarbazepine, phenobarbital, phenytoin, rifabutin,
rifapentine, efavirenz, and tipranavir/ritonavir due to decreased
concentrations of sofosbuvir and/or velpatasvir.
HARVONI: Coadministration is not recommended with oxcarbazepine,
phenobarbital, phenytoin, rifabutin, rifapentine, and
tipranavir/ritonavir due to decreased concentrations of ledipasvir and
sofosbuvir; or with co-formulated
elvitegravir/cobicistat/emtricitabine/tenofovir disoproxil fumarate due
to increased concentrations of tenofovir; or with simeprevir due to
increased concentrations of ledipasvir and simeprevir; or with
rosuvastatin due to increased concentrations of rosuvastatin.
Consult the full Prescribing Information for EPCLUSA and HARVONI for
more information on potentially significant drug interactions, including
clinical comments.
US Important Safety Information About Vemlidy
BOXED WARNING: POST TREATMENT SEVERE ACUTE EXACERBATION OF HEPATITIS B
Discontinuation of anti-hepatitis B therapy, including VEMLIDY, may
result in severe acute exacerbations of hepatitis B. Hepatic function
should be monitored closely with both clinical and laboratory follow-up
for at least several months in patients who discontinue anti-hepatitis B
therapy, including VEMLIDY. If appropriate, resumption of anti-hepatitis
B therapy may be warranted.
Warnings and Precautions
Risk of Development of HIV-1 Resistance in HBV/HIV-1 Coinfected
Patients: Due to this risk, VEMLIDY alone should not be used for the
treatment of HIV-1 infection. Safety and efficacy of VEMLIDY have not
been established in HBV/HIV-1 coinfected patients. HIV antibody testing
should be offered to all HBV-infected patients before initiating therapy
with VEMLIDY, and, if positive, an appropriate antiretroviral
combination regimen that is recommended for HBV/HIV-1 coinfected
patients should be used.
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 VEMLIDY, there have been no
cases of Fanconi syndrome or proximal renal tubulopathy (PRT). Patients
with impaired renal function and/or taking nephrotoxic agents (including
NSAIDs) are at increased risk of renal-related adverse reactions.
Discontinue VEMLIDY in patients who develop clinically significant
decreases in renal function or evidence of Fanconi syndrome. Monitor
renal function in all patients – See Dosage and Administration.
Lactic Acidosis and Severe Hepatomegaly with Steatosis: Fatal
cases have been reported with the use of nucleoside analogs, including
tenofovir DF. Discontinue VEMLIDY 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 reactions (incidence ≥5%; all grades) were headache,
abdominal pain, cough, back pain, fatigue, nausea, arthralgia, diarrhea,
and dyspepsia.
Drug Interactions
Coadministration of VEMLIDY with drugs that reduce renal function or
compete for active tubular secretion may increase concentrations of
tenofovir and the risk of adverse reactions.
Coadministration of VEMLIDY is not recommended with the following:
oxcarbazepine, phenobarbital, phenytoin, rifabutin, rifampin,
rifapentine, or St. John’s wort. Such coadministration is expected to
decrease the concentration of tenofovir alafenamide, reducing the
therapeutic effect of VEMLIDY. Drugs that strongly affect P-glycoprotein
(P-gp) and breast cancer resistance protein (BCRP) activity may lead to
changes in VEMLIDY absorption.
Consult the full prescribing information for VEMLIDY for more
information on potentially significant drug interactions, including
clinical comments.
Dosage and Administration
Dosage: Adults; 1 tablet taken once daily with food.
Renal Impairment, Screening, and Monitoring: VEMLIDY is not
recommended in patients with CrCl <15 mL/min. In all patients, assess
serum creatinine, estimated creatinine clearance, urine glucose, and
urine protein prior to initiating and during treatment, on a clinically
appropriate schedule. In patients with chronic kidney disease, also
assess serum phosphorus.
Hepatic Impairment: Not recommended in patients with
decompensated (Child-Pugh B or C) hepatic impairment.
Testing Prior to Initiation: HIV infection.
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