Gilead to Present New Data From Multiple Liver Disease Research and Development Programs at The International Liver Congress™ 2019FOSTER CITY, Calif.--(BUSINESS WIRE)--Mar 27, 2019--Gilead Sciences, Inc. (Nasdaq: GILD) today announced that data from the company’s research and development programs in nonalcoholic steatohepatitis (NASH), primary sclerosing cholangitis (PSC) and viral hepatitis will be presented at The International Liver Congress™ 2019 in Vienna, Austria from April 10-14, 2019. These data reflect Gilead’s ongoing focus and commitment to advancing research and patient care across the field of liver disease.
“For 20 years, Gilead has been focused scientifically on the treatment of liver diseases and brought innovative medicines and access programs to people around the world,” said John McHutchison, AO, MD, Chief Scientific Officer, Head of Research and Development, Gilead Sciences. “At this year’s International Liver Congress, we are proud to share new data from studies that aim to improve our understanding of challenging liver diseases such as PSC, enable broader NASH diagnosis rates and strive to bring forward new therapies for patients with unmet medical needs in NASH and viral hepatitis.” Advanced Fibrosis due to NASH
Patients with advanced fibrosis due to NASH, defined as bridging fibrosis (F3) or cirrhosis (F4), are at a significantly higher risk of liver-related mortality. Gilead will share data on multiple investigational compounds, noninvasive testing for NASH diagnosis and patient-reported outcomes.
Data being presented at the meeting highlight the potential utility of investigational compounds in development to address this significant medical need.
A combination of the ACC inhibitor GS-0976 and the non-steroidal FXR agonist GS-9674 improves hepatic steatosis and liver stiffness in patients with nonalcoholic steatohepatitis (NASH): a proof-of-concept study (poster #0352)
The addition of fenofibrate to a liver-targeted acetyl CoA carboxylase inhibitor reverses plasma TG increases and positively impacts efficacy (poster #0284)
The diagnosis of advanced fibrosis due to NASH currently requires a liver biopsy, which is an invasive procedure that can lead to serious complications. Data evaluating the use of noninvasive tests for the identification of patients with advanced fibrosis will be presented at the meeting.
Clinical utility and application of noninvasive tests of fibrosis in selection of patients with advanced fibrosis due to NASH in the Phase 2 ATLAS trial (poster #0315)
Impact of age on routinely available noninvasive tests for the discrimination of advanced fibrosis due to NASH in the Phase 3 STELLAR trials of the ASK1 inhibitor selonsertib (poster #0273)
Data regarding patient-reported outcomes from Gilead’s ongoing development program will also be presented.
What are the predictors of impairment of patient-reported outcomes in non-alcoholic steatohepatitis (poster #0151)
Patients with non-alcoholic steatohepatitis (NASH) experience severe impairment of health-related quality of life (HRQL) (poster #0348)
The presence of type 2 diabetes is independently associated with impairment of patient-reported outcomes in patients with non-alcoholic steatohepatitis (poster #0438)
Cilofexor (GS-9674), firsocostat (GS-0976) and selonsertib are investigational compounds and are not approved by the U.S. Food and Drug Administration (FDA) or any other regulatory authority. Their safety and efficacy have not been established. Primary Sclerosing Cholangitis (PSC)
PSC is a rare and chronic condition that causes inflammation and scarring of the bile ducts, which may lead to liver failure. The natural history and progression of the disease in patients are not well understood. Data being presented help inform future clinical development in PSC for which a large unmet need for effective therapy exists.
Validation of histologic and noninvasive measures of fibrosis as surrogate endpoints of disease progression in patients with primary sclerosing cholangitis (PSC) (oral presentation #0012)
Prospective evaluation of serum alkaline phosphatase variability and prognostic utility in primary sclerosing cholangitis using controlled clinical trial data (oral presentation #0016)
Methylation signatures in blood show accelerated epigenetic aging in patients with primary sclerosing cholangitis compared to healthy controls (poster #0024)
Viral Hepatitis Treatment and Cure
Gilead is committed to improving care for people living with chronic hepatitis B virus (HBV) infection and delivering the potential for cure to all chronic hepatitis C virus (HCV) patients. New HBV and HCV data being presented include safety and efficacy findings with switching to Vemlidy ® (tenofovir alafenamide 25mg, TAF) treatment in virologically suppressed HBV patients treated with tenofovir disoproxil fumarate (TDF), and safety and efficacy results with Epclusa ® (sofosbuvir 400 mg/velpatasvir 100 mg) in difficult-to-cure HCV patients. Further evidence of the use of Epclusa and Harvoni ® (ledipasvir 90mg/sofosbuvir 400mg) in a range of patient types and populations in the real-world setting will also be presented.
A Phase 3 study comparing switching from tenofovir disoproxil fumarate to tenofovir alafenamide with continued TDF treatment in virologically-suppressed patients with chronic hepatitis B (CHB): week 48 efficacy and safety results (poster #0183)
Bone and renal safety are improved in chronic HBV patients switched to tenofovir alafenamide (TAF) after either 2 or 3 years of prior tenofovir disoproxil fumarate (TDF) treatment (poster #0158)
High efficacy and improvement in CPT class with sofosbuvir/velpatasvir plus ribavirin for 12 weeks in patients with CPT C decompensated cirrhosis (poster #0138)
Ledipasvir/sofosbuvir for 8, 12, or 24 weeks is safe and effective in patients undergoing dialysis (poster #0144)
Global real-world evidence of sofosbuvir/velpatasvir as a simple, effective regimen for the treatment of chronic hepatitis C patients: Integrated Analysis of 12 clinical practice cohorts (oral presentation #0003)
Finally, as part of Gilead’s HBV cure program, the latest findings on the potential role of investigational GS-9688, will be presented.
In vitro modulation by TLR8 agonist GS-9688 of multiple regulatory cell types in patients with chronic hepatitis B (poster #0132)
EPCLUSA and HARVONI are each indicated in the U.S. for the treatment of chronic HCV infection in patients with no cirrhosis or with compensated cirrhosis: EPCLUSA for adults with genotypes 1-6; and HARVONI for adults with genotypes 1, 4, 5 and 6. EPCLUSA in combination with ribavirin is indicated in the U.S. for the treatment of chronic HCV infection in patients with decompensated cirrhosis. VEMLIDY is indicated for the treatment of chronic HBV infection in adults with compensated liver disease. The US product labels for EPCLUSA, HARVONI, and VEMLIDY each contain a BOXED WARNING: for EPCLUSA and HARVONI, the risk of HBV reactivation in HCV/HBV co-infected patients; and for VEMLIDY, the risk of post-treatment severe acute exacerbation of HBV. See below for U.S. Important Safety Information.
The safety and efficacy of HARVONI in HCV patients undergoing dialysis has not been established.
GS-9688 is an investigational compound and is not approved by the FDA or any other regulatory authority. Its safety and efficacy has not been established.
For more information, including a complete list of abstract titles at the meeting, please visit: [ https://ilc-congress.eu/programme-highlights/ ].
FRI-132
In vitro modulation by TLR8 agonist GS-9688 of multiple
regulatory cell types in patients with chronic hepatitis B
Oliver E Amin1, Emily Colbeck1, Stephane Daffis2,
Divya Pattabiraman2, Colette Sitali3, William Rosenberg4,
Simon Fletcher2, Mala Maini1, Laura J Pallett1. 1UCL, Infection and
Immunity, London, United Kingdom; 2Gilead Sciences, Foster City,
United States; 3UCL, Infection, Immunity and Transplantation, London,
United Kingdom; 4UCL, Infection, Immunity and Transplantation,
London, United Kingdom
Email: [email protected]
Background and aims: HBV-specific T cell responses are characterised
by functional exhaustion and premature deletion.
Immunosuppressive cell types targeting this antiviral T cell response
include granulocytic myeloid-derived suppressor cells (gMDSC),
CD4 + regulatory T cells (Tregs), and regulatory TRAIL + NK cells.
Signalling through different toll-like receptors (TLR) induces selective
cytokine profiles capable of differentially modulating immune cell
subsets. Herewe have tested the impact of a selective small molecule
agonist of TLR8 (GS-9688), currently in Phase 2 trials for the
treatment of chronic HBV infection (CHB), on these three different
regulatory populations and on HBV-specific CD8 + T cells in vitro.
Method: PBMC obtained from a cohort of CHB patients were treated
with 1-500 nM GS-9688 for 2-7 days. Cytokine responses were
measured by luminex assay. Sixteen-colour flowcytometry was used
to analyse changes in the frequency and phenotype of gMDSC
(CD11bhighCD33+HLADR-CD14-CD15+, n = 14 CHB patients), Tregs
(CD4+CD25hiCD127loFoxp3+, n = 8 CHB patients), NK cells (CD3-
CD56+, n = 20 CHB patients) and HBV-specific CD8+ T cells (binding a
panel of HLA-A2/peptide dextramers, n = 12 CHB patients).
Results: In line with previous studies, GS-9688 induced cytokines in
PBMC cultures (e.g. TNF-α, IFN-γ, IL-12p70 and IL-18) with the
potential to modify regulatory cell subsets. Consistent with this
cytokine profile, GS-9688 treatment induced gMDSC to switch to a
more mature and less suppressive phenotype, resulting in a > 50%
reduction in the frequency of this regulatory cell type (p < 0.001).
Similarly, GS-9688 treatment induced a dose-dependent reduction in
the frequency of conventional Tregs (p < 0.05). In contrast, GS-9688
triggered dose-dependent activation of CD56bright and CD56dim NK
cells, and a rapid upregulation of their expression of the death ligand
TRAIL (p < 0.05). Despite this, HBV-specific CD8+ T cell frequencies
remained stable, suggesting they were protected from NK cell TRAILmediated
deletion in the presence of GS-9688.
Conclusion: Overall, these in vitro data suggest that GS-9688 has the
potential to reduce the suppressive activity of regulatory populations
in the liver that collectively limit the antiviral response of HBVspecific
T cells. Further studies will explore how HBV-specific T cells
are protected from deletion by the GS-9688-driven expansion of
TRAIL+ NK cells and whether these changes are recapitulated using
intrahepatic lymphocytes. 作者: StephenW 时间: 2019-3-29 12:53