radalbuvir (GS-9669) / Gilead - LARVOL DELTA

Integrating bioinformatics, machine learning and molecular biology to elucidate the anti-allergic mechanisms of ginkgo biloba leaves. (PubMed, Comput Biol Chem) - "Initially, DEGs and WGCNA analysis were employed to preliminarily identify candidate genes associated with IgE stimulation in GSE96696 dataset...Building upon these findings, molecular biology experiments, molecular docking, and molecular dynamics simulations demonstrated that GBL flavonoids, including quercetin, amentoflavone, ginkgetin, and bilobetin, significantly inhibited the release of cytokines, blocked calcium ion influx, and suppressed degranulation potentially by targeting RELA and AKT1. Collectively, our findings not only identify key genes for IgE-mediated response but also provide preliminary mechanistic insights into GBL."

Journal • Allergy • Asthma • Atopic Dermatitis • Dermatitis • Dermatology • Food Hypersensitivity • Immunology • Pulmonary Disease • Respiratory Diseases • CDKN1A • CSF2 • EGR1 • IL13 • IL4 • NFKBIA • RELA • TNFAIP3

Insight into the drug resistance mechanisms of GS-9669 caused by mutations of HCV NS5B polymerase via molecular simulation. (PubMed, Comput Struct Biotechnol J) - "Although the recognition methods and binding pathways are distinct, the binding processes of GS-9669 with the WT and mutant NS5B polymerases are basically controlled thermodynamically. This study clearly reveals the resistance mechanisms of GS-9669 caused by M423T/I/V, L419M, R422K, and I482L mutations of HCV NS5B polymerase and provides some valuable clues for further optimization and design of novel NS5B inhibitors."

Journal • Hepatitis C • Hepatology • Infectious Disease • Inflammation

Combination therapy for chronic hepatitis C infection (clinicaltrials.gov) - P2, N=200; Recruiting; New P2 trial.

New P2 trial • Hepatitis C Virus

Annual Shareholders Meeting 2012 (Gilead) - Anticipated FDA approval in H1 2014; Anticipated composition of matter patent expiry in 2029; Anticipated completion of P3 trials for HCV in Q1/Q2 2013; Anticipated NDA submission in H1 2013; Anticipated initiation of P2 combination trial with GS-5885 + RBV in GT-1 HCV null responders in Q2 2012; Anticipated initiation of P2 combination trial with GS-9669 + RBV in GT-1 HCV null responders in Q2 2012; Anticipated initiation of P3 trial in GT-1 HCV patients in H2 2012

Anticipated FDA approval • Anticipated NDA submission • Anticipated P2 trial initiation • Anticipated P3 trial completion • Anticipated P3 trial initiation • Anticipated patent expiry • Hepatitis C Virus

Sofosbuvir Containing Regimens for the Treatment of Chronic HCV Infection in Subjects With Chronic Genotype 1, 2, 3, or 6 HCV Infection (clinicaltrials.gov) - P2; N=362; Completed; Sponsor: Gilead Sciences; Active, not recruiting -> Completed

Trial completion • Biosimilar • Fibrosis • Hepatitis C Virus • Immunology • Inflammation

Pill burden & treatment length reduce adherence to IFN-free hepatitis C therapy in an urban cohort (CROI 2014) - Abstract #667; P2, N=60; SYNERGY (NCT01805882); "Adherence to short courses of DAA therapy with 1-3 pills once a day was excellent in an urban population with multiple risk factors for non-adherence. Increased pill burden and duration of treatment decreased adherence."

P2 data • Hepatitis C Virus

Efficacy of nucleotide polymerase inhibitor sofosbuvir plus the NS5A inhibitor ledipasvir or the NS5B non-nucleoside inhibitor GS-9669 against HCV genotype 1 infection (Gastroenterology) - P2, N=113; ELECTRON (NCT01260350); Sponsor: Gilead; "SVR12 was achieved by 25/25 (100%) of treatment-naïve patients receiving sofosbuvir, ledipasvir, and ribavirin and 23/25 (92%) of those receiving sofosbuvir, GS-9669, and ribavirin....The combination of sofosbuvir and a second direct-acting antiviral agent is highly effective in treatment-naïve patients with HCV genotype 1 infection and in patients that did not respond to previous treatment."

P2 data • Hepatitis C Virus

[Late breaking abstract] Combination oral, hepatitis C antiviral therapy for 6 or 12 weeks: Final results of the SYNERGY trial (CROI 2014) - Abstract #27LB; P2, N=60; SYNERGY (NCT01805882); "The end of treatment response (HCV RNA <LLOQ) was 100%, 75% and 95% of subjects in Arms A, B and C respectively using a more sensitive HCV assay with lower limit of quantification of 12 IU/mL (Fig 1). Using an HCV RNA assay with a lower limit of quantification of <43 IU/mL 100% of patients on all arms were suppressed at EOT. 100%, 90% and 95% of patients in Arm A, B and C respectively achieved SVR12." 

P2 data • Hepatitis C Virus

High rates of SVR in patients with genotype 1 HCV infection and cirrhosis after treatment with ledipasvir/sofosbuvir+ribavirin or ledipasvir/sofosbuvir+GS-9669 for 8 weeks (AASLD 2014) - Presentation time: Tuesday, November 11, 2014; 8:00 AM - 12:00 PM; Abstract #1948; P2, N=100; NCT01984294; Sponsor: Gilead; "Ledipasvir/sofosbuvir together with RBV or GS-9669 was effective in treating HCV. Overall 87% of patients achieved SVR12. Coadministration of GS-9669 did not appear to provide additional efficacy compared to RBV. To shorten therapy further or achieve higher rates of SVR a more potent agent or one with a complimentary mechanism of action may be required. All regimens were safe and well tolerated."

P2 data • Hepatitis C Virus

Predicting response to all-oral directly acting antiviral therapy for hepatitis C using results of Roche and Abbott HCV viral load assays (APASL 2014) - Abstract #865; P2, N=60; SYNERGY (NCT01805882); "Patients who had HCV VL<LOQ at week 4 were likely to achieve SVR....This was similarly true at EOT and for patients who had HCV VL<LOD at both time points....The presence of quantifiable or detectable virus at week 4 and EOT is not predictive of viral relapse in patients treated on these regimens of potent directly acting antivirals."

P2 data • Hepatitis C Virus

Once daily sofosbuvir/ledipasvir fixed dose combination with or without RBV: The ELECTRON trials (APASL 2014) - Abstract #732; P2, N=95; ELECTRON (NCT01260350); Sponsor: Gilead; "In patients with advanced fibrosis or cirrhosis, treatment for 12 weeks with a SOF/LDV based regimen, resulted in high SVR rates which were enhanced by either RBV or GS-9669. In treatment-naïve GT-1 patients without cirrhosis, reduction in duration from 12 to 6 weeks increased the rate of relapse."

P2 data • Hepatitis C Virus

Resistance analyses using deep and population sequencing after 3 day monotherapy with GS-9669, a novel non-nucleoside NS5B inhibitor in genotype 1 HCV patients (EASL 2013) - Presentation time: 27.04.2013, 09:00-18:00; Abstract 1193; P1, N=70; NCT01431898; Sponsor: Gilead; “Phenotypic analysis demonstrated that viral isolates with multiple RAMs had reduced susceptibility to GS 9669 and VX-222, but wild-type susceptibility to other classes of HCV inhibitors including sofosbuvir (NI), GS-9451 (PI), GS-5885 (NS5A) and ribavirin”

P1 data • Hepatitis C Virus

Resistance analysis of HCV genotype 1 infected patients treated with sofosbuvir in combination with ledipasvir or the NS5b nonnucleoside inhibitor GS-9669: The ELECTRON study (EASL 2014) - Presentation time: 12.04.2014, 09:00-18:00; Abstract #P1242; P2, N=78; ELECTRON (NCT01260350); Sponsor: Gilead; "The presence of baseline NS5A RAVs did not preclude patients from achieving SVR12 when treatment included the combination of SOF and LDV (9/10 had SVR12).  NS5A RAVs, but not the NS5B SOF RAV S282T, were detected in ~55% of relapse subjects."

P2 data • Hepatitis C Virus

The paradox of highly effective sofosbuvir-based combination therapy despite slow viral decline: can we still rely on viral kinetics? (PubMed, Sci Rep) - "High sustained virologic response (SVR) rates have been observed after 6 weeks of anti-HCV treatment using sofosbuvir, ledipasvir and a non-nucleoside polymerase-inhibitor (GS-9669) or a protease-inhibitor (GS-9451) and after 12 weeks with sofosbuvir + ledipasvir. In conclusion, the rapid cure rate achieved with these combinations is largely disconnected from viral loads measured during treatment. A model assuming that rapid cure is due to a drug effect of generating non-infectious virus could be a basis for future response guided therapy."

Combination therapy • Journal