radalbuvir (GS-9669) / Gilead - LARVOL DELTA

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 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

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

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