mericitabine (RG7128) / Gilead, Roche - LARVOL DELTA

Interferon-free treatment with a combination of mericitabine and danoprevir/r with or without ribavirin in treatment-naive HCV genotype 1-infected patients (EASL 2012) - Presentation time: 19.04.2012, 09:00-18:00; P2b, N=169; INFORM-SVR (NCT01278134); An SVR-8 rate of 71% was observed among G1b patients receiving 24 weeks of mericitabine and ritonavir-boosted danoprevir plus RBV treatment

P2 data • Hepatitis C Virus

Up to 100% SVR4 rates with ritonavir-boosted danoprevir (DNVr), mericitabine (MCB) and ribavirin (R) ± peginterferon alfa-2a (40KD) (P) in HCV genotype 1-infected partial and null responders: results from the MATTERHORN study (AASLD 2012) - Presentation time: Nov 11, 2012; 5:15 AM - 5:30 PM; P2, N=379; MATTERHORN study; Addition of MCB to DNVr+P/R for 24 wks of treatment results in SVR4 in 100% of G1b and up to 83% of G1a prior P/R partial/null responders

P2 data • Hepatitis C Virus

Resistance to excision determines efficiency of inhibition of hepatitis C virus RNA-dependent RNA polymerase by nucleotide analogs including sofosbuvir. (PubMed, J Biol Chem) - "In contrast, although UMP analogs weremore slowly incorporated, UMP excision was alsoslow and inefficient, and modifications to the 2'Cof the UTP ribose ring further decreased excisionrates to an undetectable level. Taken together, theseresults suggest that the greater clinical effectivenessof the UMP analog sofosbuvir is largely due to itbeing intractable to nucleotide-mediated excisioncompared with similar NAs such as mericitabine."

Journal • Hepatitis C Virus • Immunology • Infectious Disease

Roche pipeline updated (Roche Press Release) - Anticipated NME submission in EU and US for hep C infection in 2017 or later for mericitabine and danoprevir; Anticipated regulatory submission for hep C infection for setrobuvir in 2016.

Anticipated EU regulatory • Anticipated NDA • Anticipated regulatory • Hepatitis C Virus

Roche: Q1 2014 Sales Results (Roche) - Anticipated publication of results for P2b Matterhorn combination study in hep C infection in Q2 2014

Anticipated P2 data • Hepatitis C Virus

A study of RO5024048 in combination with ritonavir-boosted danoprevir with or without copegus (ribavirin) in interferon-naïve patients , and with Copegus in interferon unable and interferon intolerant patients, with chronic hepatitis c genotype 1 (INFORM- (clinicaltrials.gov) - INFORM-SVR; P2, N=200; Recruiting; N=160 → 200

Enrollment • Hepatitis C Virus

Oral combination therapy: Future hepatitis C virus treatment? (J Hepatol) - INFORM-1; P1, N=88; At highest combination doses tested (1000mg RG7128 & 900mg danoprevir twice daily), median change in HCV RNA concentration from baseline to day 14 was -5.1 log(10)IU/ml (IQR-5.6 to -4.7) in treatment-naive pts & -4.9 log(10)IU/ml in previous SOC null responders (-5.2 to -4.5) compared with an increase of 0.1 log(10)IU/ml in placebo group; The combination of RG7128 & danoprevir was well tolerated with no treatment-related serious or severe adverse events, no grade 3 or 4 changes in laboratory parameters, & no safety-related treatment discontinuations

Hepatitis C Virus

The NS5B S282T resistant variant and two novel amino acid substitutions that affect replication capacity were identified in hepatitis C virus infected patients treated with mericitabine and danoprevir (Antimicrob Agents Chemother) - P2, N=89; INFORM-SVR (NCT01278134); Sponsor: Hoffmann-La Roche; "All 69 GT 1a patients who experienced viral breakthrough on treatment or relapsed during follow-up (relapsers) developed NS3 R155K. Among GT 1b patients, substitutions at the danoprevir resistance locus NS3 D168 were observed in 15/20 subjects....The NS5B S282T mericitabine resistant variant was rare and did not persist once drug was discontinued. NS5B Q47H and NS3 S122G are two newly identified substitutions..."

P2 data • Hepatitis C Virus

High rates of SVR24 in G1/4 patients with compensated cirrhosis, treated with a triple regimen of danoprevir/r + PegIFNα-2a/RBV (treatment naive), or with a quad regimen of danoprevir/r + mericitabine + PegIFNα-2a/RBV... (APASL 2014) - Abstract #523; P=NA, N=43; RUSHMORE; "Overall SVR24 was 39% in naives (triple) and 65% in null responders (quad), with best rates observed in G1b patients (88% and 70%, respectively)....Both regimens were well tolerated and the higher DNV exposure had no impact on safety."

Clinical data • Hepatitis C Virus

Oppenheimer Healthcare Conference (Roche) - Anticipated filing for HCV in 2016 / 2017.

Anticipated regulatory • Hepatitis C Virus

Highly efficient infectious cell culture of three HCV genotype 2b strains and sensitivity to lead protease, NS5A, and polymerase inhibitors (Hepatology) - PMID: 23913364; "NS5B inhibitors Sofosbuvir, Mericitabine, and BI207127 had activity against 1a (strain TN), 2a...and the 2b strains, whereas VX-222 and Filibuvir only inhibited 1a. Genotype 2b strains were least sensitive to seven lead protease inhibitors, including MK-5172....NS5A inhibitor Daclatasvir was exceptionally potent, but efficacy was affected by the HCV strain."

Preclinical • Hepatitis C Virus

Investigational nucleoside and nucleotide polymerase inhibitors and their use in treating hepatitis C virus (Expert Opin Investig Drugs) - "Currently, mericitabine has the most robust data but its efficacy appears to be less than optimal. Other drugs such as ALS-2200 (and its diastereomer VX-135) and BMS-986094 are promising but the data in humans are too scanty to draw conclusions about their future role at this current point in time."

Review • Hepatitis C Virus

In vivo emergence of a novel mutant L159F/L320F in the NS5B polymerase confers low-level resistance to the HCV polymerase inhibitors mericitabine and sofosbuvir (J Infect Dis) - P=NA, N=405; PROPEL and JUMP-C; "Among 405 patients treated...virologic breakthrough or nonresponse were not observed; 12 patients experienced a partial response....Introduction of double mutant L159F/L320F into genotype 1a (H77) and 1b (Con-1) replicons, respectively, increased the EC50 for mericitabine by 3.1- and 5.5-fold....The double mutant also decreased susceptibility to sofosbuvir (GS-7977) and GS-938 but not setrobuvir, relative to wild-type."

Clinical data • Hepatitis C Virus

A study of mericitabine in combination with telaprevir and Pegasys/Copegus in patients with chronic hepatitis C (clinicaltrials.gov) - P2, N=120 -> 80; Sponsor: Hoffmann-La Roche; Recruiting -> Active, not recruiting.

Enrollment closed • Hepatitis C Virus

Pharmasset to present at canaccord genuity growth conference (PRNewswire) - Pharmasset, will present at Canaccord Genuity Growth Conference to be held Aug 10 - 11, 2011 at Intercontinental Hotel, Boston, Massachusetts

Anticipated conference call • Hepatitis C Virus

Roche: Late-Stage Pipeline Event (Roche) - Anticipated NME submission in EU and US for HCV in 2016 or later

Anticipated EU regulatory • Anticipated FDA event • Hepatitis C Virus

The Combinational Polymorphisms of ORAI1 Gene Are Associated with Preventive Models of Breast Cancer in the Taiwanese. (PubMed) - "Results showed that the PSO-generated models of 2-SNP (rs12320939-TT/rs12313273-CC), 3-SNP (rs12320939-TT/rs12313273-CC/rs712853-(TT/TC)), 4-SNP (rs12320939-TT/rs12313273-CC/rs7135617-(GG/GT)/rs712853-(TT/TC)), and 5-SNP (rs12320939-TT/rs12313273-CC/rs7135617-(GG/GT)/rs6486795-CC/rs712853-(TT/TC)) displayed low values of odds ratios (0.409-0.425) for breast cancer association. Taken together, these results suggested that our proposed PSO strategy is powerful to identify the combinational SNPs of rs12320939, rs12313273, rs7135617, rs6486795, and rs712853 of ORAI1 gene with a strongly protective association in breast cancer."

Journal • Biosimilar • Breast Cancer • Oncology • Triple Negative Breast Cancer

A study of mericitabine in combination with telaprevir and Pegasys/Copegus in patients with chronic hepatitis C (clinicaltrials.gov) - P2, N=80 -> 120; Sponsor: Hoffmann-La Roche; Active, not recruiting -> Recruiting.

Enrollment change • Enrollment open • Hepatitis C Virus

Half year results 2011 (Roche) - mericitabine (RG7128) / Roche; Anticipated P2b final data PROPEL for HCV 1 and 4 in H2 '11; Anticipated P2b JUMP-C data for HCV 1 & 4 in H2 '11; Anticipated NME submission for HCV in 2013; Anticipated P2b MATTERHORN FPI for HCV in Q2 '11

Anticipated NME submission • Anticipated P2 enrollment initiation • Anticipated P2b data • Hepatitis C Virus • None

A study of mericitabine in combination with boceprevir and Pegasys/Copegus in patients with chronic hepatitis C (clinicaltrials.gov) - P2, N=60; Sponsor: Hoffmann-La Roche; Recruiting; N=100 -> 60; Change: No. of arms 3 -> 2

Clinical protocol • Enrollment change • Hepatitis C Virus

Hepatitis C viral kinetics with the nucleoside polymerase inhibitor mericitabine (RG7128) (AASLD 2011) - Presentation time: Nov 06 5:00 PM - 5:15 PM; P=NA, N=32; The observed slower initial HCV RNA decline likely represents the time needed to accumulate intracellular triphosphates & is consistent with in vitro data; When administered BID, mericitabine reached a high, dose-dependent, final effectiveness in blocking viral production that rapidly dropped upon treatment cessation

Clinical data • Hepatitis C Virus

Understanding the effect of the HCV polymerase inhibitor mericitabine on early viral kinetics in the phase 2 JUMP-C and PROPEL studies (Br J Clin Pharmacol) - P2, N=413; PROPEL (NCT00869661); P2, N=168; JUMP-C (NCT01057667); "Mericitabine-containing triple therapy reduces the impact of IL28B genotype on RVR and cEVR compared with peginterferon alfa-2a/ribavirin dual therapy. IL28B genotype, mericitabine dose and body weight are the most important factors associated with the alpha slope and there is no evidence of a pharmacokinetic drug–drug interaction between mericitabine and ribavirin."

P2 data • Hepatitis C Virus

SVR-12 among G1/4 treatment-naive patients receiving mericitabine in combination with Peg-IFNα-2a/ RBV: Interim analysis from the JUMP-C study (EASL 2012) - Presentation time: 21.04.2012, 09:00-18:00; P2b, N=166; JUMP-C; Pts on mericitabine (MCB) & Peg-IFNα-2a/RBV, 49 (60%) achieved an eRVR compared to 11 (13%) on Peg-IFNα-2a/RBV; SVR-12 rates were higher in the MCB arm compared to the control arm (58% vs. 36%)

P2 data • Hepatitis C Virus

Efficacy and safety of mericitabine (MCB) in combination with Peg-IFNα-2a/RBV in G1/4 treatment naive HCV patients: Final analysis from the PROPEL study (EASL 2012) - Presentation time: 21.04.2012, 09:00-18:00; P2b, N=413; PROPEL; Rates of HCV RNA < 15 IU/mL at weeks 4 and 12 were higher among patients treated with MCB (cEVR up to 87%) but rates of SVR and relapse were generally comparable across all arms; Rates of HCV RNA < 15 IU/mL at weeks 4 and 12 were higher among patients treated with MCB (cEVR up to 87%) but rates of SVR and relapse were generally comparable across all arms

P2 data • Hepatitis C Virus

Mericitabine and ritonavir-boosted danoprevir with or without ribavirin in treatment-naive HCV genotype 1 patients: INFORM-SVR study (Liver Int) - P2, N=132; INFORM-SVR (NCT01278134); Sponsor: Hoffmann-La Roche; "Mericitabine, danoprevir/r plus ribavirin for 24 weeks was safe and well tolerated. However, SVR rates were poor, achieving rates of only 25.0% in G1a and 63.6% in G1b patients."

P2 data • Hepatitis C Virus