Short duration treatment with AL-335 and odalasvir, with or without simeprevir, in treatment naïve patients with hepatitis C infection with or without cirrhosis

Gane, Ed; Stedman, Catherine A.; McClure, Matthew W.; Apelian, David; Westland, Christopher; Vuong, Jennifer; Patel, Meera J.; Kakuda, Thomas N.; Chanda, Sushmita; Blatt, L.M.; Beigelman, Leo; Smith, David B.; Fry, John

doi:10.1016/s0168-8278(17)30429-4

Cited by 11 publications

(10 citation statements)

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“…In 1 patient with late viral relapse, no emerging simeprevir, daclatasvir or sofosbuvir RASs were detected. Consistently, other studies have shown that, in a substantial number of patients who did not achieve SVR after short treatment durations of 4, 6 or 8 weeks with other DAA combination regimens, no emerging RASs were detected at the time of failure . Importantly, retreatment strategies have recently been studied and, in phase 3 trials, retreatment with the triple DAA combination of sofosbuvir, velpatasvir and voxilaprevir for 12 weeks of patients who failed to respond to prior treatment with DAAs was highly effective, leading to SVR12 in 99% (140/142) of noncirrhotic patients .…”

Section: Discussionsupporting

confidence: 57%

“…In a recent phase 2 study, AL‐335 (NS5B inhibitor), odalasvir (NS5A inhibitor) and simeprevir led to a 100% (20/20) SVR12 rate among treatment‐naïve noncirrhotic GT1‐infected patients treated for 6 weeks . These data suggest that 6 weeks of triple DAA treatment can lead to high rates of SVR12 in noncirrhotic patients with HCV GT1a and 1b infection.…”

Section: Discussionmentioning

confidence: 92%

“…With the goal of shortening treatment duration, multidrug regimens comprising 3 and 4 DAAs are also being evaluated. Triple DAA regimens with either AL‐335, odalasvir and simeprevir; sofosbuvir, velpatasvir and voxilaprevir; sofosbuvir, ledipasvir and radalbuvir or vedroprevir; or sofosbuvir and grazoprevir/elbasvir for 6 weeks resulted in SVR12 rates of 80%‐87% in treatment‐naïve HCV GT1‐infected patients with compensated cirrhosis or 87%‐100% in those without cirrhosis . Such high SVR12 rates following a very short treatment duration may be attributable to the more rapid decline in HCV ribonucleic acid (RNA) observed with triple DAA therapy compared with dual DAA therapy .…”

Section: Introductionmentioning

confidence: 99%

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Efficacy and safety of 6 or 8 weeks of simeprevir, daclatasvir, sofosbuvir for HCV genotype 1 infection

Sulkowski

Feld

Lawitz

et al. 2018

Journal of Viral Hepatitis

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The phase 2, open-label ACCORDION (ClinicalTrials.gov: NCT02349048) study investigated the efficacy, safety and pharmacokinetics of a 6- or 8-week regimen of simeprevir, daclatasvir and sofosbuvir in treatment-naïve patients with chronic hepatitis C virus (HCV) genotype (GT) 1 infection and either early-stage fibrosis or compensated cirrhosis. Patients were assigned to treatment groups according to their fibrosis stage. Early-stage fibrosis: simeprevir 150 mg, daclatasvir 60 mg, sofosbuvir 400 mg once daily for 6 weeks; compensated cirrhosis: same regimen for 8 weeks. The primary endpoint was sustained virologic response 12 weeks after the end of treatment (SVR12). Safety, tolerability and pharmacokinetics of simeprevir, daclatasvir and sofosbuvir were investigated. Sixty-eight patients were treated (6-week group: n = 59; 8-week group: n = 9). SVR12 was achieved by 86.4% (51/59) of patients with early-stage fibrosis and by 100% (9/9) of patients with cirrhosis. The main reason for not achieving SVR12 in the 6-week group was viral relapse (11.9%; 7/59). One patient had on-treatment failure due to an early withdrawal (lost to follow-up due to incarceration). One patient with SVR12 in the 6-week group had a late viral relapse at post-treatment week 24. No clinically significant drug-drug interactions were observed. Adverse events were reported in 63.2% of patients (43/68) and were mainly grade 1/2. None of these led to treatment discontinuation. The 3 direct-acting antiviral regimens of simeprevir, daclatasvir and sofosbuvir were safe and well tolerated in treatment-naïve, HCV GT1-infected patients with early-stage fibrosis or compensated cirrhosis.

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Section: Discussionsupporting

confidence: 57%

Section: Discussionmentioning

confidence: 92%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Efficacy and safety of 6 or 8 weeks of simeprevir, daclatasvir, sofosbuvir for HCV genotype 1 infection

Sulkowski

Feld

Lawitz

et al. 2018

Journal of Viral Hepatitis

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“…The data from this study were used to guide the initial dose selection in Phase IIa and Phase IIb studies. The Phase IIa study, AL‐335‐604 (NCT02569710), is an ongoing study assessing the safety, pharmacokinetics, and efficacy of a 2‐ and 3‐DAA regimen comprising AL‐335 in combination with odalasvir with or without simeprevir in HCV‐infected patients . The Phase IIb study, OMEGA‐1 (ClinicalTrials.gov ID: NCT02765490), is evaluating AL‐335, odalasvir, and simeprevir for 6 and 8 weeks' treatment duration in HCV genotype 1‐, 2‐, 4‐, 5‐, and 6‐infected patients without cirrhosis…”

Section: Discussionmentioning

confidence: 99%

“…The Phase IIa study, AL-335-604 (NCT02569710), is an ongoing study assessing the safety, pharmacokinetics, and efficacy of a 2-and 3-DAA regimen comprising AL-335 in combination with odalasvir with or without simeprevir in HCV-infected patients. 22 The Phase IIb study, OMEGA-1 (ClinicalTrials.gov ID: NCT02765490), is evaluating AL-335, odalasvir, and simeprevir for 6 and 8 weeks' treatment duration in HCV genotype 1-, 2-, 4-, 5-, and 6-infected patients without cirrhosis. 23 In conclusion, in this study, combinations of AL-335, odalasvir, and simeprevir were found to be well tolerated in healthy subjects despite the observed higher exposures of all drugs, in particular AL-335.…”

Section: Safetymentioning

confidence: 99%

Pharmacokinetics, safety, and tolerability of the 2‐ and 3‐direct‐acting antiviral combination of AL‐335, odalasvir, and simeprevir in healthy subjects

Kakuda¹,

McClure²,

Westland³

et al. 2018

Pharmacology Res & Perspec

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This Phase I, open‐label, two‐group, fixed‐sequence study evaluated the pharmacokinetics and safety of AL‐335, odalasvir, and simeprevir in healthy subjects. Group 1 (n = 16) received AL‐335 800 mg once daily (QD) (days 1‐3, 11‐13, and 21‐23), simeprevir 150 mg QD (days 4‐23), and odalasvir 150 mg (day 14) followed by 50 mg QD (days 15‐23). Group 2 (n = 16) received the same AL‐335 regimen as in Group 1 plus odalasvir 150 mg (day 4) followed by 50 mg QD (days 5‐23) and simeprevir 150 mg QD (days 14‐23). Blood samples were collected to determine plasma concentrations of AL‐335 (prodrug) and its metabolites, ALS‐022399 (monophosphate precursor) and ALS‐022227 (parent nucleoside), odalasvir, and simeprevir. Thirty‐two subjects were enrolled. Odalasvir and simeprevir given alone, or in combination, increased AL‐335 area under plasma concentration‐time curve over 24 hours (AUC 0‐24 h) 3‐, 4‐, and 7‐ to 8‐fold, respectively; ALS‐022399 AUC 0‐24 h increased 2‐, 2‐, and 3‐fold, respectively. Simeprevir had no effect on ALS‐022227 AUC 0‐24 h, whereas odalasvir with/without simeprevir increased ALS‐022227 AUC 0‐24 h 1.5‐fold. AL‐335 had no effect on odalasvir or simeprevir pharmacokinetics. Odalasvir and simeprevir AUC 0‐24 h increased 1.5‐ to 2‐fold for both drugs when coadministered irrespective of AL‐335 coadministration. Study medications were well tolerated with no serious adverse events. One subject prematurely discontinued study drugs (unrelated event). This study defined the preliminary pharmacokinetic and safety profiles of the combination of AL‐335, odalasvir, and simeprevir in healthy subjects. These data support the further evaluation of this combination for the treatment of chronic hepatitis C virus infection.

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Nucleoside Antiviral Agents for HCV

et al. 2020

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Short duration treatment with AL-335 and odalasvir, with or without simeprevir, in treatment naïve patients with hepatitis C infection with or without cirrhosis

Cited by 11 publications

References 0 publications

Efficacy and safety of 6 or 8 weeks of simeprevir, daclatasvir, sofosbuvir for HCV genotype 1 infection

Efficacy and safety of 6 or 8 weeks of simeprevir, daclatasvir, sofosbuvir for HCV genotype 1 infection

Pharmacokinetics, safety, and tolerability of the 2‐ and 3‐direct‐acting antiviral combination of AL‐335, odalasvir, and simeprevir in healthy subjects

Nucleoside Antiviral Agents for HCV

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