AL-335, a Once-Daily Pangenotypic Nucleotide HCV Polymerase Inhibitor, Demonstrates Potent Antiviral Activity over 7 Days in Treatment-Naïve Genotype 1-4 Patients

Berliba, Elina; Tsertsvadze, Tengiz; Ghicavii, N.; Guyader, D.; Kakabadze, Tea; Westland, Christopher; Chanda, Sushmita; Patat, Alain; Zhang, Q.; Smith, David A.; Yogaratnam, Jeysen; McClure, M O; Beigelman, Leo; Blatt, L.M.; Fry, John

doi:10.1016/s0168-8278(16)00641-3

Cited by 5 publications

(8 citation statements)

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“…ALS‐022227 exposures observed in this study at 400 mg QD (cohort 1) in combination with odalasvir/simeprevir were comparable to the same dose under monotherapy despite higher AL‐335 exposures. Therefore, the AL‐335 dose was increased to a dose previously found to be highly efficacious when given as monotherapy (800 mg QD) in subsequent treatment groups to maximize antiviral efficacy …”

Section: Discussionmentioning

confidence: 99%

“…The initial patient population (treatment‐naïve, GT1‐infected subjects without cirrhosis) and treatment regimen (AL‐335 400 mg once‐daily [QD] + odalasvir 50 mg QD + simeprevir 100 mg QD for 8 weeks) to be evaluated in cohort 1 were predefined based on the results from study AL‐335‐602 in healthy volunteers, available pharmacodynamic data from the AL‐335 monotherapy study AL‐335‐601 (NCT02339207), the phase IIa odalasvir/sofosbuvir study (ACH102‐017), and simeprevir phase II/III studies (NCT00882908; NCT01567735) . Populations and regimens to be evaluated in subsequent cohorts were determined based on emerging data.…”

Section: Methodsmentioning

confidence: 99%

“…AL‐335 is a pro‐drug of a uridine‐based nucleoside polymerase (NS5B) inhibitor that has potent antiviral activity against HCV GT1‐GT6. In a prior monotherapy study in healthy volunteers, AL‐335 demonstrated potent antiviral activity against HCV GT1‐GT4 and was well tolerated, with no identified safety signals …”

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confidence: 99%

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Short‐Duration AL‐335, Odalasvir, With or Without Simeprevir, in Patients With HCV GT1 or 3 Infection Without Cirrhosis

et al. 2018

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This open‐label, phase IIa study assessed the safety, pharmacokinetics, and efficacy of direct‐acting antiviral agent (DAA) regimens in patients with chronic hepatitis C virus (HCV) infection. Multiple 6‐12‐week oral regimens of 400‐800 mg once daily (QD) AL‐335 + 50 mg QD/every other day odalasvir ± 75‐150 mg QD simeprevir were evaluated in treatment‐naïve, HCV genotype (GT)1/3‐infected patients without cirrhosis. Safety/pharmacokinetic parameters, HCV‐RNA, and sequencing data were assessed. Treatment regimens for later study cohorts were adjusted based on emerging data. In total, 112 patients were enrolled. Three serious treatment‐emergent adverse events occurred, one of which (a Mobitz type 1 second‐degree atrioventricular block [Wenckebach]) was possibly related to high odalasvir exposure and resulted in premature discontinuation of study drugs. No other clinically significant safety findings were identified. GT1‐infected patients receiving 3‐DAA for 6‐8 weeks achieved 100% sustained virologic response 12 weeks and 24 weeks after the end of treatment (sustained virologic response [SVR12/24]). GT1‐infected patients receiving 2‐DAA or GT3‐infected patients receiving 3‐DAA had SVR12/24 less than 90%, whether treated for 8 weeks or 12 weeks. Virologic failure was associated with the emergence of generally persistent NS5A and/or transient NS5B resistance‐associated substitutions in most patients. Pharmacokinetic characteristics of the three drugs were also elucidated. Conclusions: In treatment‐naïve subjects without cirrhosis, AL‐335 + odalasvir + simeprevir for 6‐8 weeks was generally safe and highly efficacious against HCV GT1. However, inadequate efficacy was observed for the 2‐DAA regimen in GT1‐infected subjects and the 3‐DAA regimen in GT3‐infected subjects.

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Section: Discussionmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

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Short‐Duration AL‐335, Odalasvir, With or Without Simeprevir, in Patients With HCV GT1 or 3 Infection Without Cirrhosis

et al. 2018

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“…Subjects in Group 2 received odalasvir 150 mg (loading dose) on day 4, odalasvir 50 mg QD on days 5‐23, simeprevir 150 mg QD on days 14‐23, and AL‐335 800 mg QD on days 1‐3, 11‐13, and 21‐23. The doses chosen for evaluation in this study were either the highest approved dose (simeprevir) or doses found to have substantial antiviral effects in prior studies (AL‐335 and odalasvir) . For odalasvir, a loading dose was utilized to shorten the time to reach steady‐state.…”

Section: Methodsmentioning

confidence: 99%

“…AL‐335 and its metabolites do not interact with host polymerases, including the mitochondrial RNA polymerase. Dephosphorylation of ALS‐022235 yields the parent nucleoside ALS‐022227 . Both AL‐335 and its metabolites have low inhibition potential for CYPs 1A2, 2B6, 2C8, 2C9, 2C19, 2D6, and 3A4, and are therefore not expected to interact with drugs that are metabolized by the CYP enzymes.…”

Section: Introductionmentioning

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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AL-335, a Once-Daily Pangenotypic Nucleotide HCV Polymerase Inhibitor, Demonstrates Potent Antiviral Activity over 7 Days in Treatment-Naïve Genotype 1-4 Patients

Cited by 5 publications

References 0 publications

Short‐Duration AL‐335, Odalasvir, With or Without Simeprevir, in Patients With HCV GT1 or 3 Infection Without Cirrhosis

Short‐Duration AL‐335, Odalasvir, With or Without Simeprevir, in Patients With HCV GT1 or 3 Infection Without Cirrhosis

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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