tetano
Editor, Senior Moderator
Antivir Ther. 2018 Jun 21. doi: 10.3851/IMP3244. [Epub ahead of print]
[h=1]Phase I study on safety and pharmacokinetics of a novel influenza endonuclease inhibitor, AL-794 (JNJ-64155806), following single- and multiple-ascending doses in healthy adults.[/h] Kakuda TN[SUP]1[/SUP], Yogaratnam J[SUP]1[/SUP], Rito J[SUP]1[/SUP], Boyce M[SUP]2[/SUP], Mitchell T[SUP]2[/SUP], Gupta K[SUP]1[/SUP], Symons JA[SUP]1[/SUP], Chanda S[SUP]1[/SUP], Van Remoortere P[SUP]3[/SUP], Fry J[SUP]1[/SUP].
[h=3]Author information[/h]
[h=3]Abstract[/h] [h=4]BACKGROUND:[/h] This double-blind, first-in-human phase 1 study evaluated pharmacokinetics, safety and tolerability of AL-794 (prodrug of ALS-033719), a potent endonuclease inhibitor of influenza A and B in healthy volunteers.
[h=4]METHODS:[/h] Healthy adult volunteers were randomized to AL-794 (50-2000 mg single ascending doses, fasting) or placebo (5 cohorts, n=6:2 AL-794: placebo/cohort) in part 1, and AL-794 (50-600 mg multiple ascending doses, twice-daily, fed or fasted) or placebo (3 cohorts, n=8:2 AL-794: placebo/cohort) for 7 days in part 2. In part 3, 8 healthy volunteers from part 1 received 450 mg AL-794 (n=6) or placebo (n=2) following a high-fat meal. All dosing were done with an oral suspension. Blood and urine samples for pharmacokinetics were collected at scheduled times and analyzed for ALS-033719 and ALS-033927 (inactive glucuronide) plasma concentrations using LC-MS/MS.
[h=4]RESULTS:[/h] ALS-033719 plasma concentrations increased dose proportionately up to 150 mg but less proportionately above 150 mg. Steady-state was generally achieved by the third dose. ALS-033719 exposure increased following administration with a standard meal (19%-33%) or high-fat meal (3-3.6-fold). ALS-033927 was the major metabolite observed. Renal elimination was negligible (0.2%). Seventeen AL-794-treated healthy volunteers reported ≥1 treatment-emergent adverse event (TEAE, part 1: n=6, 24%; part 2: n=11, 69%). The most common TEAEs were headache (part 1: n=3; part 2: n=5) and dizziness (part 1: n=2; part 2: n=6).
[h=4]CONCLUSIONS:[/h] AL-794 up to 200 mg twice-daily achieved ALS-033719 exposures which are expected to be efficacious and were generally tolerated. Further studies are planned to characterize safety and antiviral activity.
PMID: 29927386 DOI: 10.3851/IMP3244
[h=1]Phase I study on safety and pharmacokinetics of a novel influenza endonuclease inhibitor, AL-794 (JNJ-64155806), following single- and multiple-ascending doses in healthy adults.[/h] Kakuda TN[SUP]1[/SUP], Yogaratnam J[SUP]1[/SUP], Rito J[SUP]1[/SUP], Boyce M[SUP]2[/SUP], Mitchell T[SUP]2[/SUP], Gupta K[SUP]1[/SUP], Symons JA[SUP]1[/SUP], Chanda S[SUP]1[/SUP], Van Remoortere P[SUP]3[/SUP], Fry J[SUP]1[/SUP].
[h=3]Author information[/h]
[h=3]Abstract[/h] [h=4]BACKGROUND:[/h] This double-blind, first-in-human phase 1 study evaluated pharmacokinetics, safety and tolerability of AL-794 (prodrug of ALS-033719), a potent endonuclease inhibitor of influenza A and B in healthy volunteers.
[h=4]METHODS:[/h] Healthy adult volunteers were randomized to AL-794 (50-2000 mg single ascending doses, fasting) or placebo (5 cohorts, n=6:2 AL-794: placebo/cohort) in part 1, and AL-794 (50-600 mg multiple ascending doses, twice-daily, fed or fasted) or placebo (3 cohorts, n=8:2 AL-794: placebo/cohort) for 7 days in part 2. In part 3, 8 healthy volunteers from part 1 received 450 mg AL-794 (n=6) or placebo (n=2) following a high-fat meal. All dosing were done with an oral suspension. Blood and urine samples for pharmacokinetics were collected at scheduled times and analyzed for ALS-033719 and ALS-033927 (inactive glucuronide) plasma concentrations using LC-MS/MS.
[h=4]RESULTS:[/h] ALS-033719 plasma concentrations increased dose proportionately up to 150 mg but less proportionately above 150 mg. Steady-state was generally achieved by the third dose. ALS-033719 exposure increased following administration with a standard meal (19%-33%) or high-fat meal (3-3.6-fold). ALS-033927 was the major metabolite observed. Renal elimination was negligible (0.2%). Seventeen AL-794-treated healthy volunteers reported ≥1 treatment-emergent adverse event (TEAE, part 1: n=6, 24%; part 2: n=11, 69%). The most common TEAEs were headache (part 1: n=3; part 2: n=5) and dizziness (part 1: n=2; part 2: n=6).
[h=4]CONCLUSIONS:[/h] AL-794 up to 200 mg twice-daily achieved ALS-033719 exposures which are expected to be efficacious and were generally tolerated. Further studies are planned to characterize safety and antiviral activity.
PMID: 29927386 DOI: 10.3851/IMP3244