Background: AL-8176 is a prodrug of the cytidine nucleoside analog, AL-8112, the triphosphate of which is a potent inhibitor of RSV polymerase. AL-8176 is in development as a treatment for RSV infection.
Objective: Determine safety, tolerability of single/multiple ascending doses (SAD, MAD) of AL-8176 and PK of AL-8176, AL-8112 and major inactive uridine metabolite, AL-8144, in HV.
Methods: Randomized, double blind, placebo-controlled study:
Part 1 (SAD): 5 cohorts of 8 HV (6 AL-8176: 2
placebo) received single doses (SD; 40-750mg) of study drug (fasted).
Part 2 (Food effect): After 10-14 day washout, 8 HV received a second SD of AL-8176 (250mg) or placebo (fed).
Part 3 (MAD): 5 cohorts of 12 HV (9 AL-8176: 3 placebo) were to receive two 375mg or 750mg loading doses (LD) on Day 1 followed by 125, 250 or 500mg multiple doses (MD) Q12h for 4 or 13 additional days (fasted/fed).
Results: 101 (40 SAD:61 MAD) male, largely (>95%) Caucasian HV with mean age of 33.5-38.8 years received AL-8176/placebo. No serious adverse events (AEs) or withdrawals due to AEs occurred and all treatment-emergent AEs were mild (N=14) or moderate (abdominal pain, diarrhea, headache, paresthesia; N=4). AEs reported more than once in AL-8176 treated HV were: headache (N=7), and hot flush (N=2). There were no clinically significant changes in laboratory parameters, vital signs, physical examinations or electrocardiograms.
AL-8176 was undetectable in plasma; it was rapidly converted to AL‑8112 (Tmax 15‑30 minutes). The T1/2 of AL-8112 was ~ 63 hours, however AL-8112 concentrations were minimal by 6 hours postdose, indicating rapid, extensive distribution of AL-8112. With increasing AL-8176 doses, AL-8112 and AL-8144 exposures increased linearly but less than dose proportionally. No accumulation of AL‑8112 or AL-8144 was noted following MD of AL-8176; steady‑state Cmin of AL-8112 was achieved after the 2nd dose. Administration of AL-8176 following food lowered AL-8112 Cmax by 50% without affecting the AUC0-24. AL-8112 and AL-8144 were primarily excreted in urine.
Conclusion: AL-8176 was well tolerated and demonstrated predictable PK following single doses up to 750 mg and multiple doses up to 750 mg LD/500 mg MD for up to 13 days.
J. Fry, Alios BioPharma: Employee , Salary
Q. Zhang, Alios BioPharma: Employee , Salary
L. Blatt, Alios BioPharma: Employee , Salary
L. Beigelman, Alios BioPharma: Employee , Salary
J. Symons, Alios BioPharma: Employee , Salary
N. Fauchoux, Biotrial: Research Contractor , Salary
H. Ramos, Biotrial: Employee , Salary
A. Patat, Biotrial: Employee , Salary
S. Chanda, Alios BioPharma: Employee , Salary