769. Safety, Tolerability and Pharmacokinetics (PK) Following Single and Multiple Ascending Dosing of AL-8176 In Healthy Volunteers (HV)
Session: Poster Abstract Session: Antimicrobial Agents: Novel Agents
Friday, October 9, 2015
Room: Poster Hall
Posters
  • AL-8176_SAD-MAD_ID Week 2015_McClure_Print version_JRD.pdf (757.1 kB)
  • 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.

     

    Fig: Mean PK after single or multiple (Day 5, cohorts 1-4) AL-8176 doses

     

     

    Matthew Mcclure, MD1, Abbie Oey, BS1, John Fry, RN1, Qingling Zhang, PhD1, Lawrence Blatt, PhD1, Leo Beigelman, PhD1, Julian Symons, D.Phil1, Nicolas Fauchoux, MD2, Haydee Ramos, MD, PHD2, Alain Patat, MD2 and Sushmita Chanda, PhD1, (1)Alios BioPharma Inc, South San Francisco, CA, (2)Biotrial, Rennes, France

    Disclosures:

    M. Mcclure, Alios BioPharma: Employee , Salary

    A. Oey, Alios BioPharma: Employee , Salary

    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

    Findings in the abstracts are embargoed until 12:01 a.m. PDT, Wednesday Oct. 7th with the exception of research findings presented at the IDWeek press conferences.