Treatment with Oral ALS-008176, a Nucleoside Analog, Rapidly Reduces RSV Viral Load and Clinical Disease Severity in a Healthy Volunteer Challenge Study
Background: RSV infection causes substantial morbidity and mortality including severe and often fatal cases in immunocompromized patients. However, no effective therapeutic antiviral exists. We conducted a double-blind, placebo (PLB)-controlled Phase 2a study to evaluate ALS‑008176 in adult volunteers infected with a clinical strain of RSV.
Methods: Subjects were healthy volunteers, 18-45 years, with pre-existing RSV-A specific antibody titres (lowest 25th percentile of the population). After being inoculated with RSV-A Memphis 37b virus on Study Day 0 (D0), subjects were monitored for RSV infection in nasal wash every 12 hours using a qualitative RT-PCR assay. Twelve hours after infection was detected by PCR, or 6 days after inoculation (D6), whichever was first, subjects were randomized to ALS-008176 or PLB and dosed q12 hrs X 5 days. Nasal wash viral load (VL; qPCR), RSV symptom scores, and mucus weight were evaluated multiple times daily through D12, and on D16 and D28. Safety was evaluated through D28. The primary endpoint was the area under the curve (AUC) of RSV VL from prior to 1st dose through D12. Efficacy analyses were conducted on infected subjects (intent to treat-infected (ITT-I) population).
Results: 62 subjects were randomized to PLB or 1 of 3 ALS-008176 dosing regimens (750 mg loading dose (LD)/500 mg maintenance doses (MD), 750 mg LD/150 mg MD, 375 mg Q12). 35 subjects met the criterion for infection (ITT-I population). VL AUC was reduced in all ALS-008176 dosing regimens vs. PLB (p all <0.001), and viral clearance was accelerated (p all <0.05). Symptom Score and Mucus Weight AUC were reduced for all treatment groups vs. PLB. No subject exhibited VL rebound. No clinically significant safety laboratory abnormalities were noted. All adverse events were mild or moderate and generally balanced between active and PLB groups; none were serious or led to discontinuation.
Conclusions: ALS-008176 appeared safe, and demonstrated potent antiviral activity resulting in rapid multi-log10 decline and clearance of RSV RNA, with concomitant improvements in clinical RSV disease severity. ALS 8176 should be evaluated in clinical populations with severe and life-threatening RSV infections.
Alios Biopharma Inc: Consultant, Research grant
Alnylam: Consultant, Research grant
Astra Zeneca: Consultant, Research grant
Biota: Collaborator, Consulting fee
Crucell: Consultant, Consulting fee
Genomics Institute of the Novartis Research Foundation: Consultant, Research grant
Gilead Sciences: Consultant, Consulting fee
Janssen: Consultant, Consulting fee
MedImmune: Consultant, Research grant
Teva: Consultant, Consulting fee
Novartis: Consultant, Consulting fee
M. Mcclure, Alios Biopharma Inc: Employee, Salary
C. Westland, Alios Biopharma Inc: Employee, Salary
S. Chanda, Alios Biopharma Inc: Employee, Salary
R. Lambkin-Williams, Retroscreen Virology: Employee, Salary
P. Smith, Alios Biopharma Inc: Consultant, Consulting fee
L. Harrison, None
J. Symons, Alios Biopharma Inc: Employee, Salary
C. Scaglioni-Weinlich, None
Q. Zhang, Alios Biopharma Inc: Employee, Salary
K. Nieforth, Alios Biopharma Inc: Consultant, Consulting fee
L. Beigelman, Alios Biopharma Inc: Employee, Salary
L. Blatt, Alios Biopharma Inc: Employee, Salary
J. Fry, Alios Biopharma Inc: Employee, Salary