Activity of Oral ALS-008176 in a Respiratory Syncytial Virus Challenge Study

 

Conner Mansfield, Mercer University College of Pharmacy

Respiratory Syncytial Virus (RSV) is thought to be the most common cause of lower respiratory tract infection (LRTI) in young children responsible for almost 50% of infant admissions secondary to pneumonia and for $300 to $600 million in infant hospitalization costs. It appears to be a major cause of morbidity and mortality in both young children and the elderly.1

Supportive care is considered to be the only true treatment for RSV infection. It is thought that both RSV intravenous immune globulin (RSV-IVIG) and palivzumab can prevent or attenuate RSV infections in at-risk populations. Palivzumab is considered to be a monoclonal antibody directed at a viral membrane protein responsible for viral fusion with the host cell membrane. It might attenuate infections but does not appear to prevent them.1

ALS-008176 is an orally bioavailable prodrug of ALS-008112. ALS-008112 is a cytidine nucleoside analogue that is thought to be active against RSV. ALS-008112 appears to prevent RSV replication by chain termination.2

Activity of Oral ALS-008176 in a Respiratory Syncytial Virus Challenge Study
Design Randomized, double-blind study, placebo-controlled trial; N= 64
Objective To evaluate proof of concept for the antiviral activity of ALS-008176 in healthy adults infected with a clinical strain of RSV
Study Groups Placebo, ALS-008176 750 mg by mouth once then 500 mg by mouth every 12 hours for nine doses (Group One), ALS-008176 750 mg by mouth once then 150 mg by mouth every 12 hours for nine doses (Group Two), or ALS-008176 375 mg by mouth twice daily for nine doses (Group Three)
Methods Patients were placed into quarantine and inoculated intranasally with 4 log10 plaque-forming-units (log10 PFUe) of the RSV-A Memphis 37b challenge virus. Patients were assessed for RSV infection by qualitative polymerase chain reaction. Patients were randomized to receive either ALS-008176 or placebo at roughly 12 hours after the first detection of RSV infection or on the morning post-inoculation day six if detection of RSV infection had not yet occurred. Nasal-wash samples were collected from patients twice daily on post-inoculation days two – 12 then once daily on post-inoculation days 16 and 28. Nasal-wash samples were assessed for RSV viral load reported in log10 PFUe per mL.
Duration 29 days
Primary Outcome Measure The area under the curve (AUC) for viral load in nasal washes
Baseline Characteristics Intent-to-Treat Infected Population Group One Group Two Group Three Placebo
Mean age – years 22.4 24.7 23.4 24.6
Male sex (%) 10 (71) 12 (63) 9 (82) 31 (71)
Mean viral load–log10 PFUe/mL (± Standard Deviation) 2.1 (1.2) 2.9 (1.3) 2.4 (1.4) 1.6 (1.4)
Results AUC Viral Load–log10 PFUe x hr/mL (± Standard Deviation) Placebo AUC Viral Load–log10 PFUe x hr/mL (± Standard Deviation) p-value
Group One 59.9 (69.5) 500.9 (219.9) p < 0.001
Group Two 73.7 (48.3) 500.9 (219.9) p < 0.001
Group Three 133.4 (118.4) 500.9 (219.9) p < 0.001
Adverse Events Common Adverse Events: epistaxis n = 10 (23%), upper respiratory tract infection n = 3 (7%), and cough n = 2 (5%)
Serious Adverse Events: No serious adverse events were reported.
Percentage that Discontinued due to Adverse Events: No participants were forced to discontinue treatment secondary to adverse events.
Study Author Conclusions As compared with placebo, the administration of ALS-008176 resulted in a reduction of viral load, the AUC for viral load, peak viral load, and duration of viral shedding in the 23 infected participants. These effects were associated with concomitant reductions in the severity of clinical disease.

The development of ALS-008176 is a promising step forward in the treatment of RSV. It appears to have activity against RSV and could become the first effective treatment option for the virus. It will be interesting to see how ALS-008176 performs in future studies.

References

  1. Walsh E and Hall CB. Respiratory Syncytial Virus (RSV). In: Bennett J, ed. Mandell, Douglas, and Bennett’s Principles and Practice of Infectious Diseases. 3rd ed. Philadelphia, PA: Saunders; 2015:358-376.
  2. Devincenzo JP, Mcclure MW, Symons JA, et al. Activity of Oral ALS-008176 in a Respiratory Syncytial Virus Challenge Study. N Engl J Med. 2015;373(21):2048-58.
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