RSV: Investigational Drug Shows Promise in Challenge Study

Troy Brown, RN

November 23, 2015

An experimental drug, ALS-008176, reduced viral load, hastened viral clearance, and reduced clinical disease severity in healthy adults inoculated with respiratory syncytial virus (RSV) in a randomized, double-blind, placebo-controlled clinical trial.

John P. DeVincenzo, MD, from the University of Tennessee College of Medicine and the Children's Foundation Research Institute at Le Bonheur Children's Hospital, Memphis, Tennessee, and colleagues published their findings in the November 19 issue of the New England Journal of Medicine.

Management of RSV infection is currently limited to supportive care, the authors note. ALS-008176 is an oral nucleoside analogue that was determined to be safe in phase 1 testing. The current study used an established experimental viral challenge model to evaluate proof of concept for the drug's antiviral activity in healthy adults infected with RSV.

"Viral load appears to drive the clinical manifestations of RSV disease," the authors explain. "Higher viral loads have been associated with more severe disease in infants and children, faster rates of RSV clearance are associated with more rapid improvements in hospitalized children, and the onset, peak, and resolution of disease parallel the viral dynamics in adults."

Three Doses Tested

The researchers conducted the study over the course of three separate 28-day periods. During each period, participants were confined to a specialized quarantine unit for 14 days, beginning 2 days before inoculation with the RSV virus and ending 12 days after inoculation (study days, −2 to 12).

The researchers inoculated participants intranasally with the RSV-A Memphis 37b challenge virus on study day 0. They measured RSV load in nasal washings of the participants twice daily with a qualitative reverse-transcriptase polymerase chain reaction assay from day 2 until approximately 12 hours after qualitative RSV detection or on the morning of day 6. At that time, the researchers randomly assigned 64 participants to receive ALS-008176 in one of three dosing regimens or placebo orally every 12 hours over the course of 5 days, for a total of 10 doses. (Two participants did not receive a single dose of the study drug and were not included in the analysis.)

The three dosing regimens for ALS-008176 were a single loading dose of 750 mg followed by nine maintenance doses of 500 mg (group 1; n = 14), a single loading dose of 750 mg followed by nine maintenance doses of 150 mg (group 2; n = 19), and 10 doses of 375 mg (group 3; n = 11). There were 18 participants in the placebo group.

The researchers assessed patients for symptoms of RSV infection three times per day while they were confined, and again on study day 16. They tested nasal washings for RSV on days 16 and 28 and measured the net weight of mucus within facial tissues every 24 hours.

A total of 35 participants met the definition of RSV infection: eight in group 1, seven in group 2, eight in group 3, and 12 in the placebo group.

The AUC for viral load, which was the study's primary endpoint, was significantly reduced (P ≤ .001) in the infected population for each ALS-008176 dosing group compared with placebo (59.9, 73.7, 133.4, and 500.9 log10 plaque-forming unit equivalents × hours per milliliter in group 1, group 2, group 3, and the placebo group, respectively).

The reductions of the AUC for viral load relative to placebo were 88.0% in group 1, 85.3% in group 2, and 73.4% in group 3.

The mean time to nondetectability of RSV RNA ranged from 1.3 to 2.3 days for the ALS-008176 groups compared with 7.2 days for the placebo group (P < .001 for all).

Mean peak viral loads were significantly lower for the groups that received ALS-008176 compared with the placebo group (P ≤ .001 for all).

In addition, the AUC for the RSV symptom score was significantly lower in the ALS-008176 treatment groups compared with placebo (P ≤ .05 for all comparisons); symptom scores and mucus weights in the ALS-008176 groups fell along with the reduction in viral load.

"The reason for the antiviral effect probably reflects the mechanism of action of ALS-008176, which inhibits RSV replication within cells already infected in addition to protecting uninfected host respiratory epithelial cells," the researchers write. "Other RSV antiviral drugs (e.g., monoclonal antibodies and small-molecule fusion inhibitors) prevent the infection of uninfected cells by blocking cellular entry of the virus, but these drugs do not inhibit viral replication within cells that have already been infected."

Not Only a Children's Disease

RSV is a disease not only seen in infants, Andrew Pavia, MD, Infectious Diseases Society of America spokesperson and chief, Division of Pediatric Infectious Diseases at the University of Utah in Salt Lake City, told Medscape Medical News. Although it causes about 20% of all pediatric hospitalizations during the winter season, "it mostly affects healthy children, and most of them will recover."

"It also is a very important disease among adults...about 4% of all pneumonia resulting in hospitalization in adults over 65 [years] is due to RSV," Dr Pavia said. Another study found that 10% of pneumonia in people older than 65 years is caused by RSV, he added.

"When RSV infects somebody who has a very compromised immune system, it can be's particularly important in the transplant population," Dr Pavia explained. "I think [ALS-008176 and another experimental agent, GS-5806,] are going to have a role in adults even before we prove that they're safe and effective in kids."

Although ALS-008176 and GS-5806 have been shown to be effective in healthy volunteers, their safety still needs to be studied. "[T]he next step is going to be to show that they're effective in sicker patients with natural disease who really need it," Dr Pavia said.

"It will be a longer road to demonstrate that these drugs are safe and effective for children, because the age group that we need to use them in is infants under 2. We really need to understand optimal doses, and have a pretty high bar for safety. I think we are several years away from being able to use them in the clinic," Dr Pavia concluded.

Dr DeVincenzo reports receiving grant and other support from Alios Biopharma during the conduct of the study and financial support from Alnylam Pharmaceuticals, MedImmune/AstraZeneca, Microdose Therapeutx, Teva Pharmaceuticals, Janssen Pharma, ADMA Biologics, and Gilead Sciences outside the submitted work. One coauthor reports receiving personal fees and other support from Alios BioPharma outside the submitted work and a pending patent related to substituted nucleosides, nucleotide, and analogs thereof. Eight coauthors report receiving support from Alios BioPharma outside the submitted work. Another coauthor reports receiving personal fees and other support from Alios BioPharma outside the submitted work and a pending patent related to a method of testing paramyxoviruses. Another coauthor reports receiving other support from Alios BioPharma during the conduct of the study and personal fees from Retroscreen Virology outside the submitted work. Another coauthor reports a pending patent related to substituted nucleosides, nucleotide, and analogs thereof. Another coauthor reports a pending patent related to a method of testing paramyxoviruses. Dr Pavia has disclosed no relevant financial relationships.

N Engl J Med. 2015;373:2048-2058. Abstract


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