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An investigational small molecule, EDP-938, showed promise as a treatment for respiratory syncytial virus (RSV) in a randomized human challenge trial.

At all dosing regimens tested, 5 days of treatment with the oral nonfusion replication inhibitor of RSV proved superior to placebo in lowering viral load and improving clinical symptoms, while showing no "apparent" safety concerns, Alaa Ahmad, PhD, of Enanta Pharmaceuticals in Watertown, Massachusetts, and colleagues reported.

"The results of the plasma pharmacokinetic measures of EDP-938 were generally similar to those observed in the first-in-human study," the team wrote in the . "EDP-938 was rapidly absorbed and had a half-life that supports once- or twice-daily dosing."

In an , Larry Anderson, MD, of Emory University School of Medicine in Atlanta, and Edward Walsh, MD, of the University of Rochester School of Medicine in New York, said the results support further clinical trials but also sounded a note of caution.

"Positive results of treatment in previous challenge studies have not been followed by success in later clinical trials," the duo wrote. "It is likely that the difference in the timing of treatment contributes to the discrepancy between challenge studies and clinical trials. In challenge studies, the drug is given early, whereas in clinical trials of natural RSV infection, the drug is given when viral titers have peaked, since patients generally present for care 3 to 8 days after symptom onset."

"The rapid, anamnestic immune response in adults who had been primed with RSV might outcompete the antiviral effects of a drug in clinical trials but is less likely to do so in challenge studies," added Anderson and Walsh.

Currently, aerosolized ribavirin is the only approved treatment for RSV, Ahmad's group explained, though just for hospitalized children with severe cases involving the lower airway, and the drug's poor safety profile has limited its use. Palivizumab (Synagis) is approved to prevent serious lower-airway RSV infections in high-risk children.

Study Details

The two-part double-blinded phase IIa trial included healthy adults who were exposed to RSV and tested positive at least twice on reverse-transcriptase-quantitative polymerase chain reaction (RT-qPCR). Mean participant age was 23-29 years, more than half were men (48-66%), and the vast majority were white (81-90%). Viral load was the primary endpoint, while secondary endpoints included total symptom score and change in nasal mucus weight.

In part 1, the researchers intranasally inoculated 115 individuals with RSV (Memphis 37b strain) and randomized them 1:1:1 to either EDP-938 once daily (600 mg), EDP-938 twice daily (300 mg, following a 500 mg loading dose), or placebo. In part 2, 63 inoculated participants were randomized 1:1:1 to EDP-938 twice daily (200 mg, following a 400 mg loading dose), EDP-938 once daily (300 mg, after a 600 mg loading dose), or placebo.

The study's primary endpoint was mean RSV viral load area under the curve (AUC) -- expressed as hours × log₁₀ copies per mL on RT-qPCR -- for the intent-to-treat population, which included 86 and 38 individuals who met criteria for RSV infection from the two groups, respectively.

Mean viral load was significantly lower with EDP-938 versus placebo in part 1 (AUC of 204.0 for the once-daily group and 217.7 for the twice-daily group vs 790.2 for placebo; P<0.001 for both). Part 2 showed similar results (AUC of 173.9-196.2 for the EDP-938 groups vs 879 in the placebo group; P<0.001 for both).

Total symptom score was a key secondary endpoint, and involved 10 symptoms recorded in a diary (hours × score). In part 1, the AUC for mean total symptoms score was 124.5 for the once-daily EDP-938 group, 181.8 for the twice-daily group, and 478.8 for the placebo group. Similarly, in part 2, the AUC for mean total symptom score was 89.6-99.3 in the EDP-938 groups versus 432.2 in the placebo group.

"Mean total symptom score decreased more quickly in the EDP-938 groups," the researchers noted. "In both parts of the trial, mucus production was more than 70% lower in each EDP-938 group than in the placebo group."

For safety, adverse events (AEs) occurred at similar rates, 38-55% for the EDP-938 groups and 52-55% for the placebo groups across both parts of the trial. In part 1, AEs more frequent with EDP-938 than placebo included dizziness, diarrhea, dyspepsia, and a decrease in forced expiratory volume. The researchers described most of the events as mild, with one grade 2 dyspepsia in a EDP-938-treated individual. In part 2, nausea and upper respiratory infections were more frequent in the EDP-938 groups, with one grade 2 AE of paraesthesia at the venipuncture site.

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