Interest in oral antivirals has surged in recent weeks. Merck (NYSE:MRK) announced on October 1 that the investigational antiviral molnupiravir appeared to halve the risk of hospitalization from COVID-19.

Roche (SWX:ROG) and Atea (NSDQ:AVIR) are having less luck with the oral, direct-acting antiviral drug candidate AT-527.

The two companies announced that the Phase 2 MOONSONG trial failed to meet its primary endpoint related to reducing the level of SARS-CoV-2 in patients with mild-to-moderate COVID-19 relative to placebo.

The drug appeared to be more effective in high-risk patients with underlying health conditions.

Roche and Atea are mulling whether they can modify the international Phase 3 MORNINGSKY study to increase the risk of achieving a statistically significant benefit. The companies expect data from that trial in the second half of 2022.

Both companies saw their stock price decline in the aftermath of the announcement. AVIR shares fell 62.5% to $15.15 apiece in mid-day trading. Conversely, Roche’s share price on the Swiss Stock Exchange only dipped 1.7% to 391.80 Swiss francs.

Atea noted that several factors may have influenced the results of the MOONSONG data, including the emergence of new SARS-CoV-2 variants and prior vaccination of some study participants.

“It’s become abundantly clear that COVID variants are creating new challenges for treatment and prevention,” said Dr. Janet Hammond, Atea’s chief development officer, in a call with analysts. “These variants can also make the evaluation of clinical trial results more challenging because of differences in the way the respective variants act, and how patients respond to such variants.”

The receipt of one or more COVID-19 vaccine doses likely also affected the MOONSONG trial. “Vaccinated patients tend to do pretty well” when exposed to SARS-CoV-2, Hammond said. “It’s really the high-risk patients where one is going to have the greatest likelihood of seeing an impact, clinically, and probably also from a virokinetic perspective.”

Trial participants who obtained one or two vaccine doses resulted in “background noise,” Hammond said. “I think, moving forward, one of the things that one would want to do would be to eliminate enrolling patients who have been vaccinated as we move forward with the study.”

“The big take-home” message is that high-risk patients appear to benefit most from the drug, Hammond said.