FDA clears ensitrelvir to prevent COVID-19 after household exposure; NEJM trial showed 2.9% vs 9.0% infection

The FDA on June 1 approved Shionogi’s oral antiviral ensitrelvir (Xocova) for post-exposure prophylaxis of COVID-19 in adults and adolescents 12 and older who have had household contact with an infected person, the company said. Shionogi describes it as the first and only oral option cleared in the United States to help prevent symptomatic COVID-19 after exposure, rather than treat it.

The clearance rests on SCORPIO-PEP, a Phase 3 randomized, double-blind, placebo-controlled trial sponsored by Shionogi and registered as NCT05897541. Unlike many approvals announced ahead of publication, the full dataset was already in the public record: the results appeared in the New England Journal of Medicine on May 14, 2026, weeks before the FDA decision.

What the trial reported

In the modified intention-to-treat population — the 2,041 household contacts who tested negative for SARS-CoV-2 at baseline and received at least one dose (ensitrelvir n=1,030, placebo n=1,011) — the incidence of COVID-19 by day 10 was 2.9% on ensitrelvir versus 9.0% on placebo (risk ratio 0.33; 95% CI 0.22 to 0.49; P<0.001), according to the NEJM paper. That was the prespecified primary endpoint, defined as a central-laboratory-confirmed positive RT-PCR plus at least one of 14 prespecified COVID-19 symptoms lasting at least 48 hours.

The 67% figure Shionogi leads with is the relative risk reduction (1 minus the 0.33 risk ratio). In absolute terms, the difference is about 6.1 percentage points — roughly 16 household contacts treated to prevent one case of symptomatic COVID-19 over the 10-day window.

The headline is a 67% relative reduction. The underlying numbers — 2.9% versus 9.0%, a number-needed-to-treat near 16 — are now public in NEJM, so readers can size the benefit for themselves.

The dosing regimen runs five days: a 375 mg loading dose on day one, followed by 125 mg on days two through five. On safety, the NEJM authors reported adverse events in 15.1% of the ensitrelvir group and 15.5% of placebo (serious adverse events 0.2% in each group), with no COVID-19-related hospitalizations or deaths in either arm. Those rates come from the larger safety population (ensitrelvir n=1,190, placebo n=1,187), not the modified intention-to-treat efficacy population.

How it is meant to be used — and who was not studied

This is a prescription-only, post-exposure regimen, not something to self-initiate or stockpile. In the trial, a contact could receive ensitrelvir only after a confirmed symptomatic index case in the household and a baseline-negative SARS-CoV-2 test in the contact, with randomization within 72 hours of symptom onset in the index case. Both gates — a documented infected index case and a negative test in the person being treated — are built into the regimen as studied; the dosing schedule above should not be read as a course anyone can start on their own.

Ensitrelvir is also a strong CYP3A inhibitor and carries clinically important drug-drug interactions, so real-world use requires a clinician to screen a contact’s full medication list before prescribing. SCORPIO-PEP itself excluded anyone who had used a strong CYP3A inducer or a St. John’s wort product within 14 days before enrollment, underscoring that interaction screening is part of safe use rather than an afterthought.

Several populations relevant to safe use were excluded from the pivotal trial, so the NEJM efficacy and safety data do not speak to them. SCORPIO-PEP excluded people with severe renal impairment (creatinine clearance below 30 mL/min or requiring dialysis), those with severe hepatic dysfunction such as cirrhosis or hepatic decompensation, and pregnant or lactating individuals. Clinicians weighing the drug for any of these groups are extrapolating beyond the trial population.

Two further caveats are worth flagging. The trial enrolled from June 2023 through September 2024, a window dominated by then-circulating variants; durability against newer lineages is not addressed by these data. And the ClinicalTrials.gov registry still shows no posted results table (has_results: false), so the registry-level summary lags the peer-reviewed publication. The NEJM paper, not the registry, is the primary source for the efficacy and safety figures here.