{"id":7237,"date":"2026-05-24T10:30:53","date_gmt":"2026-05-24T16:30:53","guid":{"rendered":"https:\/\/allphasepharma.com\/dir\/?p=7237"},"modified":"2026-05-24T11:54:43","modified_gmt":"2026-05-24T17:54:43","slug":"ensitrelvir-for-covid-prevention-this-emperor-has-no-clothes","status":"publish","type":"post","link":"https:\/\/allphasepharma.com\/dir\/2026\/05\/24\/7237\/ensitrelvir-for-covid-prevention-this-emperor-has-no-clothes\/","title":{"rendered":"Ensitrelvir for Covid Prevention: This Emperor Has No Clothes"},"content":{"rendered":"
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Just imagine you were tasked to conduct a seasonal flu study in household contacts of a symptomatic index case.  Your intervention may be (your choice): pre-season vaccination, pre-exposure prophylaxis, or some non-anti-infective protective measure such as wearing a face mask, taking a vitamin or analgesic that is believed to confer benefit.<\/p>\n\n\n\n

Of course, your study would be a placebo-controlled trial.  Not only because the FDA demands it, but also because a superiority study avoids a much larger NI trial.  Even so, the size of your prophylaxis study would be quite large, because the event of interest is rare.  A placebo arm is defendable as \u2018bad outcomes\u2019 are infrequent and manageable. <\/p>\n\n\n\n

Our innate immune system is well equipped to deal with viral respiratory infections.  Exceptions exist, but the common cold is usually self-limited and trivial.  Hence, in order to prove that your intervention can be effective, you would want to find patients that are neither too sick nor too healthy.  If too sick, they would not qualify for a placebo trial; if too healthy, the trial would miss a possible benefit and end up giving a false-negative result. <\/p>\n\n\n\n

Let\u2019s agree on this premise: The benefit of prophylaxis needs to be shown in some concrete and patient-relevant way.  Death is unlikely to be a discriminating feature in a flu trial, but hospitalization, prevention of complications or worsening of symptoms would seem useful as efficacy parameters.  It really boils down to demonstrating a clinically relevant benefit. <\/p>\n\n\n\n

SARS Covid-19 has changed a lot since the start of the pandemic.[1]<\/a>  Covid-19 behaves just like another common cold virus without the complications and mortality seen originally.  Like the flu, it is more a nuisance than the big scare of former years.   This makes the design of a PEP study tricky. <\/p>\n\n\n\n

Ideally, you\u2019d like to study an ambulatory group of recently exposed individuals with significant risk factors for complications, those who cannot tolerate even trivial respiratory infections too well.  PEP study candidates would have some chronic disease with mildly impaired immunity (elderly, COPD, smokers, CVD, DM, steroids, obesity); you certainly don\u2019t want to enroll healthy adolescents. Practically speaking, you would focus on an elderly population with multiple risk factors. <\/p>\n\n\n\n

Too many Covid studies failed recently because sponsors ignored the impact of vaccines. [1]<\/a><\/em>
Companies are well advised to enroll only anti-vaxxers for trials of the next Paxlovid!<\/p><\/blockquote><\/figure>\n\n\n\n

So, if you did a Covid-19 treatment trial with an antiviral in a mainly healthy, mainly mid-aged adult population without major risk factors for bad outcomes, what kind of outcome could one reasonably expect?  With early treatment of Covid-19 infected patients, ensitrelvir delivered a Tamiflu-size benefit: a shortening of symptoms by 1 day. <\/p>\n\n\n\n

Likewise, with ensitrelvir for PEP, we would predict some small protective effects, ie, a lower rate of infection, a shorter duration of viral shedding, reduction in VL, lessening of signs and symptoms related to the RTI , and faster improvement.  We would predict all of the above as a trend, not necessarily with a P-value < 0.05 \u2013 assuming drug PK in the therapeutic range.<\/p>\n\n\n\n

Indeed, such was the case with the SCORPIO-PEP ensitrelvir study.[2]<\/a>  The drug showed a lower incidence of \u201cCovid-19 infections\u201d (2.9% vs 9%) in the primary efficacy analysis. <\/p>\n\n\n\n

Let\u2019s look at some definitions more closely.  \u201cCovid-19 infection\u201d was defined as: <\/p>\n\n\n

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Except perhaps for taste and smell perversion, these are non-specific respiratory infection symptoms.  We would argue that these are inconsequential and totally irrelevant for most patients.   They may be caused by adenovirus, parainfluenza, or a hundred other viruses to which we are regularly exposed.  Attributing reduction in soft criteria to ensitrelvir puts it on the level of acetaminophen:  Tylenol could have done just as well. <\/p>\n\n\n\n

Let\u2019s face it: SCORPIO-PEP is a strange trial by design.  It was well suited to detect treatment effects of a trivial nature:<\/p>\n\n\n\n