Covid: Merck and Pfizer pills

 An efficacy study of Merck's oral medication molnupirivir for the treatment of non-hospitalized high-risk patients with symptomatic Covid found a 30% reduction in hospitalizations, in the MOVe-OUT trial (see covid molnupirivir nejm2021 in dropbox, or DOI: 10.1056/NEJMoa2116044).  for the FDA factsheet, see https://www.fda.gov/media/155054/download 

Details: 

-- 1433 participants were randomized to molnupirivir (800 mg BID for five days) versus placebo, begun within five days of the onset of symptoms, in an international study

-- median age 42 (range 18-90)/34% > 50yo, 51% female

-- all were unvaccinated adults with mild to moderate laboratory-confirmed Covid tested no more than five days earlier, and had at least one risk factor for severe Covid: age >60, active cancer, CKD, COPD, obesity, serious heart conditions, or diabetes: 

    -- obesity: 74%

    -- >60yo: 17%

    -- diabetes: 16%

    -- serious heart condition: 12%

    -- others: <6%

-- prior Covid exposure, per antibody testing: 20%

-- 95% in both the molnupirivir and placebo groups received at least 9 doses of medication

 

-- key exclusion criteria: anticipated need for hospitalization for Covid within the next 48 hours, dialysis, eGFR <30, pregnancy, unwillingness to use contraception when taking the medication and for at least 4 days after med completion, severe neutropenia, platelet count <100K

-- use of antipyretics, anti-inflammatories, or corticosteroids were permitted, though monoclonal antibodies and remdesivir were not

-- 48% had onset of signs or symptoms 3 days or less before randomization, 45% had moderate Covid

 

-- primary efficacy endpoint: hospitalization or death by day 29

-- primary safety endpoint: adverse events

-- secondary efficacy endpoints included changes in the WHO 11-point Clinical Aggression Scale and the patients' self-reported Covid signs and symptoms

 

Results:

-- SARS-CoV-2 assessment: 86% detectable by PCR

-- SARS-CoV-2 variant: 45% unknown/32% delta/11% mu/6% gamma

 

-- risk of hospitalization for any cause or death, through day 29, in interim analysis: 28 of 385 (7.3%) on molnupirivir, versus 53 of 377 (14.1%) on placebo, difference of -6.8 percentage points (-11.3 to -2.4), p=0.001

    -- because the interim analysis did show a 50% reduction, this trial was stopped early (on September 10, 2021), though the final participant was enrolled on October 2 and completed the day 29 visit on November 4

    -- the interim analysis included 54.1% of all randomized patients

 

-- in final analysis of all randomized patients: percentage of participants who were hospitalized or died through day 29: molnupirivir 6.8% (48 of 709) versus placebo 9.7% (68 of 699), difference -3.0 percentage points (-5.9to -0.1)

-- deaths: 1 on molnupirivir versus 9 on placebo, an 89% reduction

    -- all of these deaths were considered to be related to Covid

    -- but pretty small numbers of events to draw robust conclusions

 

-- Prespecified analysis of hospitalizations or deaths specifically related to Covid-19: 45 of 709 participants (6.3%) in molnupirivir group versus 64 of 699 (9.2%) in the placebo group, difference 2.8 percentage points (-5.7 to 0.0)

    -- the rate of hospitalization or death through day 29 was approximately 31% lower with molnupirivir, HR 0.69 (0.48-1.01), a very strong trend though not quite statistically significant (note overlapping confidence intervals in graph below)

--WHO Clinical Progression Scale:

    -- more on the med showed improved outcomes by day 5 with the largest differences observed between days 10 to 15 (prior days did not reach clinical significance)

-- subgroup analysis:

    -- those with prior SARS-CoV-2 infection per antibody detection and those with diabetes: benefit marginally favored placebo (though not nearly statistically significant, the trend was NOT for the med!!!)

        -- 964 participants were tested for quantitative RNA in nasopharyngeal samples at baseline; available data suggests greater reductions in mean viral load than placebo at days 3, 5, and 10

-- unable to comment on specific Covid variants, sequencing is ongoing (though, strangely, they state that “the efficacy benefit with molnupirivir treatment was consistent in many subgroups, including participants infected with the delta, gamma, and mu variants”, though no data at all were presented in the article or supplementary materials)

 

-- Adverse events: 216 of 710 (30.4%) on molnupirivir versus 231 of 701 (33.0%) on placebo

    -- adverse events felt to be related to the trial regimen: 8.0% versus 8.4%

    -- the most common adverse events were: Covid pneumonia (6.3% on molnupirivir versus 9.6% on placebo), diarrhea (2.3% versus 3%), and bacterial pneumonia (2.0% versus 1.6%). [It does seem a bit strange to include Covid pneumonia as an adverse event, given that Covid-related complications were a specific target the study]

 

Commentary: 

-- molnupirivir is a small molecule ribonucleoside prodrug of N-hydroxycytidine (NHC), which has activity against several RNA viruses including SARS-CoV-2, as well as a high barrier to the virus’ developing resistance.

    -- After being phosphorylated, NHC triphosphate is incorporated into the viral RNA, and subsequently interferes with viral replication through its effects on guanosine or adenosine (the resulting errors in transcription lead the virus to being unable to replicate)

-- there are concerns that molnupirivir might have teratogenic effects, as has been found in animal studies. this study appropriately excluded all pregnant women, so no further information on this potential issue

-- the efficacy of 30% in this formal report was different from in the interim analysis, where they found a 50% efficacy from molnupirivir; however they state that the incidence of hospitalization or death remained consistent in the molnupirivir group but fell on the placebo group in this updated (and published) analysis, for unknown reasons (though there were different numbers of people in these analyses, there may have been shifts in the epidemiology of the SARS-CoV-2 variants since the final analysis included a later time period, and possibly regional differences represented in these two studies)

   -- other studies have suggested that molnupirivir maintains antiviral activity against the SARS-CoV-2 variants, which was anticipated since the spike protein (where most of the mutations occurred) is not the target of this medication. However, the references included in the paper to justify this statement all predated the omicron variant (ie, I don’t think we really can definitively state the med works on omicron, though it likely does). so, molnupirivis may be better than the monoclonal antibodies for omicron or newer viruses that may develop with more spike protein mutations (though one of the 3 monoclonal antibodies, sotrovimab, does seem to have omicron effectiveness (see https://www.nature.com/articles/d41586-021-03829-0 )

    -- it is notable that at each point in time, the trend to molnupirivir benefit overlapped that of the placebo (ie, not statistically significant). i suspect that the overall trend may have been statistically significant, though there was no comment on this in the article

    -- also interesting that the benefit waned so much going from the interim analysis (which led to stopping the study because of "benefit ) to the final outcomes above (going from the 50% to 30% benefit).  I had mentioned in many past blogs that stopping a study early because of benefit had the potential distortion of overvaluing the benefit (since that was obvious early) but not allowing sufficient time to assess adverse effects (since the study was stopped early). this study added the additional issue: stopping early may distort the benefit: in this case by allowing the placebo group to do better over time!!!

Limitations:

-- this study was too small to develop much granularity in their conclusions, given that only a small percentage of patients infected with SARS-CoV-2 developed serious enough diseases to be hospitalized. A much larger study would be needed for that

-- this study was done in unvaccinated people, limiting generalizability to those who had been vaccinated; the fact that those with prior Covid (per antibody testing) may have done worse on the medication does not necessarily bode well for those who were vaccinated!!!

-- no omicron variants have been formally tested, though omicron likely will be sensitive to molnupirivir 

-- the lack of effect on those with diabetes is concerning. it was only 16% of the participants (which seems pretty low...), but would be a major issue in many communities in the US.... there really needs to be more diabetic patients in subsequent trials, since this study suggests that there is a big uncertainty if molnupirivir would work in this common group of patients

-- molnupirivir should not be used in pregnant women or those not on birth control, based on the animal studies (though, a rather unfortunate problem, since covid outcomes can be worse in pregnant women: eg see http://gmodestmedblogs.blogspot.com/2021/03/covid-probs-in-pregnancy-recs-on.html )

 

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The Pfizer pill (nirmatrelvir with ritonavir, given the company name Paxlovid, a bit easier to say) has also been approved for emergency use, though all I can access publicly on the study is the company press release (see https://www.pfizer.com/news/press-release/press-release-detail/pfizer-announces-additional-phase-23-study-results ), and FDA info (see below)

 

Details, per their news release:

-- EPIC-HR study included 2246 high risk patients >17yo from North and South America, Africa, and Asia, followed from day 1 through day 28

-- patients were randomized to one pill BID for five days for the active medication or placebo

-- exclusion criteria: no prior SARS-CoV-2 infection, no medical history of active liver disease or moderate to severe renal impairment, known HIV with viral load >400, suspected or confirmed concurrent active systemic infection, taking medicine that would interfere with the CYP3A4 clearance or a strong inducers of this enzyme, no prior Covid vaccination except in those with underlying medical conditions “associated with an increased risk of developing severe disease from Covid 19” (not defined further), oxygen saturation <92%, females were pregnant or breastfeeding

 

Results:

-- reduced risk of hospitalization or death by 89% for those given the medication within 3 days of symptom onset, and 88% within 5 days of symptom onset, versus placebo

    -- for those treated within 5 days of symptom onset: 8/1039 hospitalized (0.8%) with no deaths on nirmatrelvir/ritonavir versus 66 /1046 (6.3%) with 12 deaths on placebo, p<0.0001

    -- in those >65yo: 1.1% on nirmatrelvir/ritonavir (1/94 hospitalized with no deaths) versus 16.3% on placebo (16/98 hospitalized, with six deaths), p<0.0001

-- secondary endpoint: nirmatrelvir/ritonavir reduced viral load by 10-fold relative to placebo, controlling for baseline viral load, geographic region, and serology status
-- treatment-related adverse effects: nirmatrelvir/ritonavir 23%, placebo 24%, most were mild in intensity

    -- serious adverse events (1.6% versus 6.6%) and discontinuation of the study drug from adverse events (2.1% versus 4.2%), favoring nirmatrelvir/ritonavir

 

--EPIC-SR (standard risk adults): interim analysis found a 70% reduction in hospitalization and no deaths in the treated population versus placebo, and a 10-fold decrease in viral load in those on nirmatrelvir/ritonavir versus placebo

    -- the interim analysis did not find sustained alleviation of all symptoms for 4 consecutive days versus placebo, though this study is continuing

    -- for this standard risk group, exclusion criteria: having received a Covid-19 vaccine, except for participants with an underlying medical condition associated with increased risk of developing severe Covid; prior diagnoses of Covid; known medical history of liver disease or known renal impairment; known HIV infection with viral load >400; no active systemic infection other than Covid; taking medicine that would interfere with the CYP3A4 clearance or a strong inducers of this enzyme, oxygen saturation <92% on room air, pregnant or breast-feeding women (see https://clinicaltrials.gov/ct2/show/record/NCT05011513 )

    --cannot comment further on this study, too early (and what i have noted above is the extent of the public information i have found). i am including this just to let you know that there is an on-going study in non-high-risk individuals

 

Commentary:

-- nirmatrelvir is an inhibitor of the SARS-CoV-2 main protease (Mpro), also called 3C-like protease or nsp5 protease, rendering the SARS-CoV-2 incapable of processing polyprotein precursors and preventing viral replication. Ritonavir inhibits metabolism of the nirmatrelvir, increasing its plasma concentrations
-- the results of the study are quite impressive, significantly more so than in the above molnupirivir study

-- one concern with nirmatrelvir/ritonavir is that its supply is relatively limited compared to molnupirivir at this time, though Pfizer does indicate they can increase production significantly after the EUA approval of 12/22/2021 (see https://www.fda.gov/news-events/press-announcements/coronavirus-covid-19-update-fda-authorizes-first-oral-antiviral-treatment-covid-19 ), with a few extra comments by the FDA:

    --this med should not be given to those with uncontrolled or undiagnosed HIV (does this mean we should wait for HIV results prior to starting the med? and not using the med if the patient is HIV positive, presumably because ritonavir resistance could affect the effectiveness of some future HIV treatment regimen???). however, the FDA notes that there is no problem giving nirmatrelvir/ritonavir in those on HIV meds containing ritonavir or cobicistat (?should there be a formulation of nirmatrelvir/ritonavir without the ritonavir for these people??)

    -- not give if GFR <30 (and dose-adjust if 30-60), severe hepatic impairment

    -- not give if on some of the many meds using the CYP3A4 system: including lovastatin/simvastatin, colchicine, several antiarrhythmics, phenobarbital, phenytoin, carbamazepine, rifampin, st john's wort (for full list see https://www.fda.gov/media/155050/download )

-- a common situation where ritonavir has been used extensively in the past is with HIV treatment regimens, where ritonavir (and its newer cousin cobicistat) can both lead to severe Cushing’s syndrome with coadministration of steroids, including intranasal, inhaled, and intra-articular steroids (see http://gmodestmedblogs.blogspot.com/2019/05/hiv-meds-local-steroids-and-cushings.html ). so, though the concern with Cushing's is in those with chronic ritonavir, I personally would avoid or discontinue these steroids when taking  nirmatrelvir/ritonavir for the five-day course. the FDA suggests change to beclomethasone and prednisolone if steroids are necessary.

-- no fertility or teratogenic effects in rats, though the human studies did not include pregnant women, so no human data on this

 

Limitations:

-- the most impressive limitation is the fact that we cannot see the full data, only their press release. And, I personally am skeptical about drug company press releases, since drug companies typically design their studies to optimize the results they want, which increases the odds of a positive finding that augments their already overflowing coffers

-- both of these Pfizer studies were basically of unvaccinated individuals, limiting their generalizability to the significant majority of people who have been vaccinated. The high-risk study above (EPIC-HR) did allow for vaccination in those considered to have an underlying medical condition associated with increased risk of severe Covid (not sure what this really means, since these were supposedly already high-risk patients, nor what they included in underlying medical conditions that allowed vaccine, nor how many people actually had received a prior vaccination, nor if their results differed from those not vaccinated)

    -- might have been useful to know if people with positive SARS-CoV-2 antibodies (ie old infections) responded similarly to the antibody negative participants. Concerning that the molnupirivir did not seem to work as well in those with prior Covid infections...

-- little information on subgroup analyses, comparing efficacy in those with different types of high-risk conditions, for example

so, though we do not have enough data to really understand nirmatrelvir/ritonavir's specifics, it does seem that it is a really great drug (for those without contraindications), with efficacy paralleling that of vaccines (and perhaps more so as the spike protein mutations increase with evolution of the virus and increasing vaccine resistance).  molnupirivir may well be a reasonable alternative for those with mild-to-moderate Covid infections, especially if nirmatrelvir/ritonavir is unavailable/contraindicated or sotrovimab if not an option. 

Still, the mainstay of SARS-CoV-2 management is prevention (ie, vaccination). Mitigation strategies certainly help as well.

geoff

 

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