By Jake Scott, MD
Clinical Assistant Professor, Infectious Diseases and Geographic Medicine, Stanford University School of Medicine; Antimicrobial Stewardship Program Medical Director, Stanford Health Care Tri-Valley
SYNOPSIS: In this Phase II-III randomized controlled clinical trial (EPIC-SR), nirmatrelvir-ritonavir was not associated with a significant difference in time to alleviation of symptoms nor COVID-19-related hospitalization or death from any cause as compared with placebo in unvaccinated individuals without risk factors for severe disease or in vaccinated individuals with a least one risk factor for severe disease.
SOURCE: Hammond J, Fountaine RJ, Yunis C, et al. Nirmatrelvir for vaccinated or unvaccinated adult outpatients with COVID-19. N Engl J Med 2024;390:1186-1195.
Hammond and colleagues conducted the Evaluation of Protease Inhibition for COVID-19 in Standard-Risk Patients (EPIC-SR) trial, a double-blind, randomized, placebo-controlled trial that compared nirmatrelvir-ritonavir (NMV-r, brand name Paxlovid) to placebo in unvaccinated individuals without risk factors for severe disease and in vaccinated individuals with at least one risk factor for severe disease.1 Pfizer, the manufacturer of NMV-r, was responsible for the trial design, conduct, data analysis, and interpretation of the trial and funded the drafting of the manuscript. The study randomized 1,296 adult patients with COVID-19 between Aug. 25, 2021, and July 25, 2022. The results from this long-awaited trial were first published on April 4, 2024.
Participants were randomized within five or fewer days of symptom onset and were assigned in a 1:1 ratio to receive either NMV-r (300 mg of nirmatrelvir and 100 mg of ritonavir) or placebo (which consisted of inactive ingredients) every 12 hours for five days total. COVID-19 was confirmed for all participants by either reverse-transcriptase polymerase chain reaction (RT-PCR) or rapid antigen tests. Patients with an underlying condition associated with a greater risk of severe COVID-19 were eligible if they had received a complete primary series of an authorized COVID-19 vaccine, although participants were excluded if they had active liver, renal, or human immunodeficiency virus (HIV) disease. Patients without any predefined underlying conditions were eligible if they had not received any COVID-19 vaccine.
Medication adherence and the presence and severity of COVID-19 signs or symptoms were regularly recorded electronically by participants. The primary end point was efficacy of NMV-r based on difference in time to sustained alleviation of all predefined COVID-19 signs and symptoms through day 28. Predefined symptoms included cough, shortness of breath or difficulty breathing, feeling feverish, chills or shivering, muscle or body aches, diarrhea, nausea, vomiting, headache, sore throat, and stuffy or runny nose. Severity of symptoms was recorded by participants using a four-point scale (0, absent; 1, mild; 2, moderate; 3, severe). Sustained alleviation was defined as occurring on the first of four consecutive days or symptomatic improvement. Key secondary end points were COVID-19-related hospitalization or death from any cause through day 28. Related secondary end points included the number of medical visits and the number of days in the hospital or intensive care unit (ICU) related to COVID-19 through day 28. The viral load was assessed on day 5 as at or above the lower limit of quantification or below the lower limit of quantification (< 2 log10 copies per mL). Viral load rebound was assessed on day 10 or day 14 and symptom rebound also was assessed after abatement of symptoms. Safety data were evaluated through day 34.
A total of 1,560 patients were screened and 1,296 were ultimately randomized and included in the full analysis population (658 in the NMV-r group and 638 in the placebo group). Among the participants included in the analysis, 636 had at least one risk factor for severe COVID-19 and were vaccinated, and 649 were unvaccinated and without risk factors. Slightly more than half (54%) of participants were female (52.6% in the NMV-r group and 55.5% in the placebo group). The median age was 42 years (range 18-87 years), and the median body mass index (BMI) was 24.9 (range 14.2-58.8). The majority (78.5%) of participants were white, 3.9% were Black, 11.0% were Asian, and 41.4% were Hispanic or Latino. One-third of participants were enrolled in the United States, one-third were enrolled in Europe, and one-third were enrolled in other parts of the world. Slightly more than half (56.9%) of all participants included in the full analysis had been vaccinated at baseline (56.8% in the NMV-r group and 57.1% in the placebo group) and 73.8% of participants were seropositive for SARS-CoV-2 at baseline as determined by the detection of antibodies to either the nucleocapsid antigen or the spike antigen (73.3% in the NMV-r group and 74.5% in the placebo group). Baseline COVID-19 was considered to be mild in 29.6% of participants, moderate in 47.5%, and severe in 18.8%. The median time from onset of symptoms to the start of treatment was three days in both groups (range 0-5 in the NMV-r group and 0-6 in the placebo group). Of the participants, 49/1% were considered to be high risk and 50.1% were considered to be standard risk. The most common risk factors for severe COVID-19 included a BMI of 30 or higher (17.8%), smoking (13.3%), hypertension (12.3%), diabetes mellitus (5.1%), and age of 65 years or older (5.0%). Adherence (defined as having taken at least 80 of the expected number of tablets) was 94.8% in the NMV-r group and 96.5% in the placebo group.
There was no significant difference in the time to sustained alleviation of symptoms between the NMV-r group and the placebo group. Among the 1,288 participants who received at least one dose of NMV-r (654 participants) or placebo (634 participants) and had at least one post-baseline visit, the median time to sustained alleviation of all targeted COVID-19 signs or symptoms through days 28 was 12 days (95% confidence interval [CI], 11 to 13 days) in the NMV-r group and 13 days (95% CI, 12-14 days) in the placebo group (P = 0.60). The mean time to sustained alleviation was 13.8 days in the NMV-r group and 14.1 days in the placebo group. There also was no statistically significant difference in the key secondary end point; five of the 654 participants (0.8%) in the NMV-r group and 10 of the 634 (1.6%) in the placebo group were hospitalized for COVID-19 or died from any cause through day 28 (difference, -0.8 percentage points; 95% CI, -2.0 to 0.4). One death occurred in the placebo group. In a subgroup analysis of high-risk participants, COVID-19-related hospitalization or death from any cause occurred in three patients (0.9%) in the NMV-r group and seven patients (2.2%) in the placebo group (difference, -1.3 percentage points; 95% CI, -3.3 to 0.7). Additional subgroup analyses found numerically higher numbers of COVID-19-related medical visits among participants in the NMV-r group than among those in the placebo group, but the differences were not statistically significant. Viral rebound occurred by day 14 in 4.3% of the participants in the NMV-r group and 4.1% in the placebo groups.
Adverse events of any type that emerged during the treatment period occurred in 25.8% of those in the NMV-r group and 24.1% in the placebo group. No serious adverse events occurred in either group that were considered by the investigator to be related to either NMV-r or placebo. The most commonly reported adverse events among participants in the NMV-r group were dysgeusia (6.7%), diarrhea (4.0%), and nausea (3.1%), compared to 0.5%, 3.0%, and 2.7% in the placebo group, respectively. Eighty-three participants (12.7%) had adverse events that were considered by the investigator to be related to NMV-r, compared to 31 (4.9%) that were attributed to the placebo. Of these, 11 participants (1.7%) in the NMV-r group and two (0.3%) in the placebo group had adverse events that led to discontinuation of the study drug or placebo.
COMMENTARY
Although NMV-r was not shown to provide any significant benefit to unvaccinated individuals without risk factors for severe disease or vaccinated individuals with a least one risk factor for severe disease, which is the population most relevant to the current era, it is worth briefly reviewing the broader context of this drug. Coronaviruses contain two protease enzymes that play a pivotal role in the viral life cycle: 3-chymotrypsin-like cysteine protease (3CLpro or Main Mpro) and papain-like serine protease (PLpro). Mpro is well characterized and highly conserved among coronaviruses as well as other ribonucleic acid (RNA) viruses, and there are no homologous proteins in human cells, making it an appealing target for antiviral agents.2 Nirmatrelvir (NMV) was demonstrated in a mouse-adapted model to be a potent inhibitor of the SARS-CoV-2 Mpro protease and to achieve plasma concentrations exceeding the in vitro antiviral cell potency when administered orally in a Phase I clinical trial in human participants.3 NMV is mainly metabolized by the cytochrome P4503A4 (CYP3A4) isoenzyme and is co-administered with ritonavir, a potent CYP3A4 inhibitor, to boost NMR plasma concentrations.4 Ritonavir has no activity against SARS-CoV-2 on its own.
In a Phase II-III clinical trial, the Evaluation of Protease Inhibition of COVID-19 in High-Risk Patients (EPIC-HR), the efficacy of a five-day course of NMV-r was evaluated in 2,246 unvaccinated, high-risk adults with mild to moderate COVID-19 after being taken within five days of symptom onset.5 Participants were enrolled between July 16 and Dec. 9, 2021, during a period when the B.1.617.2 (Delta) variant predominated. Those with previous confirmed SARS-CoV-2 infection were excluded, as were those who had previously received any SARS-CoV-2 vaccine.
When initiated within five days of symptom onset, NMV-r was associated with an 88% relative risk reduction in hospitalization or death from any cause through day 28 (P < 0.001); eight out of 1,039 participants (0.77%) in the NMV-r group were hospitalized, compared to 66 of 1,046 participants (6.31%) in the placebo group. The incidence of adverse events that emerged during the treatment period that were considered by investigators to be related to the trial drug or placebo was higher among those who received NMV-r compared to placebo recipients (7.8% vs. 3.8%), mainly due to higher rates of dysgeusia (4.5% vs. 0.2%, respectively). These impressive results led to NMV-r being issued an Emergency Use Authorization (EUA) by the United States Food and Drug Administration (FDA) on Dec. 22, 2021, and to its use being recommended by guidelines for those considered to be at risk for severe COVID-19.6,7
As levels of population immunity progressively increased with vaccination, prior infection, and hybrid immunity, the relevance of the results from EPIC-HR became less and less clear, since participants with baseline immune protection were excluded from the trial. Although EPIC-SR began randomization of participants on Aug. 25, 2021, roughly one month after randomization for EPIC-HR was initiated, the findings of the trial were not revealed until a manufacturer press release on June 14, 2022, when it was reported that the trial failed to show a significant difference in sustained symptom alleviation through day 28 as compared with placebo.8
In addition to questions about the utility of NMV-r in vaccinated individuals, the effectiveness of NMV-r against infection with the Omicron variant also remained unclear, although several in vitro studies demonstrated that activity was retained.9-11 While the publication of the findings from the EPIC-SR trial was pending, the void of randomized controlled trial data for NMV-r in vaccinated individuals was filled by results from multiple observational studies.12-15 However, conclusions from observational data need to be interpreted with caution, especially when it comes to therapeutics. These studies are intrinsically susceptible to various biases, including confounding by indication, residual confounding by prior immune protection, and immortal time bias. The effect of NMV-r on hospitalization and death among COVID-19 patients with high levels of immunity is currently being evaluated in a United Kingdom-based trial, called Platform Adaptive Trial of Novel Antivirals for Early Treatment of COVID-19 in the Community (PANORAMIC), the results of which have yet to be published.
While the EPIC-SR trial was placebo-controlled, NMV-r is widely known for causing dysgeusia. Therefore, this relatively common side effect may well have limited the blinding effect for participants who received the study drug and for those who received placebo, as the authors noted. For example, if a participant developed worsening COVID-19 symptoms during the treatment period and did not experience any dysgeusia, the participant may have had a greater concern about their illness trajectory based on an assumption that they were not on effective treatment. This in turn may have resulted in a lower threshold to seek medical care, which would have biased the study in favor of NMV-r over placebo in terms of this secondary endpoint.
Given that NMV-r was not found to provide significant benefit in terms of shortening the duration of symptoms, the potential downsides of the drug need to be considered. Since ritonavir is a strong CYP3A4 inhibitor, the co-administration of NMV-r with other medications can lead to significant drug-drug interactions. Although the trial found low rates of symptom and viral rebound among NMV-r recipients (1.2%, as compared with 0.5% in the placebo group), the incidence of rebound after NMV-r has been significantly higher in other studies that were not sponsored by Pfizer. In a prospective cohort study, viral rebound was found in 14% of NMV-r recipients (n = 127) compared to 9% of controls (n = 43), and symptom rebound in 19% and 7%, respectively.16 A randomized controlled trial found that 10% (six of 58) of those who received NMV-r experienced virologic rebound compared to 1% (one of 84) of those who received no study drug.17 Another prospective cohort study found evidence of viral rebound in 20.8% (n = 15) of those who received NMV-r vs. 1.8% (n = 1) who did not receive treatment (absolute difference, 19.0% [95% CI, 9.0 to 29.0%]; P = 0.001). All patients with viral rebound had a positive viral culture result after a prior negative result and prolonged shedding of replication-competent virus (median, 14 vs. three days) compared with those who did not have viral rebound, indicating that there is a risk of transmission during the viral rebound phase. In addition to dysgeusia and gastrointestinal side effects, the significant cost of NMV-r ($1,390 for a five-day course) also needs to be seriously considered.
It remains unknown whether NMV-r provides significant benefit to severely immunocompromised individuals. EPIC-SR excluded people with active HIV disease, yet it is unclear whether other immunocompromising conditions also were excluded. Further studies are needed to address this important question.
In summary, although EPIC-HR demonstrated that NMV-r provided significant benefit to non-hospitalized individuals without prior SARS-CoV-2 immunity during the Delta-predominant era, EPIC-SR failed to show that NMV-r shortens the duration of symptoms or provides significant protection against COVID-19-related hospitalization or all-cause mortality among either vaccinated individuals with a least one risk factor for severe disease or unvaccinated individuals without risk factors for severe disease.
REFERENCES
- Hammond J, Fountaine RJ, Yunis C, et al. Nirmatrelvir for vaccinated or unvaccinated adult outpatients with Covid-19. N Engl J Med 2024;390:1186-1195.
- Cannalire R, Cerchia C, Beccari AR, et al. Targeting SARS-CoV-2 proteases and polymerase for COVID-19 treatment: State of the art and future opportunities. J Med Chem 2022;65:2716-2746.
- Owen DR, Allerton CMN, Anderson AS, et al. An oral SARS-CoV-2 Mpro inhibitor clinical candidate for the treatment of COVID-19. Science 2021;374:1586-1593.
- Sevrioukova IF, Poulos TL. Structure and mechanism of the complex between cytochrome P4503A4 and ritonavir. Proc Natl Acad Sci U S A 2010;107:18422-18427.
- Hammond J, Leister-Tebbe H, Gardner A, et al. Oral nirmatrelvir for high-risk, nonhospitalized adults with Covid-19. N Engl J Med 2022;386:1397-1408.
- U.S. Food and Drug Administration. Coronavirus (COVID-19) update: FDA authorizes first oral antiviral for treatment of COVID-19. Dec. 22, 2021. https://www.fda.gov/news-events/press-announcements/coronavirus-covid-19-update-fda-authorizes-first-oral-antiviral-treatment-covid-19
- Bhimraj A, Morgan RL, Shumaker AH, et al. Infectious Diseases Society of America Guidelines on the Treatment and Management of Patients with COVID-19. Clin Infect Dis 2020; Apr 27:ciaa478. [Online ahead of print].
- Pfizer. Pfizer reports additional data on Paxlovid supporting upcoming new drug application submission to U.S. FDA. June 14, 2022. https://www.pfizer.com/news/press-release/press-release-detail/pfizer-reports-additional-data-paxlovidtm-supporting
- Imai M, Ito M, Kiso M, et al. Efficacy of antiviral agents against Omicron subvariants BQ.1.1 and XBB. N Engl J Med 2023;388:89-91.
- Takashita E, Kinoshita N, Yamayoshi S, et al. Efficacy of antiviral agents against the SARS-CoV-2 Omicron subvariant BA.2. N Engl J Med 2022;386:1475-1477.
- Vangeel L, Chiu W, De Jonghe S, et al. Remdesivir, molnupiravir and nirmatrelvir remain active against SARS-CoV-2 Omicron and other variants of concern. Antiviral Res 2022;198:105252.
- Arbel R, Wolff Sagy Y, Hoshen M, et al. Nirmatrelvir use and severe Covid-19 outcomes during the Omicron surge. N Engl J Med 2022;387:790-798.
- Najjar-Debbiny R, Gronich N, Weber G, et al. Effectiveness of Paxlovid in reducing severe coronavirus disease 2019 and mortality in high-risk patients. Clin Infect Dis 2023;76:e342-e349.
- Dryden-Peterson S, Kim A, Kim AY, et al. Nirmatrelvir plus ritonavir for early COVID-19 in a large U.S. health system: A population-based cohort study. Ann Intern Med 2023;176:77-84.
- Shah MM, Joyce B, Plumb ID, et al. Paxlovid associated with decreased hospitalization rate among adults with COVID-19 — United States, April-September 2022. MMWR Morb Mortal Wkly Rep 2022;71:1531-1537.
- Pandit JA, Radin JM, Chiang DC, et al. The Coronavirus Disease 2019 Rebound Study: A prospective cohort study to evaluate viral and symptom rebound differences in participants treated with nirmatrelvir plus ritonavir versus untreated controls. Clin Infect Dis 2023;77:25-31.
- Schilling WHK, Jittamala P, Watson JA, et al. Antiviral efficacy of molnupiravir versus ritonavir-boosted nirmatrelvir in patients with early symptomatic COVID-19 (PLATCOV): An open-label, phase 2, randomised, controlled, adaptive trial. Lancet Infect Dis 2024;24:36-45.
In this Phase II-III randomized controlled clinical trial (EPIC-SR), nirmatrelvir-ritonavir was not associated with a significant difference in time to alleviation of symptoms nor COVID-19-related hospitalization or death from any cause as compared with placebo in unvaccinated individuals without risk factors for severe disease or in vaccinated individuals with a least one risk factor for severe disease.
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