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Addition of molnupiravir in the evolving SARS-CoV-2 treatment landscape

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Dr. Marissa Grifasi Williams

Global Director,
Medical Affairs, COVID-19,
Merck Sharp & Dohme Corp.

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Dr. Yap, Yat-Hin Desmond

Clinical Associate Professor,
Department of Medicine,
Li Ka Shing Faculty of Medicine,
The University of Hong Kong

At a symposium organized by the Hong Kong Society for Infectious Diseases, Dr. Marissa Grifasi Williams kicked off the symposium by sharing how the evolution of virus has changed the management of SARS-CoV-2, highlighting the current guidelines to recommend molnupiravir as an oral therapy for the coronavirus disease 2019 (COVID-19). She further discussed the MOVe-OUT trial, which demonstrated that molnupiravir reduced the risk of hospitalization or death in at-risk and unvaccinated COVID-19 adults. Concluding her presentation, Dr. Williams featured the additional data of molnupiravir from the European Congress of Clinical Microbiology and Infectious Diseases (ECCMID) 2022, validating that molnupiravir was effective in clearing the virus as early as 3 days, as well as improving symptoms. Then, Dr. Yap, Yat-Hin Desmond shared his experience in managing COVID-19 patients with renal failure in Hong Kong.

 

Viral evolution calls for changes in SARS-CoV-2 management

COVID-19 was declared a global pandemic by the World Health Organization (WHO) on March 11, 2020.1 To date, 5 different variants of concern were seen and each with different attributes in the transmission and severity of the disease.2 Despite having very effective vaccines for SARS-CoV-2, the global pandemic is still prevailing at present. While the number of local COVID-19 cases is reducing, Dr. Williams highlighted that “in the 5th wave of outbreak in Hong Kong, the elderly including those older than 70 years old, accounted for a disproportionately large share of death and severe cases during this wave, relative to the 13% population share. Similarly, those aged 60-69 disproportionally shared most of the intensive care unit (ICU) cases, and noticeably, most of the deceased cases involved unvaccinated persons.”3

While it is likely that there will be more variants, it is yet to be determined what impact of these variants will be on those vaccinated and not vaccinated people, and their effects on the currently available therapies and the future ones.

Updates of international treatment guidelines on oral treatments for mild-to-moderate COVID-19 patients

Key international guidelines, including those from the National Institutes of Health (NIH), the Infectious Diseases Society of America (IDSA) and the WHO, cover recommendations for the use of therapeutics in the treatment of mild-to-moderate COVID-19.4-6 The NIH guidelines focus on the therapeutic management of non-hospitalized adults, where nirmatrelvir/ritonavir or intravenous remdesivir is recommended for treating patients who are at a high risk of progressing to severe COVID-19.4 Additionally, molnupiravir is recommended for use when neither of the preferred therapies is available, feasible or clinically appropriate.4 Looking at the IDSA guidelines, molnupiravir and nirmatrelvir/ritonavir are the oral options suggested for the treatment of mild-to-moderate COVID-19.5 For nirmatrelvir/ritonavir, Dr. Williams emphasized that dosing should be based on renal function, and medications ought to be screened for serious interactions.5 Regarding the WHO living guidelines for non-severe COVID-19 where there are no hierarchies or preferences of treatment, Dr. Williams highlighted that there are recommendations in favor of molnupiravir for those at the highest risk of hospital admissions.6

Molnupiravir as an important oral antiviral adding to counter the pandemic

Dr. Williams covered data of the latest available and guideline-recommended oral therapies, including nirmatrelvir/ritonavir and molnupiravir. Molnupiravir, an oral and small-molecule antiviral, is a nucleoside analog prodrug being incorporated into viral ribonucleic acid (RNA) by the viral RNA polymerase, leading to an accumulation of errors in the viral genome and resulting in the inhibition of virus replication.7 MOVe-OUT is a phase 3, double-blind, randomized, placebo-controlled trial which evaluated the efficacy and safety of molnupiravir in non-hospitalized, unvaccinated adults with mild-to-moderate COVID-19 and at least 1 risk factor for progression to severe diseases.7 Results showed that early treatment with molnupiravir reduced the risk of hospitalization or death in at-risk and unvaccinated adults with COVID-19, where there was an absolute risk reduction (ARR) of 3% and a relative risk reduction (RRR) of 31% observed with molnupiravir vs. placebo (figure 1).7 Overall, molnupiravir was shown to be very well tolerated, with the most common adverse events (AEs) being diarrhea, nausea and dizziness.7

On the other hand, nirmatrelvir/ritonavir, an oral antiviral that targets the SARS-CoV-2 3CL protease enzyme, resulted in 89.1% RRR in hospitalization or death in non-hospitalized adults at high risk for progression to severe disease.8

Latest updates of ECCMID 2022 support the benefits of molnupiravir

On top of the results published in the MOVe-OUT trial, additional data of molnupiravir were presented at the ECCMID 2022, showing no notable differences in virologic outcomes in immunocompromised participants when compared with non-immunocompromised participants. Moreover, participants receiving molnupiravir also showed sustained improvements of symptoms.9,10

In the post-hoc analysis of the MOVe-OUT trial comparing immunocompromised participants with non-immunocompromised participants, no infectious virus was recovered in any immunocompromised participants in the molnupiravir group on day 3 or later vs. 42.9% in the placebo group on day 3.9 Furthermore, safety profile was comparable in the molnupiravir and the placebo groups, regardless of the immunocompromised status.9

Lastly, an analysis detailing self-reported symptoms evaluated key secondary efficacy endpoints from the MOVe-OUT trial and analyzed the distinctive COVID-19 symptoms commonly associated with COVID-19.10 For most COVID-19 symptoms, it was found that the molnupiravir group was more likely to achieve sustained improvement and resolution through day 29 when compared with placebo.10 There was also a 3-day improvement in one of the main indicators, i.e., shortness of breath, in the molnupiravir group vs. the placebo group.10

CKD is a key risk factor for COVID-19 mortality in Hong Kong

Following Dr. Williams’ presentation, Dr. Yap shared his clinical opinions on treating COVID-19 in patients with renal failure. COVID-19 infection has a major impact on the kidneys, and those infected may have reported proteinuria or acute kidney injury (AKI).11 Although vaccination is a very important means to combat COVID-19 in patients with renal failure, the immune response is likely impaired in chronic kidney disease (CKD) patients, and thus the immunogenicity of vaccination is subsequently impaired.12-15 Added to that, Dr. Yap stressed that “the use of immunosuppressants would also impair the immune response in patients with chronic renal failure, especially those with kidney transplant. For example, antimetabolites such as mycophenolate mofetil (MMF) would affect B-cell maturation and differentiation. The calcineurin inhibitor (CNI) would affect the follicular T-cell, which is important in B-cell maturation and producing a robust antibody response. Corticosteroids also have a wide range of effects on the immune reactive cells.”

Based on these backgrounds, Dr. Yap and his team conducted a meta-analysis to investigate the vaccination efficacy and immunogenicity in patients with renal failure after 2 doses of vaccine.15 Results showed that the seropositivity after 2 doses of COVID-19 vaccine among patients with renal failure was 44% lower than in the general population.15 The seropositivity rates in kidney transplant recipients (KTRs) were only 26.1% vs. 84.3% in hemodialysis (HD) patients and 92.4% in peritoneal dialysis (PD) patients.15 When compared with the healthy individuals, KTRs were 80% less likely to develop antibodies after COVID-19 vaccination.15 On the other hand, patients receiving HD and PD was 18% and 11% less likely to develop antibodies after COVID-19 vaccination, respectively.15 The use of immunosuppressive treatments also matters, in which every 1% use of MMF among the KTRs was associated with a reduction of 0.92% in seropositivity after COVID-19 vaccination.15 In general, the 2-dose COVID-19 vaccine was well-tolerated in patients with renal failure, having an overall rate of AE of around 2.1% only.15

Clinical experience of COVID-19 management in patients with renal failure

Dr. Yap then shared his clinical experience and opinions of how oral antivirals are used in patients with renal failure and the potential problems that may arise. During the 1st wave of COVID-19 outbreak in Hong Kong, Dr. Yap had a 31-year-old female KTR on prednisolone, tacrolimus and MMF. Unfortunately, the patient was infected with COVID-19 during a cruise trip to Japan and did not receive antiviral medicines in Japan. She developed fever and no vaccination was available back then. At that time, the only treatment available was lopinavir/ritonavir, which was initiated to her. After lopinavir/ritonavir, her CNI level became sky high, which was associated with AKI, contributed by both very excessive level of tacrolimus (FK level) and a viropathic effect on the kidneys. As a result, tacrolimus was stopped, and it took a month for the FK level returning to normal. After developing AKI on top of CKD, the patient’s renal function was deteriorated and subsequently developed renal allograft failure 6 months later. Eventually, she had to return to hemodialysis.16 Apart from this case, Dr. Yap further shared cases involving the use of anti-interleukin-6 and dexamethasone initially, followed by nirmatrevir/ritonavir with cyanuric acid (CYA) dosage pre-emptively reduced, and then CYA resumed gradually on a very low dose. Though an excessive level of CYA was observed, luckily that AKI was not developed in the patient. Dr. Yap suggested that the use of ritonavir-based treatment may associate with an increase in the CYA level, resulting in renal toxicity.

Having gained these previous experiences, along with the expanded use of COVID-19 oral drugs in Hong Kong during the 5th of COVID-19 wave, Dr. Yap also shared his recent clinical opinions on the use of molnupiravir in KTRs and HD patients. Usually, patients with renal failure would remain clinically stable while on molnupiravir, which was well tolerated with no major AEs. Molnupiravir did expedite much the pace of putting patients with renal failure back to the clean zone of the dialysis unit. It is suggested that molnupiravir should be a good therapeutic option for COVID-19 patients with renal failure, particularly in KTRs, where there is no interaction with CNIs and no renal adjustment is required. Similarly, molnupiravir was shown to be well tolerated with no renal dose adjustment in HD and PD patients.

Conclusion

In general, COVID-19 vaccination is well tolerated in patients with renal failure, but the immunogenicity is substantially impaired, especially in KTRs as compared with dialysis patients. Impaired viral clearance, potential side effects and drug-drug interactions of the COVID-19 treatment, and the required adjustment of the immunosuppressive treatment have all attributed to the challenges of treating COVID-19 patients with renal failure.12-15 As demonstrated in the MOVe-OUT trial and from the additional data presented at the ECCMID 2022, molnupiravir, an oral antiviral recommended in the international guidelines for the treatment of COVID-19, has shown treatment benefits for mild-to-moderate COVID-19 patients, which included reducing the risk of hospitalization or death, actively eliminating the virus as early as day 3 of starting the treatment, clearing virus equally well in the immunocompromised population, and achieving sustained improvement and resolution of COVID-related symptoms.7,9,10 In fact, renal failure has a significant impact on the outcomes of COVID-19 infection where it is associated with high infection rates and mortality rates.11 As demonstrated in Dr. Yap’s clinical case, patients with renal failure remained clinically stable while on molnupiravir, which was well tolerated with no major AEs. All in all, molnupiravir is suggested to be a good therapeutic option for COVID-19 patients with renal failure.

 

MOLNUPIRAVIR Selected Safety Information

Authorized Use 1. Molnupiravir is authorized for use under an Emergency Use Authorization (EUA) for the treatment of mild-to-moderate coronavirus disease 2019 (COVID-19) in adults: • with positive results of direct SARS-CoV-2 viral testing, and • who are at high risk for progression to severe COVID-19, including hospitalization or death, and • for whom alternative COVID-19 treatment options approved or authorized by FDA are not accessible or clinically appropriate 2. Molnupiravir is not approved for any use, including the treatment of COVID-19, but is authorized for emergency use by the FDA under an Emergency Use Authorization (EUA). 3. The emergency use of molnupiravir is only authorized for the duration of the declaration that circumstances exist justifying the authorization of the emergency use of drugs and biological products during the COVID-19 pandemic under Section 564(b)(1) of the Federal Food, Drug, and Cosmetic Act, 21 U.S.C. § 360bbb-3(b)(1) unless the declaration is terminated or authorization revoked sooner. Limitations of Authorized Use 4. Molnupiravir is not authorized: • for use in patients who are less than 18 years of age • for initiation of treatment in patients hospitalized due to COVID-19. Benefit of treatment with molnupiravir has not been observed in subjects when treatment was initiated after hospitalization due to COVID-19 • for use for longer than 5 consecutive days • for pre-exposure or post-exposure prophylaxis for prevention of COVID-19 5. Molnupiravir may only be prescribed for an individual patient by physicians, advanced practice registered nurses, and physician assistants that are licensed or authorized under state law to prescribe drugs in the therapeutic class to which molnupiravir belongs (i.e., anti-infectives). Selected Safety Information Contraindications 6. No contraindications have been identified based on the limited available data on the emergency use of molnupiravir authorized under this EUA. Warnings and Precautions 7. There are limited clinical data available for molnupiravir. Serious and unexpected adverse events may occur that have not been previously reported with molnupiravir use. 8. Molnupiravir is not recommended for use during pregnancy. Based on findings from animal reproduction studies, molnupiravir may cause fetal harm when administered to pregnant individuals. There are no available human data on the use of molnupiravir in pregnant individuals to evaluate the risk of major birth defects, miscarriage or adverse maternal or fetal outcomes. 9. Molnupiravir is authorized to be prescribed to a pregnant individual only after the healthcare provider has determined that the benefits would outweigh the risks for that individual patient. If the decision is made to use molnupiravir during pregnancy, the prescribing healthcare provider must document that the known and potential benefits and the potential risks of using molnupiravir during pregnancy were communicated to the pregnant individual. 10. Advise individuals of childbearing potential of the potential risk to a fetus and to use an effective method of contraception correctly and consistently during treatment with molnupiravir and for 4 days after the final dose. 11. Prior to initiating treatment with molnupiravir, assess whether an individual of childbearing potential is pregnant or not, if clinically indicated. 12. Hypersensitivity reactions, including anaphylaxis, have been reported with molnupiravir. If signs and symptoms of a clinically significant hypersensitivity reaction or anaphylaxis occur, immediately discontinue molnupiravir and initiate appropriate medications and/or supportive care. 13. Molnupiravir is not authorized for use in patients less than 18 years of age because it may affect bone and cartilage growth. The safety and efficacy of molnupiravir have not been established in pediatric patients. Adverse Reactions 14. The most common adverse reactions occurring in ≥1% of subjects in the molnupiravir treatment group in the Phase 3 double-blind MOVe-OUT study were diarrhea (2% versus placebo at 2%), nausea (1% versus placebo at 1%), and dizziness (1% versus placebo at 1%) all of which were Grade 1 (mild) or Grade 2 (moderate). Serious adverse events occurred in 7% of subjects receiving molnupiravir and 10% receiving placebo; most serious adverse events were COVID-19 related. Adverse events leading to death occurred in 2 (<1%) of the subjects receiving molnupiravir and 12 (2%) of subjects receiving placebo. Drug Interactions 15. No drug interactions have been identified based on the limited available data on the emergency use of molnupiravir. No clinical drug-drug interaction trials of molnupiravir with concomitant medications, including other treatments for mild to moderate COVID-19, have been conducted. Breastfeeding 16. There are no data on the presence of molnupiravir or its metabolites in human milk. It is unknown whether molnupiravir has an effect on the breastfed infant or effects on milk production. Based on the potential for adverse reactions in the infant from molnupiravir, breastfeeding is not recommended during treatment with molnupiravir and for 4 days after the final dose. A lactating individual may consider interrupting breastfeeding and may consider pumping and discarding breast milk during treatment and for 4 days after the last dose of molnupiravir. Males of Reproductive Potential 17. Nonclinical studies to fully assess the potential for molnupiravir to affect offspring of treated males have not been completed. Advise sexually active individuals with partners of childbearing potential to use a reliable method of contraception correctly and consistently during treatment and for at least 3 months after the last dose of molnupiravir. The risk beyond three months after the last dose of molnupiravir is unknown.

Before prescribing, please consult the full Prescribing Information.

This health column is published with MSD support.

 

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