The Long View on COVID-19 Theranostics and Oral Antivirals: Living with Endemic Disease and Lessons from Molnupiravir

The Rise of Oral Antivirals for COVID-19

The COVID-19 pandemic is continuing with new virus variants and wide disparities in access to vaccines around the world. Until the COVID-19 vaccines are broadly and equitably accessible around the world, the pandemic will, unfortunately, likely continue in 2022 and possibly beyond. Meanwhile, efforts are underway for oral antiviral drugs for COVID-19, in addition to the vaccines, thus raising some possibility of the pandemic evolving into an endemic disease in the near future, and provided that equitable access to the pandemic health interventions is achieved (Dal-Ré et al., 2022).

Oral antiviral drugs are of broad interest to planetary health in the battle against COVID-19 (Bajaj and Stanford, 2022). Molnupiravir and nirmatrelvir–ritonavir are oral antivirals becoming available around the world in the current historical moment when we are facing the spread of omicron Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) variant globally (Saravolatz et al., 2022). In the case of molnupiravir, the evidence base is evolving (EMA, 2022; WHO, 2022); the drug offers a therapeutic option within 5 days of symptom onset after confirmation of SARS-CoV-2 infection to treat nonhospitalized patients with mild-to-moderate COVID-19 who are at risk of progressing to severe illness (Dal-Ré et al., 2022; Jayk Bernal et al., 2022).

It can be anticipated that the guidelines on oral antiviral drugs will continue to be shaped further as new evidence becomes available on their efficacy and safety, for example, in vaccinated versus unvaccinated persons, across communities with different vaccination histories (e.g., type and dose of vaccines used), COVID-19 disease severity, inpatient and outpatient status, comorbid diseases, virus variants presently known and those that may emerge in the future, among other variables that shape the clinical outcomes with COVID-19 antivirals.

The long view on living with COVID-19 as an endemic disease requires rethinking and expanding the planetary health toolbox (Ho et al., 2022; Imran et al., 2021). We will need an armamentarium of vaccines, small molecule oral antiviral drugs, and biomarkers to forecast drug efficacy and safety. Oral antivirals, as with all drugs, are subject to the age-old adage “one size dose and prescription does not fit all.” There is a need for COVID-19 antiviral drug intervention outcomes to be more predictable, for example, through information garnered from biomarkers and molecular signatures of drug efficacy and safety (Biswas et al., 2022). In this realm, theranostics refers to the fusion of therapeutics and diagnostics scholarship to be able to forecast drug and other health intervention outcomes before they are administered.

COVID-19 Antiviral Theranostics

Theranostics is crucial to individually optimize the emerging COVID-19 oral antiviral medications for their efficacy and safety. Pharmacogenomics is one of the oldest fields under the umbrella concept of theranostics. Pharmacogenomics aims to develop diagnostics for drug efficacy and safety and can be defined as the study of genome-by-drug interactions. Pharmacogenomics, and its processor field pharmacogenetics, offer valuable insights into mechanisms of interindividual variability in drug efficacy and safety (Kalow, 1962; Motulsky, 1957).

As COVID-19 oral antiviral drugs are beginning to emerge in clinical practice, it is time to recall the science of pharmacogenomics and other subspecialties of theranostics such as pharmacoproteomics and pharmacometabolomics. Multiomics research on drug effects and natural products is particularly valuable for drug discovery and development because it helps to triangulate the data-driven findings across the biological hierarchy of molecules and pathways from genomes to proteome to metabolome (Şardaş and Kendirci, 2019; Şardaş et al., 2020; Tietel et al., 2021). Understanding the mechanisms of variations in drug safety and efficacy is fundamental to rational drug development, theranostics, and precision/personalized medicine in the battle against COVID-19.

Pharmacogenomics and theranostics are not in conflict with public health responses against COVID-19 because they contribute to development of new evidence and drugs by helping forecast their pharmacokinetic and pharmacodynamic variability early in the discovery and clinical trials phase.

We examine below the emerging guideposts and ideas of relevance to theranostics discovery and development for COVID-19 oral antiviral drugs with molnupiravir as a case study. The lessons from molnupiravar are of interest to future design of COVID-19 theranostic research with other oral antiviral medications as well (De Anda et al., 2022; Thorlund et al., 2022a, 2022b). There are prospects to advance COVID-19 oral antiviral drugs for planetary health, provided that theranostics is considered and implemented adequately. Theranostics, as already noted, includes and goes beyond pharmacogenomics to make health intervention outcomes more predictable and evidence based.

In addition, placebo and nocebo effects and associated variability in clinical trials might have genetic components based on recent studies. Placebogenomics and nocebogenomics examine the placebo/nocebo–genome interactions, respectively, and, therefore, can inform the design and interpretation of future theranostic research and clinical trials of COVID-19 oral antiviral drugs as well.

Emerging Theranostic Guideposts from Molnupiravir

Oral antivirals that target the viral RNA-dependent RNA polymerase are drawing growing attention in a context of stemming the current COVID-19 pandemic, and looking further into the future, for governance of the endemic disease (Masyeni et al., 2022). Oral antiviral therapies that prevent the progression of COVID-19 would also have crosscutting positive impacts by preventing or reducing the pressures on health systems and services around the world. The burden of COVID-19 on national health systems negatively impacts the care of other infectious diseases or common chronic diseases such as cancer or elective surgeries. Oral antivirals for management of COVID-19 as a pandemic and endemic disease would help relieve the pressures on national health systems to be sure.

Molnupiravir offers interesting theranostic prospects in a realm of oral antivirals. Theranostics would guide clinical use of oral antivirals toward precision medicine but also help interpret the COVID-19 clinical trial outcomes. The World Health Organization (WHO) living guideline on the clinical question of “what is the role of drugs in the treatment of patients with COVID-19?” follows a stepwise approach to monitor, synthesize, and curate evidence and recommendations (WHO, 2022). Accordingly, the guideline published on March 3, 2022, suggests “administering molnupiravir in patients with non-severe illness, who are at highest risk of hospitalization with implementation of mitigation strategies to reduce potential harms” and “excluding pregnant and breastfeeding women, and children” at this time.

Although the guideline is a “living” document, and will certainly evolve and change with time and new evidence, the emerging lessons from molnupiravar are informative for the precision design of COVID-19 antiviral theranostics.

On the efficacy dimension, as an oral antiviral medication, molnupiravir is the 5′-isobutyrate prodrug of the antiviral ribonucleoside analogue β-D-N⁴-hydroxycytidine (NHC). The mechanism of action of molnupiravir is based on lethal RNA mutagenesis and, thus, differs from other nucleoside analogue antivirals (e.g., remdesivir) that cause chain termination (Gordon et al., 2021; Kabinger et al., 2021). Molnupiravir is an inhibitor of the viral RNA-dependent RNA polymerase that plays an important role in the replication of SARS-CoV-2 (Fig. 1).

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FIG. 1.

Emerging pathways to theranostic innovation for molnupiravir efficacy and safety clinical endpoints. NHC, β-D-N⁴-hydroxycytidine.

The cellular uptake results in endogenous phosphorylation to ribonucleoside triphosphate β-D-N⁴-hydroxycytidine-triphosphate (NHC-TP), the active form of molnupiravir, which binds to the genome of viral RNA (guanosine or adenosine), and then can be substituted to either cytidine or uridine triphosphate by viral RNA polymerase. The NHC incorporated by the SARS-CoV-2 RNA-dependent RNA polymerase results in NHC-containing RNAs that cannot form functional viruses. Molnupiravar is administered twice daily as an oral medication that might offer advantages in the COVID-19 clinic to fight both the pandemic and its future envisioned endemic disease form, compared with other antivirals such as remdesivir administered by intravenous infusion once daily.

On the safety dimension, as of March 2022, per the WHO living guideline already noted (WHO, 2022), it is acknowledged that there is uncertainty on whether or not molnupiravir is carcinogenic in humans. It is noted that although molnupiravir is mutagenic in vitro, animal models do not presently support mutagenicity. This uncertainty also offers a window for future theranostic studies that can examine molnupiravir mutagenicity as well as side effects in clinical trials, for example, in relation to interindividual variabilities in pharmacokinetic exposures and its activation from prodrug to the active form.

Molnupiravir is reportedly hydrolyzed to NHC by high capacity esterases CES1 and CES2 and “in intestinal and liver microsomes as well as plasma” (EMA, 2022). Per European Medicines Agency (EMA) assessment report dated January 27, 2022, on use of mulnopiravir for treatment of COVID-19, “in vitro, NHC was found to be a substrate of the human nucleoside transporters CNT1, CNT2, CNT3, and ENT2 while molnupiravir was a comparatively weak substrate of CNT1, and neither molnupiravir nor NHC were substrates of human MDR1 P-gp or BCRP” (EMA, 2022).

We note that at this early days of theranostics considerations for oral antivirals against COVID-19, these emerging evaluations offer important molecular leads from a preclinical standpoint that warrant evaluation in vivo and in clinical biomarker studies. Genetic and multiomics variations in these molecular candidates can form a useful basis to design clinical studies aimed at explaining variable pharmacokinetics and pharmacodynamics of both molnupiravar and its active form.

For both efficacy and safety endpoints of molnupiravar, and based on studies in vitro, the EMA assessment highlights that “molnupiravir is not an inhibitor of major human CYPs (CYP1A2, 2B6, 2C8, 2C9, 2C19, 2D6, and 3A4),” although these observations were made at an NHC concentration “approximately 10-fold the clinical Cmax” values and, therefore, offering rather limited informational value for mulnopiravar pharmacokinetic variability or the risk for drug–drug or drug–herb interactions. In this context, we wish to emphasize that theranostic studies are of interest not only for explaining and forecasting efficacy and safety endpoints but also for the propensity for drug–drug and drug–herb interactions.

At present, rational treatment of COVID-19 with molnupiravar and other oral medications is hampered by several issues, from access to medicines to the presence of marked heterogeneity and interindividual variations in treatment outcomes, and lack of reported theranostic and multiomics diagnostics of treatment outcomes, be it efficacy or safety related.

The recently reported phase 3 double-blind randomized placebo-controlled trial with molnupiravar is of particular interest (Jayk Bernal et al., 2022). The latter clinical trial evaluated the “efficacy and safety of treatment with molnupiravir started within 5 days after the onset of signs or symptoms in nonhospitalized, unvaccinated adults with mild-to-moderate, laboratory-confirmed COVID-19 and at least one risk factor for severe COVID-19 illness” (Jayk Bernal et al., 2022). Participants received 800 mg of molnupiravir or placebo twice daily for 5 days in a randomized design.

The incidence of hospitalization or death at day 29 was the primary efficacy end point. The trial authors concluded that “early treatment with molnupiravir reduced the risk of hospitalization or death in at-risk, unvaccinated adults with COVID-19.” (Jayk Bernal et al., 2022). However, the treatment effects were substantially attenuated when examining the full data. Hence, there is a need for ongoing evaluation and trials of molnupiravir in diverse clinical contexts, for example, in vaccinated and unvaccinated persons, different virus variants, and in persons who are seropositive due to natural immunity (see also Thorlund et al., 2022a).

All in all, the phase 3 clinical trial already noted (Jayk Bernal et al., 2022) and the current debates on utility of molnupiravir in the battle against the COVID-19 pandemic and as an endemic disease would be well informed by investments in theranostic research to determine the mechanisms and biomarkers of clinical effects of molnupiravir in subpopulations and individual patient resolution. In this context, a conceivable focus area for theranostics research is the reported variations in the omicron variant that has mutations in the RNA-dependent RNA polymerase, the target for antiviral drugs such as molnupiravir.

Bansal and Kumar reported that “18,261 mutations were detected among 302 high-quality genomes of omicron variant majority of which were non-synonymous in the coding region” (Bansar and Kumar, 2022). About 20% of the nonsynonymous mutations were noted in the RNA-dependent RNA polymerase. In contrast, the preclinical activity of molnupiravir against the omicron variant appears to be maintained (Takashita et al., 2022), whereas clinical data are lacking in this context.

This is also the very context and opportunity for clinical theranostics studies in relation to the reported genetic variations in the omicron viral RNA-dependent RNA polymerase, with an eye to explaining and forecasting the clinical outcomes in molnupiravir-treated patients. Such theranostic studies ought to be designed carefully because multiple factors can confound the interpretation of variability in COVID-19 clinical outcomes in patients administered molnupiravir.

Two years into the pandemic, there are wide disparities in access to COVID-19 vaccines, not to mention differences in infection history and the prevalence of virus variants in various countries and geographies. Chief among the confounders that need to be accounted for are previous vaccination history, the country-specific virus variant prevalence rates, and prior documented infection history. Other confounders such as age, comorbid illness, obesity, outpatient or inpatient status, the dose range of the oral antiviral medication used to treat COVID-19, timing of the pharmacotherapy intervention (early or late in the course of the clinical signs and symptoms), among others, warrant careful planning in design and interpretation of clinical theranostic studies in the future.

Outlook

We anticipate that the current focus on categorically establishing, at a group or categorical level, the efficacy and safety of emerging oral antiviral medications for COVID-19, will soon be expanding with guidance from “the science of variability” or pharmacogenomics and allied disciplines of theranostics scholarship.

As the field of COVID-19 medications evolves from discerning their effects at group resolution to a finer granular scale at the level of subpopulations or individual patients, genetic variations in the RNA-dependent RNA polymerase, and other molecular leads of interest to molnupiravir (Fig. 1) in current and future virus variants will likely draw considerable theranostics research attention and investments. The design and data interpretation-related considerations noted in this article are broadly relevant to clinical theranostic studies of other oral antivirals, and be it for treatment or prevention from COVID-19.

One of the key considerations to sort out the veritable hope from oral antivirals for COVID-19 versus hype versus reality is to better understand the preclinical and clinical consequences of genetic and other biological (structural and/or functional) differences in drug targets as well as in their pharmacokinetics. For the latter, there has not been adequate research attention on the extent to which exposure to molnupiravar and its active form in the peripheral blood compartment versus at the tissue level impacts the clinical outcomes. It is noteworthy in this context that Fitzgerald et al. (2022) observed “saliva NHC concentrations that were 3% that of plasma, whereas exposure in nasal secretions and tears was higher at approximately 20% that of plasma (based on pooled AUC_0-4 ratios).”

Because COVID-19 is a systemic disease affecting multiple organs, clinical theranostic studies would be well served by including multiple end points related to established and putative effects of the virus in multiple organ systems and biological pathways. In effect, this would enrich the phenotype data that can be harnessed for theranostic biomarker discovery in ways that stand the test of the complexities of clinical practice and the virus variants.

With new virus variants, genetic changes in the molnupiravir efficacy target, viral RNA-dependent RNA polymerase, variability in pharmacokinetics and exposure to molnupiravir active moiety in fluids on virus entry points to the host (e.g., saliva, tears, and nasal secretions), activation from prodrug molnupiravir to its active form, variability in putative adverse effects on human/host cells, all warrant attention for prospects and challenges vis à vis theranostics biomarker discovery.

Regulatory agencies, the pharmaceutical industry, research funders, governments, and the ministries of health have important stewardship roles to play to advance the subpopulation level analyses of clinical trial data on oral antiviral drugs for COVID-19. This would help address the current lag in development of clinically relevant theranostics and multiomics biomarkers on antivirals drugs for COVID-19.

We do not currently know the long-term effects, in the order of years and decades, of repeated exposures and episodes of COVID-19 on human health and in special populations. To the extent that COVID-19 will likely stay with humans as an endemic disease, drug interventions will be important to prevent and treat COVID-19 and its long-term consequences. Looking further, let us bear in mind that natural products and systems ecology will also play a role in COVID-19 drug discovery (Şardaş et al., 2020). This is also the very context wherein we will need to sort out the hope, hype, and reality.

Tietel et al. (2021) have recently noted in a context of the value of multiomics systems science research, “plant omics research offers an important avenue to inform, verify, and strengthen the evidentiary base and clinical testing of herbs with medicinal potentials.” Grounding the current and future scholarly inquiries on COVID-19 antivirals and theranostic discoveries on evidence substantiated by omics systems science data, both in preclinical and clinical phases, would be invaluable to dissect the hype and reality and build on the latter instead of the former in future public health innovations to end the COVID-19 pandemic and for its long-term governance in planetary health.

Although the genetic determinants, mechanisms, and theranostic biomarkers are established and deployed to date for many pharmaceuticals, biomarkers for emerging COVID-19 antivirals and molecular candidates have not been firmly on the global research and development agenda. We think that it should. This article advocates for a vision that embodies evidence-based precision medicine and theranostics-guided development of COVID-19 oral antivirals, and in ways informed by validated biomarker evidence. Incorporating in-depth knowledge of theranostics and multiomics systems science should, therefore, be prioritized in clinical studies in the near future.