Guest Column | September 8, 2023

Vulnerable Populations Need Safer, More Effective COVID-19 Antivirals

By Robert Murphy, M.D.

COVID-oral antiviral therapeutic treatment-GettyImages-1310961647

The U.S. federal and state governments, together with global governmental and non-governmental entities, no longer classify COVID-19 as a public health emergency, largely due to unprecedented innovations in vaccines and antiviral treatments. But this determination and these tools leave elderly and immunocompromised individuals vulnerable to severe outcomes.1,2,3 As such, we as drug developers must adapt our approach to the treatment of COVID-19 by delivering innovative next-generation oral antivirals through clinical trials that incorporate the lessons we have learned during the pandemic over the past three years and address the pressing needs of these high-risk patients.

High-risk Groups Remain Vulnerable To COVID-19

According to the CDC, even now, over 7,000 individuals are hospitalized with COVID-19 each week, and an alarming majority of these cases are elderly individuals. In a recent CDC analysis, people between the ages of 65-74 were five times more likely to be hospitalized and 60 times more likely to die from COVID-19 compared to adults aged 18-29. These risks rise significantly with age, as people above 75 are over nine times more likely to be hospitalized and over 140 times more likely to die from COVID-19 compared to 18-29-year-olds.4

People over 65 generally experience age-related declines in the immune system and are more likely to have one or more chronic health conditions that can make COVID-19 more severe.5,6 For example, those with cardiovascular disease, diabetes, dementia, or chronic lung disease are at an increased risk of developing severe complications from COVID-19.3

Additionally, immunocompromised people, those with weakened immune systems due to a medical condition (e.g., cancer, HIV/AIDS, organ transplantation) or certain immunosuppressive medications (e.g., steroids), are also at an increased risk of severe COVID-19 outcomes.7 Although vaccines can provide some protection, vaccinated people with suppressed immune systems are about 2.5 times more likely to be hospitalized with COVID-19 and 2.8 times more likely to die from COVID-19 than vaccinated immunocompetent patients, as immunocompromised patients are often unable to mount a robust immune response to the vaccine.8,9

Therefore, there is a need for new oral antiviral drugs that offer improved treatment options for these vulnerable populations.

Essential Features Of Next-generation Oral COVID-19 Antiviral Drugs

A new generation of oral antiviral drugs is being developed to keep pace with the current treatment challenges and address future needs. Next-generation COVID-19 oral antivirals must incorporate lessons learned from the COVID-19 pandemic and help close lingering treatment gaps by providing a robust line of defense, ensuring greater safety and tolerability for use with concurrent therapies and for future combination therapies, sustaining efficacy against future viral variants, and allowing convenient oral delivery.

Robust Line of Defense

Oral antiviral drugs serve as a critical line of defense, especially as the rapidly evolving SARS-CoV-2 virus evades other protective measures like vaccines and monoclonal antibodies (mAbs).

The effectiveness of vaccines can vary depending on the individual’s immune response and the specific variant of COVID-19. For example, initial mRNA vaccines developed by Pfizer-BioNTech and Moderna were 95% effective at preventing symptomatic COVID-19 in adults against the original COVID-19 strain.10 Updated bivalent boosters of these vaccines, however,  are only around 58% effective at preventing hospitalizations due to COVID-19 Omicron variants.11 Similarly, the original mAbs, which once protected individuals with weakened immune systems, became ineffective against emerging COVID-19 viral variants, leaving these patients with limited protective options.12,13

Therefore, next-generation oral antiviral drugs must strengthen the lines of defense against severe COVID-19 outcomes, particularly in elderly and immunocompromised populations, and given that the effectiveness of oral antivirals does not solely rely on the individual’s immune response but on the ability to inhibit viral replication, oral antivirals are well suited for this.14 Two antiviral drugs are currently approved by the FDA, and one is authorized under an Emergency Use Authorization to treat mild to moderate COVID-19. Next-generation COVID-19 antiviral drugs should continue to build upon this success while addressing additional limitations.15

Remain Active Against Variants

SARS-CoV-2 continues to be a rapidly mutating virus, with several variants of concern emerging since the start of the COVID-19 pandemic, including Alpha, Beta, Gamma, Delta, and Omicron variants, each with additional sublineage variants. These evolutions have made the virus more transmissible and resistant by evading natural immunity, vaccine-induced immunity, or mAbs.16

Vaccines and mAbs primarily target specific parts of the SARS-CoV-2 virus that are highly susceptible to mutations, such as the spike protein; however, when the virus undergoes mutations, it can alter these spike protein targets, hindering the ability of vaccines and mAbs to bind effectively, thereby reducing their efficacy. Additionally, these rapidly evolving resistance mechanisms make it challenging for the immune system to keep pace, leading to a decline in the natural immunity acquired from previous infections.16

Thus, next-generation COVID-19 oral antivirals need to confront these challenges and ensure broad protection against both present and future COVID-19 variants. Promising solutions include targeting areas of the virus less prone to mutation or employing antiviral strategies with multiple mechanisms of action to create a higher barrier to resistance.17

Effective and Safer With Improved Tolerability for Therapeutic Combinations

The current generation of COVID-19 antiviral treatments has the ability to reduce the risk of severe outcomes.18,19 There are currently two approved antiviral therapies: Veklury (remdesivir) and Paxlovid (ritonavir-boosted nirmatrelvir) and one authorized antiviral, Lagevrio (molnupiravir). These current antiviral treatments, however, pose efficacy, safety, and tolerability concerns, such as intravenous administration in the case of Veklury, significant drug-drug interactions in the case of Paxlovid, and potency concerns in the case of Lagevrio, that frequently prevent or discourage vulnerable patients from receiving these treatments.

For example, Paxlovid has shown a significant risk for dangerous drug-drug interactions with many commonly prescribed medications, including heart, neuropsychiatric, and pulmonary hypertension drugs.20 These interactions are particularly concerning for elderly adults, who are most at risk for severe COVID-19 but also likely to have comorbidities requiring many of these concurrent medications.21 Additionally, while the data on drug-drug interactions are limited for the only approved COVID-19 drug, Veklury, a drug that can only be administered intravenously, there have been toxicity concerns for patients with renal insufficiencies.22 Lagevrio, an orally administered antiviral treatment, has potency concerns and may be harmful to the fetus if given during pregnancy.23

Therefore, next-generation COVID-19 oral antiviral treatments must be designed and clinically investigated with these safety and tolerability limitations in mind. In addition to comorbidity medications, new COVID-19 treatments should be tolerable and safe enough to be combined with one or more other antiviral drugs to enhance efficacy through combination treatment regimens like those that have shown success against other viral threats like HIV and hepatitis C virus.24

Next-generation COVID-19 treatments can achieve this by selectively targeting the SARS-CoV-2 virus by utilizing mechanisms of action or metabolic pathways that do not interfere or interact with other medications or antivirals.

Oral Delivery Offers Upsides for Patients, Pharma, and HCPs

Veklury, one of the two approved antiviral COVID-19 treatments, requires intravenous infusions at a healthcare facility for three consecutive days, which can be inconvenient and burdensome for many patients.22 Therefore, next-generation COVID-19 antiviral drugs must enable convenient oral delivery without sacrificing efficacy and safety to ease the burden on patients and their caregivers.

Moreover, oral treatments are more accessible with improved scalability, as they can be generally manufactured at less cost and distributed more readily than injectable medications.25 These features are especially crucial in communities where geographical or financial barriers limit healthcare access.26

Oral antiviral treatments, which can be safely administered at home, also reduce the unprecedented strain on healthcare systems that the COVID-19 pandemic placed on hospitals and clinics worldwide.27 This convenience of administration is important to reduce overall healthcare costs and will be particularly instrumental in easing strains on healthcare systems during potential future COVID-19 outbreaks.

Clinical Trial Designs Must Evolve As COVID-19 Evolves

Beyond drug design, delivering successful next-generation COVID-19 treatments also requires clinical trial innovation. After initially hastening trials early in the pandemic, designing trials that address the most pressing current unmet needs is now most crucial. These include prioritizing vulnerable populations, selecting meaningful endpoints, and investigating combination approaches that can protect against unpredictable future variants.

Rather than casting a wide net, clinical trials should now exclusively enroll participants from high-risk groups (e.g., elderly and immunocompromised adults) to investigate the efficacy and safety of next-generation COVID-19 treatments in those who stand to benefit the most and who likely respond differently than less-vulnerable individuals. This tailored approach also can help assess the tolerability of these treatments with other medications that trial participants may be taking to identify potential drug-drug toxicities as early as possible.

And now that the goals for COVID-19 therapies have become more evident since we better understand its disease progression patterns, drug developers should prioritize the most meaningful trial endpoints for these vulnerable groups at this stage. This means moving away from symptom-focused primary endpoints toward those that include all-cause hospitalization and mortality, with secondary endpoints that address lingering COVID-19 complications commonly referred to as long COVID or post-COVID conditions.

Additionally, COVID-19 has continued to evolve rapidly and evade existing antiviral tools, making it difficult for drug developers and clinical trials to keep pace.16 But history shows that combination antiviral regimens are the most effective at fighting highly resistant viral threats.24 So, trial designs incorporating antiviral combination arms will likely produce the most effective, comprehensive solutions for unpredictable future viral threats.

Of course, these additional clinical trial considerations will likely require innovations and adaptive measures to ensure sufficient trial participation from intended groups and robust evaluable data. Potential solutions include adopting decentralized trial models that can reach participants in diverse locations, using remote patient health and compliance monitoring technologies, integrating real-world evidence to complement randomized clinical trial data, and incorporating flexible trial designs that adapt to address ongoing trial challenges.28,29

The SUNRISE-3 trial (NCT05629962) is an example of an ongoing trial that has been designed to meet the most pressing continuing challenges associated with COVID-19. The global Phase 3 registrational trial, which is investigating the oral antiviral drug bemnifosbuvir, will consist of patients ≥70 years old (regardless of other risk factors), patients ≥55 years old with one or more risk factors, patients ≥50 years old with two or more risk factors, and patients ≥18 years old with certain risk factors, including immunocompromised conditions, all regardless of COVID-19 vaccination status. Patients with decreased renal function also will be eligible for the trial.30

The trial also prioritizes meaningful endpoints for these high-risk groups, with a primary endpoint of all-cause hospitalization or death through Day 29 in the population of approximately 2,200 patients evaluating bemnifosbuvir as a monotherapy. Secondary endpoints include COVID-19 complications, medically attended visits, symptom rebound/relapse, and viral load rebound. The trial also incorporates outpatient care and allows co-administration of the locally available standard of care as a secondary analysis in a separate combination antiviral population.30

Overall, COVID-19 is still threatening many vulnerable groups, and we must leverage key lessons learned to innovate next-generation antiviral treatments and progress clinical trials to address the most pressing needs of vulnerable patients. Such innovations should deliver targeted, comprehensive, and robust therapeutics for these vulnerable groups, ultimately enabling more definitive control over COVID-19.


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About The Author:

Dr. Robert Murphy is Professor of Medicine and Biomedical Engineering, the John P. Phair Professor of Infectious Diseases, and executive director of the Havey Institute for Global Health at Northwestern University in Chicago.