Urgent needs to accelerate the race for COVID-19 therapeutics
Sustainable Development Goals: 3
- SDG 3 - Good Health and Well-Being
On December 8, 2020, a 91-year-old woman made history as the first person to receive the COVID-19 vaccine in the United Kingdom. Worldwide vaccination coverage will take time, especially in low-middle-income countries (LMICs) where access to coronavirus vaccines is limited and health systems are ill equipped to deal with sustained pressures associated with COVID-19. Meanwhile, hospital and critical care capacity will remain strained and basic therapies, including oxygen, are in urgent short supply.
COVID-19 has disproportionately impacted the world's poorest and most vulnerable, posing additional challenges in achieving the Sustainable Development Goals.
In addition to basic supportive therapies, there are still not enough effective therapeutic interventions widely available. There remains an urgent need to develop efficacious COVID-19 therapeutics to prevent severity and mortality, and to forestall the collapse of overburdened health systems in resource-limited settings.
It has been over a year since the world's biomedical community began to contend this novel coronavirus. Having effective treatments to target COVID-19 stages would lead to significant benefits. These include treatments to (i) prevent the development of infections (ii) prevent disease progression, and (iii) reduce mortality. To better understand COVID-19 therapeutics, much had to be learned about the virus, disease evolution, how to conduct trials under pandemic conditions, and how to link testing and treatment strategies.
Two major therapeutic strategies based on disease pathophysiology were developed: antiviral agents, which aim to stop virus spread in the respiratory tract, and host-directed therapeutics (anti-inflammatory and immunomodulators), which have mostly become later-stage interventions aimed at preventing downstream consequences of severe COVID-19.
Initial efforts focused primarily on stemming the high mortality rates in critical patients and in drug repurposing. Several drugs demonstrated mechanistic plausibility and were initially tested for their in vitro activity on virus replication. Antiparasitic drugs, such as hydroxychloroquine and ivermectin, and antiviral drugs, such as lopinavir/ritonavir, were widely used while clinical trials were being conducted. Despite early hopes, results from multiple clinical studies did not meet expectations, hence not supporting use of these drugs especially for severe cases. However, despite lack of evidence, indiscriminate prescription with these drugs in many countries has fueled misinformation and controversy.
According to WHO, more than 2800 COVID-19 drug trials have been registered thus far. International platforms, such as RECOVERY, SOLIDARITY, PRINCIPLE, DISCOVERY, REMAP-CAP, TOGETHER, ANTICOV, are leading efforts to recruit large numbers of subjects while pharmaceutical companies are conducting their own trials. Global coordination, increased funding, comparable endpoints, open-source data repository and real-time information sharing will be key to meeting increasing demands for effective COVID-19 therapeutics.
Although much has been learned, questions remain about predictive factors for disease evolution and best approaches across the COVID-19 continuum, ranging from asymptomatic or mildly symptomatic patients to those hospitalized or who are critically ill, and to those living with long-term sequela of infection, as well as the impact of emerging variants on treatment efficacy. Therefore, widely available safe and effective antiviral therapies, administered early could help alleviate patient burden and potentially diminish the need for hospitalization.
To date only few drugs have been approved, registered, received Emergency Use Authorization (EUA) or qualified for WHO Emergency Use Listing. These include dexamethasone, remdesivir, bamlanivimab administered with etesevimab, casirivimab plus imdevimab, convalescent plasma, and the combination of baricitinib and remdesivir. Variable recommendations by different entities reflect the challenges to analyze, standardize and translate evidence into clinical guidelines including updates for immunomodulators such as tocilizumab and medications used for thromboprophylaxis. This reinforces the need to both harmonize and streamline clinical trials, while avoiding using the pandemic as an exception to Good Clinical Practices.
Despite considerable policy and financing attention on vaccine development, the world still faces shortfalls in manufacturing capacity and supply for vaccines that have received emergency use authorization. This reinforces the need for greater global collaboration at early stages (pre-approval) so that overall capacity (especially biologics capacity) is optimally allocated to the most efficacious and field-adapted therapeutics (Table 1). It will also facilitate addressing proactively any upstream supply constraints. This is the mandate of the therapeutics pillar of ACT-A.