PCORI Biweekly COVID-19 Scan: Treatments for Hospitalized Patients and Patients with Mild to Moderate COVID-19 (October 28-November 10, 2021)
The Briefing provides an at-a-glance view of some important developments in the information universe surrounding COVID-19. The views presented here are solely those of ECRI Horizon Scanning and have not been vetted by other stakeholders.
The quest to develop antivirals to treat COVID-19 before hospitalization is at a turning point. Study results were reported for molnupiravir (Lagevrio), which cut the risk of hospitalization and death by 50%, and results are also available for Paxlovid, which decreased risk by 89% (see Topics to Watch). Developers are now executing plans to submit for Emergency Use Authorization (EUA) as soon as possible to make these treatments available to patients.
Concerns exist, however, regarding treatment timing, the risks of antiviral resistance due to viral mutations, and the risks to patients taking the medicine. In addition, antiviral drugs must be taken while the virus is replicating, but before widespread inflammation begins. Some experts, interviewed by Science, do not share these concerns though and note that the combination of 2 antivirals, such as molnupiravir and Paxlovid, could reduce the chance of the coronavirus becoming resistant to either drug.
Vaccination remains the best defense against severe COVID-19. A recent case-control study of more than 4000 hospitalized participants showed that mRNA vaccines are associated with an 85% reduction in COVID-related hospitalization.
ECRI Horizon Scanning has selected the topics below as those with potential for impact relative to COVID-19 in the United States within the next 12 months. All views presented are preliminary and based on readily available information at the time of writing.
Because these topics are rapidly developing, we cannot guarantee the accuracy of this information after the date listed on this publication. In addition, all views expressed in the commentary section are solely those of ECRI Horizon Scanning and have not been vetted by other stakeholders. Topics are listed in alphabetical order.
EB05 to Treat Patients Hospitalized with COVID-19
At a Glance
- Investigators are studying EB05, a monoclonal antibody, to treat patients hospitalized with a COVID-19–related respiratory disease.
- EB05 purportedly inhibits Toll-like receptor 4 (TLR4) signaling to alter inflammatory signaling and dampen the proinflammatory cascade associated with severe COVID-19 outcomes, including organ failure and death.
- Data released in October 2021 showed that EB05 given with standard of care resulted in a reduction in risk of death for multiple patient groups, including patients who were critically ill and hospitalized and patients with acute respiratory distress syndrome (ARDS) receiving supplemental oxygen.
- Basing its decision on favorable signals from a phase 2 trial, the manufacturer has announced plans to continue development in a phase 3 trial.
EB05 (Edesa Biotech, Inc, Markham, Ontario, Canada) is an investigational monoclonal antibody under development to treat patients hospitalized with a COVID-19–related respiratory disease.
One of the leading causes of death in patients with COVID-19 is ARDS. During initial infection, the viral spike protein purportedly binds to and activates TLR4, a transmembrane protein that triggers the release of proinflammatory cytokines. Proinflammatory cytokines are a natural part of combating infection, but an excessive release of these cytokines leads to ARDS, resulting in critical lung injury, organ failure, and death. EB05 dampens TLR4 signaling by blocking receptor aggregation to limit inflammatory signaling in patients with COVID-19 and prevent further injury to the body.
Results from a phase 2 trial investigating the use of EB05 given with the standard of care (SOC) to 396 hospitalized patients with COVID-19 found that the treatment resulted in mortality reductions across multiple patient groups. When compared with placebo and SOC, critically ill hospitalized patients treated with EB05 and SOC had a 68.5% reduction in mortality. Death at 28 days for patients with severe ARDS, who were receiving supplemental oxygen, was 16.7% for the EB05 and SOC group compared with 42.9% in the control group receiving placebo and SOC. Confirmatory efficacy signals were also found in patients with mild to moderate ARDS given EB05 plus SOC, who had a 28-day mortality rate of 7.8% compared with 11% in the placebo plus SOC group. In the trial, EB05 was administered as a single intravenous infusion at a dose of 15mg/kg.
The company announced plans to conduct a phase 3 trial to evaluate the efficacy of EB05, with priority given to enrolling participants who are critically ill with COVID-19. We were unable to find information regarding the potential cost of a treatment course of EB05.
Uncontrolled protein signaling and release of cytokines as a result of COVID-19 infection can be detrimental to patients. Treatment with EB05 might improve patient health outcomes by mitigating hyperinflammatory immune responses associated with ARDS.
Early feedback from ECRI internal stakeholders suggested that, if effective, EB05 might improve patient health outcomes by ameliorating hyperinflammation-induced injury to multiple organs and reducing risk of death due to COVID-19. Although there may be a significant initial cost of treatment, the treatment might reduce overall healthcare costs associated with hospitalizations and intensive care resources, thereby lessening the burden on the healthcare system. The initial data from the phase 2 trial suggesting that EB05 reduces COVID-19 mortality are encouraging. More data and additional clinical trials are needed to determine how effective the treatment is relative to other COVID-19 treatments and to better define which patient populations are most likely to benefit.
Stakeholders expressed concerns that EB05 might increase healthcare disparities for patients who are unable to access the infusion centers that are offering this intravenous treatment. Media coverage of improved treatments might also deter unvaccinated individuals from getting vaccinated because of the belief that effective treatment is available if they were to become infected.
- Areas of potential impact: Patient outcomes, patient management, health care disparities, health care costs
PF-07321332 Plus Ritonavir (Paxlovid) to Treat Mild to Moderate COVID-19
At a Glance
- PF-07321332 in combination with ritonavir (Paxlovid) is an oral antiviral that Pfizer is investigating to treat adults who have symptomatic COVID-19 in the outpatient setting.
- A protease inhibitor, PF-07321332 is thought to hinder the activity of the main protease enzyme that the SARS-CoV-2 virus requires for replication.
- Interim data from a phase 2/3 randomized controlled trial in nonhospitalized adult patients with COVID-19 at high risk of progressing to severe illness found that Paxlovid reduced hospitalization or death by 89% in patients treated within 3 days of symptom onset.
- Basing its decision on these data, the manufacturer plans to submit an EUA to the US Food and Drug Administration (FDA) for Paxlovid.
PF-07321332 in combination with ritonavir (Paxlovid) is an oral antiviral under investigation to treat nonhospitalized adults who have symptomatic COVID-19. Although most people with COVID-19 develop mild symptoms, individuals can develop severe disease regardless of their risk factors. Paxlovid might address the unmet need for an oral COVID-19 treatment that patients can take early in the disease course to prevent disease progression, hospitalization, and death from COVID-19.
PF-07321332 is a 3-chymotrypsin-like (3CL) cysteine protease inhibitor that purportedly binds to and hinders the activity of SARS-CoV-2-3CL protease. The SARS-CoV-2-3CL protease breaks down polyproteins into mature nonstructural proteins required for viral replication. PF-07321332 was developed to interfere with this process, preventing replication of the virus. Ritonavir was added to the drug formulation to slow the metabolism of PF-07321332, allowing it to stay in the body longer at higher concentrations. In clinical trials, Paxlovid is taken by mouth at an unspecified dose every 12 hours for 5 days.
In November 2021, interim data were reported from a phase 2/3 randomized controlled trial in 1219 nonhospitalized adult patients with COVID-19 at high risk of progressing to severe illness. Investigators found that Paxlovid reduced hospitalization or death by 89% in patients treated within 3 days of symptom onset compared with placebo (0.8% vs 7%) through 28 days after treatment. No deaths were reported in the Paxlovid group, compared with 7 deaths in the placebo group.
Basing its decision on this positive data, Pfizer has halted the EPIC-HR study and plans to submit the data to the FDA to support a rolling EUA submission. Paxlovid is also being studied in 2 additional phase 2/3 trials: a trial in patients at low risk of disease progression had primary completion expected in October 2021, while a trial of Paxlovid as a postexposure prophylaxis has a primary completion date of December 2021. We were unable to find information regarding the potential cost of a treatment course of Paxlovid.
Paxlovid is an investigational oral antiviral therapy for treating mild to moderate COVID-19 in the outpatient setting. Early treatment with Paxlovid might prevent progression to severe disease and limit community transmission, improving patient and population health outcomes.
Initial feedback from ECRI internal stakeholders suggested that an oral treatment that patients can take at home might be more convenient and improve treatment compliance, compared with monoclonal antibody treatment that requires intravenous administration in a healthcare setting. If Paxlovid inhibits viral replication and shortens the duration of infection, it might reduce the burden of COVID-19 on the health care system by decreasing costs, resource use, hospitalizations, long-term complications, and death.
However, the availability of outpatient treatments might dampen efforts to increase the vaccination rate, potentially prolonging the pandemic and increasing the risk of more infectious variants. Additional data on this intervention and comparative effectiveness studies for this indication are needed.
- Categories: Treatment
- Areas of potential impact: Patient outcomes, patient management, health care disparities, health care costs
Horizon scanning is a systematic process that serves as an early warning system to inform decision makers about possible future opportunities and threats. Health care horizon scanning identifies technologies, innovations, and trends with potential to cause future shifts or disruptions—positive or negative—in areas such as access to care, care delivery processes, care setting, costs of care, current treatment models or paradigms, health disparities, health care infrastructure, public health, and patient health outcomes.
The PCORI Health Care Horizon Scanning System (HCHSS) conducts horizon scanning to better inform its patient-centered outcomes research investments. Initially, PCORI defined the HCHSS project scope to focus on interventions with high potential for disruption in the United States in 5 priority areas: Alzheimer’s disease and other dementias, cancer, cardiovascular diseases, mental and behavioral health conditions, and rare diseases. In addition, the system captures high-level disruptive trends across all clinical areas, which may lead PCORI to expand the project scope to include other priority areas in the future.
In early 2020, the COVID-19 pandemic created a fast-moving, widespread public health crisis. In May 2020, PCORI expanded its HCHSS to elucidate the landscape of potentially impactful applications for COVID-19. The HCHSS COVID-19 supplement scans for, identifies, monitors, and reports on emerging and available COVID-19-related treatments, diagnostics, preventive measures, management strategies, and systems changes with potential for high impact to patient outcomes—for individuals and populations—in the United States in the next 12 months.
The HCHSS COVID-19 supplement produces 3 main outputs:
- Biweekly COVID-19 Scans (eg, this document) provide ECRI Horizon Scanning with a vehicle to inform PCORI and the public in a timely manner of important topics of interest identified during ongoing scanning and topic identification or through the ECRI stakeholder survey process.
- Status Reports (quarterly) briefly list and describe all COVID-19-related topics identified, monitored, and recently archived.
- High Impact Reports (every 4 months) highlight those topics that ECRI internal stakeholders (eg, physicians, nurses, allied health professionals, public health professionals, first responders, health systems experts, clinical engineers, researchers, business and finance professionals, and information technology professionals) have identified as having potential for high impact relative to COVID-19 in the United States.
Commentary in this COVID-19 Scan reflects preliminary views of ECRI Horizon Scanning and internal ECRI stakeholders.
The information contained in this document has not been vetted by other stakeholders.
We welcome your comments on this Scan. Send them by email to [email protected]
or by mail to: Patient-Centered Outcomes Research Institute, 1828 L Street, NW, Suite 900, Washington, DC 20036.
Posted: November 22, 2021