Operation Warp Speed (OWS), an initiative of the US Department of Health and Human Services and the Department of Defense in partnership with the private sector, provides financial investment, scientific support, regulatory expertise and logistical assistance in delivering vaccines, therapy, and diagnostics of SARS-CoV-2 to the US public as soon as possible. Much attention is focused on OWS ‘goal of delivering significant quantities of safe and effective vaccines by early 2021. But the initiative also aims to combat Covid-19 by improving the use of existing therapies and providing additional treatment options. In this way, we hope to improve the pandemic while we wait for the American people to be fully immunized.
Effective therapy can reduce the severity and frequency of hospitalization of the disease, shorten hospital stays and reduce mortality and ease the burden on patients, families and the health care system. If therapy is used for prophylaxis in at-risk populations, they may also prevent disease and reduce the spread of SARS-CoV-2.
We have used three criteria to select candidate therapy for support: timeliness, robust science, and ability to produce quickly on a scale. First, OWS therapy must be in the clinic by early fall at the latest with the potential for emergency approval or authorization (EUA) by the end of 2020. Although challenging, this time frame allows for recycled drugs ̵
Second, sound science is crucial. Researchers are constantly evaluating potential drugs. Government agencies such as the National Institutes of Health (NIH), the Biomedical Advanced Research and Development Authority (BARDA) and the Defense Advanced Research Projects Agency (DARPA); NIH’s Accelerating Covid-19 Therapeutic Interventions and Vaccines (ACTIV) Public-Private Partnership1; and the OWS team is looking for all candidates who show promise in vitro and in animal models and clinical trials at an early stage. When scientific evaluation predicts a reasonable probability of success, OWS investments and resources can be quickly marched to accelerate development and production.
Third, we seek scalability within the desired time frame. With help, production of hundreds of thousands of doses should be achievable during 2020.
An arsenal of infectious diseases requires tools to target the virus itself and to treat disease symptoms and complications. OWS considers the extent of clinical needs, ranging from pre-exposure prophylaxis through the convalescence period. Many candidates are evaluated using master protocols developed by the ACTIV program, which enable the comparison of efficiencies between therapies, save patients using shared control groups, and can accommodate different types of interventions.
Therapeutic agents that attack the virus are the simplest to identify and develop and thus account for the majority of our efforts. Within this group, there are two primary mechanisms: the provision of passive immunity and the inhibition of viral replication.
Antibody therapy, usually defined by the ability to neutralize the virus in vitro, has provided passive immunity in some viral infections. Antibody-based therapies include convalescent plasma, hyperimmune globulin, and monoclonal antibodies. For many infectious diseases, plasma treatment isolated from convalescent patients has been a pragmatic early countermeasure, but it has limitations: it is usually most effective early in the infection, must be obtained from donors in a relatively narrow period, requires blood type matching, and does not scale to large populations. Hyperimmune globulin produced by convalescent plasma, on the other hand, may have a standard activity level per Dose, does not require blood type matching and can often be concentrated for intramuscular delivery – a significant advantage over intravenous plasma administration.
Highly potent neutralizing monoclonal antibodies (mAbs) can be derived from patients who have recovered from Covid-19 using one of several well-established isolation platform technologies. Antibodies can then be prepared on a scale to allow for more intervention points: prevention of infection, treatment of early disease in outpatients, or treatment of diseases at a later stage in inpatients. These antibodies have the advantages of being strongly characterized, exhibiting consistent levels of neutralizing activity and can be produced on a very large scale.
Early investment by DARPA in antibody detection platforms has enabled rapid response functions: highly potent neutralizing mAbs were isolated, characterized and moved to phase 1 safety testing within 90 days of receiving the sample. With additional investment, regulatory expertise and logistical assistance, we plan to support the manufacture of the most potent mAb products with (financial) risk, so that if clinical trials succeed, hundreds of thousands of doses could be used in the fall and winter.
In terms of inhibition of viral replication, antiviral small molecules can take years to identify and develop. To meet our aggressive deadlines, we have focused on antiviral drugs developed for other pathogens, such as remdesivir, which were developed for Ebola but may be effective against SARS-CoV-2. Antiviral substances whose safety profiles are already known may enter Phase 2 and 3 clinical trials shortly after demonstration of activity against SARS-CoV-2 in vitro and in animal models.
To optimize the assessment of these antiviral strategies, two phase 2-3 master protocols have been established – ACTIV-2 (outpatients) and ACTIV-3 (inpatients) – in addition to company-sponsored studies. Neutralizing mAbs will also be tested as prophylaxis in high-risk cohorts, such as residents and caregivers at long-term care facilities, employees at meat packaging facilities where infection has been detected, or households with confirmed Covid-19 cases.
We also pursue candidates targeted at the main causes of illness and death from Covid-19. Although much is still unknown about SARS-CoV-2, we know that complications of severe Covid-19 include hyperinflammation with potential cytokine release syndrome and thrombotic events including stroke, venous thromboembolism, and thrombotic microangiopathy. Attempts to modulate host immune responses, however, go a fine line between disrupting host defenses and limiting hyperinflammation. OWS tracks studies of immune modulators in patients with Covid-19. If and when we detect positive signals, OWS will move to accelerate clinical development and invest in risk in manufacturing as needed.
In addition, NIH in collaboration with OWS will implement the ACTIV-1 study of immune modulators,2 and the OWS-supported ACTIV-4 trial will test anticoagulation regimens at different disease sites.
Several therapeutic products are advancing with OWS support. In April 2020, the FDA and clinical partners announced an expanded access protocol for the administration of convalescent plasma. Together with the NIH, OWS supports rapid performance of randomized clinical trials in inpatients and outpatients to evaluate the efficacy of convalescent plasma. Early analysis of results suggests clinical benefit of passive transfer of immunity – the FDA recently awarded an EUA for convalescent plasma – and validates our prioritization of antibody products.
One such antibody product is hyperimmune globulin from SAb Biotherapeutics, derived from genetically modified cows that produce human IgG. Cows were immunized with the SARS-CoV-2 tip protein to generate a polyclonal antibody response that has high neutralizing activity against the virus. A phase 1 clinical safety study of the treated hyperimmune globulin from these cows began in August and evaluation in the ACTIV-2 master protocol is expected. OWS is investing in the danger of upscaling production from this herd of cows so that tens of thousands of doses could be produced this year.
Our portfolio includes three mAb development programs from NIH, BARDA and DARPA and in the private sector. Two candidate antibodies are evaluated for treatment in outpatients and inpatients and for prophylaxis in high-risk populations. A Phase 3 prophylaxis study for a third mAb product is expected to begin in September.
On July 6, OWS announced support for taking the first therapeutic candidate through commercial manufacturing – a mAb cocktail made by Regeneron. This product is in phase 2 trials for prophylaxis and hospitalization and outpatient treatment. If a trial is successful, Regeneron estimates that this $ 450 million investment could produce 70,000 to 300,000 treatment doses (depending on the dose), with starting doses ready over the next 3 months.
A mAb product discovered by AbCellera Biologics and developed by Eli Lilly is currently in ACTIV-2 and ACTIV-3 trials, and a Lilly-sponsored prophylaxis study in nursing homes and caregivers is ongoing. A combination of two mAbs developed by AstraZeneca (licensed from Vanderbilt University) and designed to have an extended half-life could be particularly useful for prophylaxis; it is being tested at nursing homes, meat packing plants and other settings starting in October.
We are also evaluating small molecule antivirals, including a nucleoside analogue, EIDD-2801, developed by Ridgeback Biotherapeutics and acquired by Merck as a potential inhibitor of SARS-CoV-2 replication. It is now in phase 2 trials with outpatients and inpatients. Finally, three immune modulators and three anticoagulants were selected for testing in ACTIV-1 and ACTIV-4 studies, respectively, to assess potential efficacy in inpatients.
It is difficult to predict drug performance in a new disease. Many candidates may not show efficiency or have security issues. However, it is necessary to take a financial risk early on to scale up the manufacture to have drug supply at hand if the results are positive. If we wait for readings of clinical trials before starting large-scale production, it may take months or years to develop a sufficient supply.
Developing a vaccine by January 2021 will represent remarkably rapid scientific progress. But with therapy, we may be able to get started with the virus before we can fully use a vaccine. With increasing numbers of deaths, increasing caseloads and public confusion, we face a huge task. We are taking important steps towards bringing therapies to the American public as soon as possible.