Virus World

Immunocompromised people get a new drug to protect against Covid-19 for the first time since the Omicron variants forced another drug off the market. The Food and Drug Administration on Friday authorized a new antibody to protect immunocompromised individuals against Covid-19. The drug, known as Pemgarda and marketed by the biotech Invivyd, is the first such drug to become available since the agency pulled AstraZeneca’s Evusheld off the market in January 2023. New Omicron variants had rendered Evusheld ineffective. Some immunocompromised patients — a group that includes certain cancer patients, patients with some autoimmune or genetic disorders, and organ transplant recipients — have been eagerly awaiting the new prophylactic. Because their condition or drugs they take for it weaken their immune systems, they don’t always get adequate protection from vaccination. Antibody treatments can add additional protection.  There remains a need for additional Covid protections. Last week, over 10,000 patients with Covid-19 were admitted to U.S. hospitals. 

Still, it’s not clear how many patients will avail themselves of the new treatment. Invivyd, the drug’s developer, estimated there are 9 million immunocompromised people in the U.S., but its initial focus will be on the 485,000 with the most acute need: Stem cell transplant recipients, organ transplant recipients, and blood cancer patients. Evusheld itself had gone vastly underused when it was available, prompting the federal government to launch efforts to educate the public about its existence. And the need is probably less acute now for some: Although immunocompromised patients have a reduced response to vaccination, many may still gain some protection from multiple rounds of vaccination and exposure to the virus. Uptake for other measures to mitigate Covid risk, such as boosters and Paxlovid upon infection, has also declined precipitously, despite public health efforts. 

“We will explore having it available at our institution, so that our very compromised patients and the services and specialities that take care of those patients know that it’s an option,” said Priya Nori, an infectious disease specialist at Albert Einstein College of Medicine. “But we’re not expecting gangbusters in terms of interest.” Invivyd has not yet disclosed a price.  The company was originally founded in 2020 by antibody expert Tillman Gerngross, under the name Adagio, and raised $309 million in an IPO a year later. But the company’s original antibody — which had been designed to be all but variant-proof — was soon rendered ineffective by the advent of Omicron, eventually leading to Gerngross’s resignation and a series of high-level changes at the company. Pemgarda is a re-engineered version of the original antibody, designed to cover Omicron variants. That gave Invivyd a faster path to getting a new preventative on the market than competitors who started from scratch.

FDA EUA letter (March 22, 2024):

https://www.fda.gov/media/177068/download 

Invivyd Press release: 

https://investors.invivyd.com/news-releases/news-release-details/invivyd-announces-fda-authorization-emergency-use-pemgardatm 

Highlights

Summary

Human monoclonal antibodies (mAbs) that target the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike protein have been isolated from convalescent individuals and developed into therapeutics for SARS-CoV-2 infection. However, therapeutic mAbs for SARS-CoV-2 have been rendered obsolete by the emergence of mAb-resistant virus variants. Here we report the generation of a set of six human mAbs that bind the human angiotensin-converting enzyme-2 (hACE2) receptor, rather than the SARS-CoV-2 spike protein. We show that these antibodies block infection by all hACE2 binding sarbecoviruses tested, including SARS-CoV-2 ancestral, Delta and Omicron variants at concentrations of ~7–100 ng ml−1. These antibodies target an hACE2 epitope that binds to the SARS-CoV-2 spike, but they do not inhibit hACE2 enzymatic activity nor do they induce cell-surface depletion of hACE2. They have favourable pharmacology, protect hACE2 knock-in mice against SARS-CoV-2 infection and should present a high genetic barrier to the acquisition of resistance. These antibodies should be useful prophylactic and treatment agents against any current or future SARS-CoV-2 variants and might be useful to treat infection with any hACE2-binding sarbecoviruses that emerge in the future. A suite of human monoclonal antibodies block infection by all human ACE2 binding sarbecoviruses, including severe acute respiratory syndrome coronavirus 2 variants, at subnanomolar concentrations in cell culture and protect mice against severe acute respiratory syndrome coronavirus 2 infection.

Published in Nature Microbiology (May 15, 2023):

https://doi.org/10.1038/s41564-023-01389-9 

Pan-betacoronavirus neutralizing antibodies may hold the key to developing broadly protective vaccines against novel pandemic coronaviruses and to more effectively respond to SARS-CoV-2 variants. The emergence of Omicron and subvariants of SARS-CoV-2 illustrates the limitations of solely targeting the receptor binding domain (RBD) of the Spike (S)-protein. Here, we isolated a large panel of broadly neutralizing antibodies (bnAbs) from SARS-CoV-2 recovered-vaccinated donors that target a conserved S2-region in the betacoronavirus spike fusion machinery. Select bnAbs showed broad in vivo protection against all three deadly betacoronaviruses, SARS-CoV-1, SARS-CoV-2 and MERS-CoV, that have spilled over into humans in past two decades. Structural studies of these bnAbs delineated the molecular basis for their broad reactivity and revealed common antibody features targetable by broad vaccination strategies. These bnAbs provide new insights and opportunities for antibody-based interventions and for developing pan-betacoronavirus vaccines.

Published in Immunity (Feb. 15, 2023):

https://doi.org/10.1016/j.immuni.2023.02.005 

[11/30/2022] The U.S. Food and Drug Administration today announced bebtelovimab is not currently authorized for emergency use in the U.S. because it is not expected to neutralize Omicron subvariants BQ.1 and BQ.1.1., according to data included in the Health Care Provider Fact Sheet.  

Nowcast data from the Centers for Disease Control and Prevention published last week estimates that the combined proportion of COVID-19 cases caused by the Omicron BQ.1 and BQ.1.1 subvariants to be above 57% nationally, and already above 50% in all individual regions but one, and data shows a sustained trend of increasing prevalence across all regions. Given that a COVID-19 infection is likely to be caused by a non-susceptible SARS-CoV-2 variant, and consistent with the terms and conditions of the Letter of Authorization, bebtelovimab is not currently authorized for emergency use in any U.S. region at this time.   Eli Lilly and its authorized distributors have paused commercial distribution of bebtelovimab until further notice by the Agency. Additionally, the Administration for Strategic Preparedness and Response (ASPR) has paused the fulfillment of any pending requests under its Bebtelovimab Product Replacement Initiative.  The U.S. Government recommends all product be retained in the event that SARS-CoV-2 variants susceptible to bebtelovimab, which are currently circulating at lower prevalence, become more prevalent in the future in the United States. Retained product must be appropriately held in accordance with storage conditions detailed in the authorized Fact Sheet for Health Care Providers and the Letter of Authorization for bebtelovimab.  Health care providers should use other approved or authorized products that are expected to retain activity against BQ.1 and BQ.1.1 as they choose appropriate treatment options for patients, which include the following: 

• Paxlovid is authorized for the treatment of mild-to-moderate COVID-19 in adults and pediatric patients (12 years of age and older weighing at least 40 kg) with positive results of direct SARS-CoV-2 viral testing, and who are at high risk for progression to severe COVID-19, including hospitalization or death. 
• Veklury is approved for the treatment of adults and pediatric patients (28 days of age and older and weighing at least 3 kg) with positive results of direct SARS-CoV-2 viral testing, who are not hospitalized and have mild-to-moderate COVID-19 and are at high risk for progression to severe COVID-19, including hospitalization or death. 
• Lagevrio is authorized for the treatment of mild-to-moderate COVID-19 in adults with positive results of direct SARS-CoV-2 viral testing who are at high risk for progression to severe COVID-19, including hospitalization or death, and for whom alternative COVID-19 treatment options approved or authorized by FDA are not accessible or clinically appropriate. 

In addition, COVID-19 convalescent plasma with high titers of anti-SARS-CoV-2 antibodies is authorized for the treatment of COVID-19 in patients with immunosuppressive disease or receiving immunosuppressive treatment, in inpatient or outpatient settings. Individuals for whom COVID-19 vaccination is recommended should consider getting vaccinated with the primary series or, if vaccinated with the primary series, boosted with an updated bivalent vaccine when eligible to increase protection against the most serious consequences of COVID-19, including hospitalization and death. For more information related to the therapeutic management of non-hospitalized patients with mild-to-moderate COVID-19, refer to the NIH COVID-19 Treatment Guidelines.  

All treatment sites can continue ordering Paxlovid, Veklury, and Lagevrio by following the existing ordering processes and reporting procedures, as applicable.  FDA will continue to work with ASPR, the CDC, and the National Institutes of Health on surveillance of variants that may impact the use of the therapies authorized for emergency use. We will provide further updates and consider additional action as new information becomes available.

The Omicron variant of SARS-CoV-2 evades antibody-mediated neutralization with unprecedented efficiency. At least three Omicron sublineages have been identified, BA.1, BA.2 and BA.3, with BA.2 exhibiting increased transmissibility. However, it is currently unknown whether BA.2 differs from the other sublineages regarding cell entry and antibody-mediated inhibition. Here, we show that BA.1, BA.2 and BA.3 enter and fuse target cells with similar efficiency and in an ACE2-dependent manner. However, BA.2 was not efficiently neutralized by seven of eight antibodies used for COVID-19 therapy, including Sotrovimab, which robustly neutralized BA.1. In contrast, BA.2 and BA.3 but not BA.1 were appreciably neutralized by Cilgavimab, which may constitute a treatment option. Finally, all sublineages were comparably and efficiently neutralized by antibodies induced by BNT162b2 booster vaccination after previous two-dose homologous or heterologous vaccination. Collectively, the Omicron sublineages show comparable cell entry and neutralization by vaccine-induced antibodies but differ in susceptibility to therapeutic antibodies.

Published in Cell Host  Microbe (May 5, 2022):

https://doi.org/10.1016/j.chom.2022.04.017 

The omicron (B.1.1.529) variant of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which is responsible for coronavirus disease 2019 (Covid-19), has spread rapidly around the world and has already become the predominant variant circulating in many countries. As of February 2022, omicron variants have been divided into four distinct sublineages: BA.1, BA.1.1, BA.2, and BA.3.1 Most circulating omicron variants belong to sublineage BA.1; however, in Denmark, India, and the Philippines, the sublineage BA.2 is now becoming dominant.

As compared with the Wuhan/Hu-1/2019 reference strain, the sublineage BA.2 of the omicron variant has 16 amino acid substitutions in the receptor-binding domain of the spike (S) protein of SARS-CoV-2,2 which is the primary target for monoclonal antibody–based therapy. The BA.2 and BA.1 variants share 12 of these 16 substitutions; however, BA.2 has four substitutions in the receptor-binding domain (i.e., S371F, T376A, D405N, and R408S) that differ from those in BA.1. These findings suggest that there may be differences in the effectiveness of monoclonal antibodies against these different omicron sublineages. Accordingly, we examined the neutralizing ability of therapeutic monoclonal antibodies that have been approved by the Food and Drug Administration, individually and in combination, against the omicron BA.2 subvariant hCoV-19/Japan/UT-NCD1288-2N/2022 (omicron/BA.2; NCD1288), which was isolated from a traveler who arrived in Japan from India. Whole-genome sequencing analysis of the NCD1288 virus stock confirmed that it had the 16 substitutions that are characteristic of the omicron variant in the receptor-binding domain of the S protein, as compared with the Wuhan/Hu-1/2019 reference strain...

The susceptibilities of omicron/BA.2 (NCD1288) to remdesivir, molnupiravir, and nirmatrelvir were similar to those of the ancestral strain and other variants of concern (i.e., 50% inhibitory concentration values for these three agents that differed by factors of 2.5 to 4.5, 0.7 to 1.6, and 1.5 to 3.3, respectively) (Table 1).3 Clinical studies are warranted to determine whether these antiviral therapies are indeed effective against omicron/BA.2 infections. Our data indicate that some therapeutic monoclonal antibodies (REGN10987–REGN10933, COV2-2196–COV2-2130, and S309) have lower neutralizing activity against omicron/BA.2 than against earlier variant strains.

Published in NEJM (March 9, 2022):

https://doi.org/10.1056/NEJMc2201933 

Glaxo (GSK) and Vir Biotechnology announce promising pre-clinical data from the study of their antibody candidate, sotrovimab, against mutations found in the Omicron variant. The antibody candidate has shown activity against several deadly mutants of coronavirus including Delta, Delta plus and Mu in clinical studies. Amid rising concerns of an Omicron outbreak, the encouraging pre-clinical data against the variant supports its strong potential as an enduring COVID-19 treatment option going forward.  Pre-clinical data included results of testing of sotrovimab against pseudo-viruses with each containing a specific individual mutation found in the Omicron variant. Glaxo and Vir Biotechnology are currently conducting an in-vitro test of their antibody drug against all mutations found in the Omicron variant in a single pseudo-virus. Data from this test will demonstrate the neutralizing ability of sotrovimab against a combination of the Omicron mutations. An update on the data from this in-vitro study is expected by the end of 2021. The companies stated that sotrovimab targets a specific portion of the coronavirus, which makes it more difficult for the variants to develop resistance against the candidate. We note that Glaxo and Vir Biotechnology’s sotrovimab, as an intravenous administration, was granted emergency use authorization (“EUA”) for treating mild-to-moderate COVID-19 in adult and pediatric patients in May. The intravenous drug is available under the tradename of Xevudy.

The approval was based on data from a late-stage study that demonstrated that treatment with sotrovimab achieved 79% reduction in risk of hospitalization or death. Glaxo’s shares have gained 12.7% so far this year compared with the industry’s 12.6% increase. In a separate press release, the companies announced that sotrovimab was granted conditional marketing authorization in the United Kingdom for the treatment of symptomatic adults and adolescents. The drug is authorized for use in patients with acute COVID-19 infection without any requirement of oxygen supplementation with increased risk of progressing to severe infection. The drug needs to be administered within five days of the onset of COVID-19 infection symptoms.  Glaxo and Vir Biotechnology already have a supply agreement in place with the government of the United Kingdom for the supply of sotrovimab. The investigational therapy is also authorized for temporary/conditional use in several other countries including Japan and Canada. It is also under review in Europe. Glaxo and Vir Biotechnology have agreements with several entities across the globe in place for supply of more than 750,000 doses of sotrovimab. The companies also have an agreement with the European Commission for additional doses.

A report released by another COVID-19 drugmaker, Regeneron REGN earlier this week stated that vaccine-induced and monoclonal antibody-conveyed neutralization activity will reduce against the Omicron variant, implying lower effectiveness of available COVID-19 solutions against the new variant of concern, including Regeneron’s antibody cocktail, REGEN-COV. Further tests are being conducted to understand the impact using the actual Omicron variant sequence.  Regeneron’s REGEN-COV comprises two monoclonal antibodies, casirivimab and imdevimab., which have demonstrated strong effectiveness against previous coronavirus strains. Regeneron added $3.5 billion to its top line from sales of REGEN-COV, leading to more than 100% increase in total revenues in the first nine months of 2021...

Vir Biotechnology press release (December 2, 2021):

https://investors.vir.bio/news-releases/news-release-details/preclinical-data-demonstrate-sotrovimab-retains-activity-against 

See also preprint here (Dec. 1, 2021):

https://doi.org/10.1101/2021.03.09.434607

The emergence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants of concern threatens the efficacy of existing vaccines and therapeutic antibodies and underscores the need for additional antibody-based tools that potently neutralize variants by targeting multiple sites of the spike protein. We isolated 216 monoclonal antibodies targeting SARS-CoV-2 from plasmablasts and memory B cells collected from patients with coronavirus disease 2019. The three most potent antibodies targeted distinct regions of the receptor binding domain (RBD), and all three neutralized the SARS-CoV-2 Alpha and Beta variants. The crystal structure of the most potent antibody, CV503, revealed that it binds to the ridge region of SARS-CoV-2 RBD, competes with the angiotensin-converting enzyme 2 receptor, and has limited contact with key variant residues K417, E484, and N501.

We designed bispecific antibodies by combining nonoverlapping specificities and identified five bispecific antibodies that inhibit SARS-CoV-2 infection at concentrations of less than 1 ng/ml. Through a distinct mode of action, three bispecific antibodies cross-linked adjacent spike proteins using dual N-terminal domain–RBD specificities. One bispecific antibody was greater than 100-fold more potent than a cocktail of its parent monoclonals in vitro and prevented clinical disease in a hamster model at a dose of 2.5 mg/kg. Two bispecific antibodies in our panel comparably neutralized the Alpha, Beta, Gamma, and Delta variants and wild-type virus. Furthermore, a bispecific antibody that neutralized the Beta variant protected hamsters against SARS-CoV-2 expressing the E484K mutation. Thus, bispecific antibodies represent a promising next-generation countermeasure against SARS-CoV-2 variants of concern.

Published in Science Translational Medicine (Sept. 2021):

https://doi.org/10.1126/scitranslmed.abj5413 

BACKGROUND

Patients with underlying medical conditions are at increased risk for severe coronavirus disease 2019 (Covid-19). Whereas vaccine-derived immunity develops over time, neutralizing monoclonal-antibody treatment provides immediate, passive immunity and may limit disease progression and complications.

METHODS

In this phase 3 trial, we randomly assigned, in a 1:1 ratio, a cohort of ambulatory patients with mild or moderate Covid-19 who were at high risk for progression to severe disease to receive a single intravenous infusion of either a neutralizing monoclonal-antibody combination agent (2800 mg of bamlanivimab and 2800 mg of etesevimab, administered together) or placebo within 3 days after a laboratory diagnosis of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. The primary outcome was the overall clinical status of the patients, defined as Covid-19–related hospitalization or death from any cause by day 29.

RESULTS

A total of 1035 patients underwent randomization and received an infusion of bamlanivimab–etesevimab or placebo. The mean (±SD) age of the patients was 53.8±16.8 years, and 52.0% were adolescent girls or women. By day 29, a total of 11 of 518 patients (2.1%) in the bamlanivimab–etesevimab group had a Covid-19–related hospitalization or death from any cause, as compared with 36 of 517 patients (7.0%) in the placebo group (absolute risk difference, −4.8 percentage points; 95% confidence interval [CI], −7.4 to −2.3; relative risk difference, 70%; P<0.001). No deaths occurred in the bamlanivimab–etesevimab group; in the placebo group, 10 deaths occurred, 9 of which were designated by the trial investigators as Covid-19–related. At day 7, a greater reduction from baseline in the log viral load was observed among patients who received bamlanivimab plus etesevimab than among those who received placebo (difference from placebo in the change from baseline, −1.20; 95% CI, −1.46 to −0.94; P<0.001).

CONCLUSIONS

Among high-risk ambulatory patients, bamlanivimab plus etesevimab led to a lower incidence of Covid-19–related hospitalization and death than did placebo and accelerated the decline in the SARS-CoV-2 viral load. (Funded by Eli Lilly; BLAZE-1 ClinicalTrials.gov number, NCT04427501. opens in new tab.)

Published in NEJM (July 14, 2021):

https://doi.org/10.1056/NEJMoa2102685 

The Food and Drug Administration (FDA) rescinded its emergency use authorization for the monoclonal antibody bamlanivimab to be used on its own as treatment against COVID-19 due to variants' resistance to the therapy. The federal agency declared its cancelation of bamlanivimab-only COVID-19 therapy hours after the company Eli Lilly requested the FDA revoke the emergency authorization because the variants resistant to the treatment have become more common. With the number of resistant infections growing, the agency concluded that the benefits of treating COVID-19 with only bamlanivimab “no longer outweigh the known and potential risks for its authorized use.”   The FDA cited data that as of mid-March about 20 percent of variants in the U.S. were expected to be resistant to bamlanivimab, compared to 5 percent in January. But the FDA still grants bamlanivimab and another monoclonal antibody, etesevimab, to be used together to treat COVID-19 under an emergency use authorization. In a March study, Eli Lilly determined the combination of monoclonal antibodies — lab-created proteins that copy how the immune system responds to viruses — reduced the risk of hospitalization and death from COVID-19 by 87 percent.

“Other monoclonal antibody therapies authorized for emergency use remain appropriate treatment choices when used in accordance with the authorized labeling and can help keep high risk patients with COVID-19 out of the hospital,” Patrizia Cavazzoni, the director of the FDA’s Center for Drug Evaluation and Research, said in a release.  “We urge the American public to seek out these therapies when needed while we continue to use the best data available to provide patients with safe and effective treatments during this pandemic,” Cavazzoni added.  The emergency use authorization for bamlanivimab-only COVID-19 treatment, granted in November, was the first monoclonal antibody approved to treat mild to moderate COVID-19 cases. It originally allowed it to be used alone for mild-to-moderate COVID-19 adult patients and some children at high risk of severe coronavirus illness or hospitalization.   The federal agency said it will work with the Centers for Disease Control and Prevention (CDC) and the National Institutes of Health (NIH) to monitor how variants impact the treatments authorized for emergency use.  Eli Lilly called for the FDA to end emergency authorization for bamlanivimab-only COVID-19 treatment “due the evolving variant landscape in the U.S. and the full availability of bamlanivimab and etesevimab together.” The company noted its request for authorization to be revoked was “not due to any new safety concern.”

Vir Biotechnology and GlaxoSmithKline are stopping a phase 3 clinical trial of their COVID-19 antibody early for efficacy after seeing an 85% reduction in hospitalization or death at an interim review. The trial provided further evidence of the efficacy of anti-SARS-CoV-2 antibodies in ambulatory patients.  As of the interim review, 583 people recently infected with COVID-19 had received VIR-7831, also known as GSK4182136, or placebo. The participants were all at high risk of progression, based on their age or other factors, but were unlikely to require hospitalization in the next 24 hours and had oxygen saturation of 94% or greater at the time of enrollment. In those patients, the anti-SARS-CoV-2 antibody reduced the number of patients who died or needed hospitalizing for more than 24 hours in the 29 days after randomization by 85%. The effect was large enough to prompt the independent data monitoring committee to recommend stopping enrollment.     The study remains blinded while Vir and GSK complete the 24 weeks of follow-up on patients already in the study. Vir and GSK plan to share additional data once the clinical trial is complete but already see enough promise to outline plans to seek emergency use authorization in the U.S. and equivalent approvals in other markets.

The US National Institutes of Health (NIH) has announced that preliminary results from a Phase III clinical trial of Eli Lilly and Company’s investigational monoclonal antibody, LY-CoV555, showed it failed to provide clinical benefit in hospitalised Covid-19 patients. Discovered by AbCellera Biologics and the National Institute of Allergy and Infectious Diseases (NIAID)’s Vaccine Research Center, LY-CoV555 is developed and manufactured by Eli Lilly and Company, in collaboration with AbCellera. In October, the trial halted new enrolment after an independent Data and Safety Monitoring Board (DSMB) recommended so. The trial, which is part of the Accelerating COVID-19 Therapeutic Interventions and Vaccines (ACTIV) programme, is sponsored by NIH unit NIAID. The randomised, placebo-controlled ACTIV-3 trial used a master protocol, which would aid in analysing various investigational agents versus placebo in hospitalised adult patients with Covid-19.

In the trial, participants randomly received either an experimental agent or a matched placebo along with the standard of care, including the antiviral remdesivir.  The LY-CoV555 sub-study enrolled 326 participants. Around 314 subjects randomly received either LY-CoV555 or placebo. NIH noted that after five days, 50% of those received LY-CoV555 and 54% of placebo recipients were in one of the two most favourable outcome categories. The investigators concluded that LY-CoV555 did not expedite clinical improvement versus placebo at day five in hospitalised Covid-19 patients without end-stage organ failure.

In addition, no difference in time to hospital discharge or the primary outcome of sustained recovery, back at home for 14 days were observed among those who received the treatment as compared with placebo. In November, the US Food and Drug Administration granted emergency use authorisation (EUA) to LY-CoV555 to treat non-hospitalised adolescents and adults with mild to moderate Covid-19 symptoms who are at the risk of progressing to severe Covid-19. In August, the NIH initiated a Phase III ACTIV-3 trial to evaluate various types of monoclonal antibodies as potential treatments for hospitalised Covid-19 patients. Separately, three global trials, notably REMAP-CAP, ACTIV-4 and ATTACC, analysing the effects of full doses of anticoagulants (blood thinners) in Covid-19 patients have paused the enrolment for critically ill Covid-19 patients requiring intensive care unit (ICU) support.

Findings Published in NEJM (Dec. 22, 2020):

https://doi.org/10.1056/NEJMoa2033130

Three coronaviruses have spilled over from animal reservoirs into the human population and caused deadly epidemics or pandemics. The continued emergence of coronaviruses highlights the need for pan-coronavirus interventions for effective pandemic preparedness. Here, using LIBRA-seq, we report a panel of 50 coronavirus antibodies isolated from human B cells. Of these antibodies, 54043-5 was shown to bind the S2 subunit of spike proteins from alpha-, beta-, and deltacoronaviruses. A cryo-EM structure of 54043-5 bound to the pre-fusion S2 subunit of the SARS-CoV-2 spike defined an epitope at the apex of S2 that is highly conserved among betacoronaviruses.

Although non-neutralizing, 54043-5 induced Fc-dependent antiviral responses, including ADCC and ADCP. In murine SARS-CoV-2 challenge studies, protection against disease was observed after introduction of Leu234Ala, Leu235Ala, and Pro329Gly (LALA-PG) substitutions in the Fc region of 54043-5. Together, these data provide new insights into the protective mechanisms of non-neutralizing antibodies and define a broadly conserved epitope within the S2 subunit.

Pre-print in bioRxiv (Jan. 16, 2024): 

https://doi.org/10.1101/2024.01.15.575741 

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the causative agent of coronavirus disease 2019 (COVID-19), has been responsible for a global pandemic. Monoclonal antibodies (mAbs) have been used as antiviral therapeutics; however, these therapeutics have been limited in efficacy by viral sequence variability in emerging variants of concern (VOCs) and in deployment by the need for high doses. In this study, we leveraged the multi-specific, multi-affinity antibody (Multabody, MB) platform, derived from the human apoferritin protomer, to enable the multimerization of antibody fragments. MBs were shown to be highly potent, neutralizing SARS-CoV-2 at lower concentrations than their corresponding mAb counterparts.

In mice infected with SARS-CoV-2, a tri-specific MB targeting three regions within the SARS-CoV-2 receptor binding domain was protective at a 30-fold lower dose than a cocktail of the corresponding mAbs. Furthermore, we showed in vitro that mono-specific MBs potently neutralize SARS-CoV-2 VOCs by leveraging augmented avidity, even when corresponding mAbs lose their ability to neutralize potently, and that tri-specific MBs expanded the neutralization breadth beyond SARS-CoV-2 to other sarbecoviruses. Our work demonstrates how avidity and multi-specificity combined can be leveraged to confer protection and resilience against viral diversity that exceeds that of traditional monoclonal antibody therapies.

Published in ScienceTranslational Medicine (May 24, 2023):

https://doi.org/10.1126/scitranslmed.adf4549 

A study by UPMC and the University of Pittsburgh School of Medicine found that monoclonal antibody treatments significantly reduced the risk of hospitalization or death from COVID-19. The research underscores the importance of investing in infrastructure and healthcare professional skills to efficiently deliver these treatments, particularly in case of more lethal virus variants emerging in the future. The COVID-19 pandemic created a real-life experiment that demanded health care providers nationwide rapidly stand up clinics to administer an evolving offering of monoclonal antibody treatments that — while initially proven safe and effective in clinical trials and approved under federal emergency use authorization — had never been tested at such a scale. The task was massive and the real-world benefit was uncertain, particularly for monoclonals approved later in the pandemic based only on laboratory data. An analysis published today (April 3, 2023) in the Annals of Internal Medicine by UPMC and University of Pittsburgh School of Medicine clinicians and scientists shows that it was worth it. “The virus was a moving target, and, for two years, monoclonal antibodies were approved, revoked, sometimes reauthorized, and sometimes scarce,” said lead author Kevin Kip, Ph.D., vice president of clinical analytics at UPMC. “Using UPMC’s database of patients treated with monoclonal antibodies —one of the largest in the U.S. — we are finally able to conclude that pushing through all these challenges unequivocally saved lives and prevented hospitalizations.” Monoclonal antibodies are human-made antibodies specifically designed to prevent a pathogen — in this case, the virus that causes COVID-19 — from entering human cells, replicating, and causing serious illness. The U.S. Food and Drug Administration granted emergency use authorization to five different COVID-19 monoclonal antibody treatments at various times between 2020 and 2022. All were restricted to people aged 12 and older with risk factors that made them more susceptible to bad outcomes from COVID-19. The treatments had to be administered intravenously or through injection by a healthcare professional. As the virus evolved, new monoclonal antibodies were introduced and older ones, which were no longer effective, were removed.

Starting with the first authorization at the end of 2020, UPMC opened dozens of clinics, set up emergency department infrastructure, and arranged home visits to maximize its ability to provide monoclonal antibodies to patients in Pennsylvania, New York, and Maryland. After the emergency use authorization was revoked for the last monoclonal antibody on November 30, 2022, and no new monoclonal antibodies were introduced, UPMC pulled anonymous clinical data on 2,571 patients treated with monoclonal antibodies and matched them with data from 5,135 patients with COVID-19 who were eligible for monoclonal antibodies but did not receive them. On average, people who received monoclonal antibodies within two days of a positive COVID-19 test reduced their risk of hospitalization or death by 39% compared to their peers who did not receive the treatment. Patients with immunocompromising conditions, regardless of their age, had an even greater reduced risk. Patients treated when the alpha and delta variants of the virus were circulating experienced greater benefit than their untreated peers compared to those treated when the omicron variant was circulating, likely because earlier variants were more deadly and people had less prior immunity from previous infection or vaccination. By the time omicron was circulating, risk of death and hospitalization had fallen in general, so monoclonal antibody treatment had less overall benefit, but still clinically meaningful benefit, particularly in vulnerable patients, explained co-author Erin McCreary, Pharm.D., director of infectious diseases improvement and clinical research innovation at UPMC. “Right now, COVID-19 has a relatively low risk of death for the general population, but we have seen how quickly this virus can mutate and spread. Nobody can say with certainty that a future variant won’t be more deadly,” McCreary said. “Should that happen, our real-world data give reassurance that investing in the infrastructure and healthcare worker knowledge to quickly give antibody treatments keeps people in the communities we serve alive and out of the hospital.”

Study published April 4, 2023 (Annals of Int. Medicine):

https://doi.org/10.7326/M22-1286

The Food and Drug Administration has approved Tocilizumab for use against moderate to severe Covid-19 symptoms. The FDA has approved an early gift for those suffering from Covid-19 this holiday season. Tocilizumab, branded Actemra by pharmaceutical company Genentech, is a monoclonal antibody now approved for treating Covid-19 in hospitalized adult patients in moderate to severe conditions. All treatments to this point of the pandemic were only temporarily approved via emergency use authorization, speaking to the value of Tocilizumab. Here we discuss how the antibody was discovered and how it works. Unlike many monoclonal antibody treatments we discuss, Tocilizumab has a long history dating back 25 years. Clinical development of the antibody began in 1997 by Chugai Pharmaceuticals in Japan to treat rheumatoid arthritis. Chugai Pharmaceuticals and Genentech are now under the Roche Group umbrella, a Swiss multinational healthcare company. The researchers at Chugai Pharmaceuticals found that specific mouse antibodies contained anti-human IL-6 receptors. Interleukin-6, or IL-6, is a secreted cytokine protein expressed by white blood cells. In terms of disease, IL-6 stimulates inflammatory processes when the body is exposed to various pathogens and clinical conditions such as diabetes, multiple sclerosis, and rheumatoid arthritis.

Upon identifying the anti-human IL-6 receptors in mice, the researchers grafted the receptor onto a human IgG constant Fc region using recombinant DNA technology, effectively humanizing the receptor. Later research by Kishimoto et al. confirmed that the engineered mouse antibody receptor grafted to the human IgG constant Fc exclusively blocked IL-6 trans-signaling without affecting other significant pathways. IL-6 inhibition sufficiently blocks inflammation without inhibiting other immune defenses against infection. Contrary to popular belief, many of the classic symptoms we experience when we are sick are not directly caused by an invading pathogen but rather consequences of our immune system fighting off the pathogen. Inflammation is one of the most prominent causes of body pain, fatigue, fever, rash, and other significant symptoms most endure during sickness. In severe cases, inflammation may cause severe pain, lack of appetite, and severe headaches and chills. To produce the drug en masse, Chugai Pharmaceutical used genetic manipulation of host cells. They encoded the genes that code for tocilizumab production onto a human host T-cell. The encoded T-cell is then transfected into Chinese hamster ovary cells. These cells are then manipulated to express countless tocilizumab genes, creating a master that can be copied several times.

Vaccination represents the key strategy to control the COVID-19 pandemic through induction of neutralising antibody responses and T cell-associated immunity that substantially decrease the risk of developing severe disease.  However, individuals who are immunocompromised (eg, because of comorbidities, high age, or immunosuppressive treatment) might not mount a full adaptive immune response and thus remain susceptible. For individuals at high risk, individual monoclonal antibodies (mAbs) or cocktails of mAbs are administered as prophylaxis or therapy.  All mAbs currently approved by the US Food and Drug Administration (FDA) or European Medicines Agency (EMA) target the spike (S) protein.  During the course of the COVID-19 pandemic, several SARS-CoV-2 lineages evolved mutations that confer partial or full resistance against some mAbs. Consequently, only few mAbs remain suitable for treatment of individuals at high risk, and only bebtelovimab shows high efficacy against multiple omicron sublineages. However, novel omicron sublineages have been detected, harbouring additional S protein mutations within the epitopes of bebtelovimab and other mAbs. Novel sublineages include BA.4.6 (with increasing incidence in several countries worldwide), BA.2.75.2 (with increasing incidence in India), BJ.1 (mainly observed in India and Bangladesh; notably BJ.1 is one parental lineage of the currently increasing XBB recombinant), and BQ.1.1 (with increasing incidence in the USA and Europe).

Despite the success of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccines, there remains a need for more prevention and treatment options for individuals remaining at risk of coronavirus disease 2019 (COVID-19). Monoclonal antibodies (mAbs) against the viral spike protein have potential to both prevent and treat COVID-19 and reduce the risk of severe disease and death. Here, we describe AZD7442, a combination of two mAbs, AZD8895 (tixagevimab) and AZD1061 (cilgavimab), that simultaneously bind to distinct, nonoverlapping epitopes on the spike protein receptor binding domain to neutralize SARS-CoV-2. Initially isolated from individuals with prior SARS-CoV-2 infection, the two mAbs were designed to extend their half-lives and reduce effector functions. The AZD7442 mAbs individually prevent the spike protein from binding to angiotensin-converting enzyme 2 receptor, blocking virus cell entry, and neutralize all tested SARS-CoV-2 variants of concern. In a nonhuman primate model of SARS-CoV-2 infection, prophylactic AZD7442 administration prevented infection, whereas therapeutic administration accelerated virus clearance from the lung. In an ongoing phase 1 study in healthy participants (NCT04507256), a 300-mg intramuscular injection of AZD7442 provided SARS-CoV-2 serum geometric mean neutralizing titers greater than 10-fold above those of convalescent serum for at least 3 months, which remained threefold above those of convalescent serum at 9 months after AZD7442 administration. About 1 to 2% of serum AZD7442 was detected in nasal mucosa, a site of SARS-CoV-2 infection. Extrapolation of the time course of serum AZD7442 concentration suggests AZD7442 may provide up to 12 months of protection and benefit individuals at high-risk of COVID-19.

Published in Science Translational Medicine (March 2022):

https://doi.org/10.1126/scitranslmed.abl8124 

The BA.2 COVID variant now spreading worldwide disarms a crucial monoclonal-antibody therapy in laboratory tests.  The rapidly spreading BA.2 variant of SARS-CoV-2 could once again make doctors rethink antibody treatments for COVID-19. Manufactured immune molecules called monoclonal antibodies are essential for keeping people with COVID-19 out of hospital. Now, early laboratory data1,2 hint that the key antibody sotrovimab could lose effectiveness against the rapidly spreading BA.2 variant. Sotrovimab is one of the few therapies for COVID-19 caused by the Omicron variant, which overpowers several antibody treatments that were effective against previous strains. Just in time, US regulators have given emergency approval to another monoclonal antibody, bebtelovimab, that inhibits both the original Omicron strain3 and BA.21 in laboratory assays.  But for many researchers, the sotrovimab findings are a testament to the uphill battle of keeping up with SARS-CoV-2 as it evolves to evade immune systems, antibody treatments and vaccines. “With monoclonal antibodies, we’re trying to hit a moving target,” says David Ho, a virologist at Columbia University in New York City and a co-author of one of the studies. “It’s a really difficult endeavour to chase after a virus.” Most antibody treatments target and attach to SARS-CoV-2’s spike protein, which the virus uses to enter cells. But the protein is also a hotbed for mutations as the coronavirus evolves to evade the immune system. Omicron, for example, has dozens of new mutations in its spike protein. These might explain why two monoclonal-antibody cocktails used to treat the highly virulent Delta variant proved powerless against Omicron4. That left sotrovimab as the only FDA-approved monoclonal-antibody treatment option for infected people at high risk of developing severe COVID-19. The first known variant of Omicron, named BA.1, remains the most prevalent variety of the virus in many countries, including the United States and the United Kingdom. But cases of BA.2, which is related to BA.15, are rising in countries including Denmark, India and China.

Antibody escape

To see how common antibody treatments stood up to the newer varieties of SARS-CoV-2, Ho and his colleagues tested the treatments against a purpose-built virus that included the BA.2 spike. The results1, which have not been peer reviewed, revealed a steep drop in sotrovimab’s ability to neutralize BA.2. Those findings were reinforced by another preprint2, in which a team at the New York University Grossman School of Medicine reported a similar reduction in sotrovimab’s neutralization strength against BA.2. But researchers caution that it is too early to say what these numbers mean for the front-line treatment of COVID-19. “We cannot extrapolate laboratory findings to human treatment outcomes,” says Ho. “We’re just drawing attention to the fact that BA.2 is quite resistant to sotrovimab in the lab, and that raises questions about whether you can adequately cover BA.2 in patients.” Ho notes that sotrovimab also showed reduced efficacy against BA.2 in a preprint6 posted 18 February by scientists at Vir Biotechnology, the company based in San Francisco, California, that produces the antibody. The study has not yet been peer reviewed. In a statement, Vir says the research suggests that sotrovimab “retains neutralizing activity” against BA.2.

A new antibody to the rescue?

Regardless of sotrovimab’s abilities, bebtelovimab could become a go-to antibody to prescribe for people infected with BA.2. Ho and his colleagues found that it is active against both BA.1 and BA.2. The possibility of sotrovimab losing its edge against a new variant isn’t unexpected, says Miles Davenport, an immunologist at the University of New South Wales in Sydney, Australia. Like vaccines, he says, antibody treatments can become less effective when the virus evolves. But he adds that even if sotrovimab doesn’t provide the same level of protection that it did against previous variants, it could still give some relief to people infected with BA.2. “Just because monoclonal antibodies bind less well to the variants, does not mean they will be useless,” he says.

Keeping ahead of the virus

Rajesh Gandhi, an infectious-disease physician at Massachusetts General Hospital in Boston, says that sotrovimab will probably continue to be used while BA.1 remains prevalent. In the meantime, he and other experts say that the questions about sotrovimab underline the need to develop and deploy treatments for COVID-19 that remain effective even when the virus mutates. “If COVID has taught us anything, it’s that we need to prepare,” says Gandhi. “If BA.2 doesn’t become the most dominant variant, good. But if it does, it’s good to have some thoughts around it, so we can optimize treatments for our patients.”

Published in Nature (Feb. 23, 2022): 

https://doi.org/10.1038/d41586-022-00419-6 

Regeneron said that a single dose of its antibody cocktail REGEN-COV reduced the risk for COVID-19 by nearly 82% up to 8 months after administration in a phase 3 trial. REGEN-COV, which contains 600 mg each of the monoclonal antibodies casirivimab and imdevimab, was authorized for emergency use by the FDA in November 2020 for the treatment of mild to moderate COVID-19 in high-risk patients. The FDA expanded the emergency use authorization in July to include post-exposure prophylaxis.  Trial results announced Monday by Regeneron showed that, compared with placebo, people who received a single dose of REGEN-COV had an 81.6% reduced risk for developing COVID-19 during a 2-to-8-month follow-up period (95% CI, 59.8%-91.6%) and an 81.5% reduced risk for developing COVID-19 at any time during the 8 months after receiving REGEN-COV (95% CI, 70.6%-88.4%). Myron S. Cohen, MD, who leads the monoclonal antibody efforts for the NIH-sponsored COVID Prevention Network and is director of the Institute for Global Health & Infectious Diseases at the University of North Carolina at Chapel Hill, said the findings “demonstrate how a single dose of REGEN-COV can help protect people from COVID-19 for many months after administration.” "These results demonstrate that REGEN-COV has the potential to provide long-lasting immunity from SARS-CoV-2 infection, a result particularly important to those who do not respond to COVID-19 vaccines, including people who are immunocompromised,” Cohen said.

Regeneron said the data build on previously published findings in The New England Journal of Medicine, which reported a risk reduction of 81.4% in the first month. The newly announced findings were from an 8-month follow-up that continued to compare outcomes from more than 1,600 people assigned to receive a single dose of the cocktail or placebo. In all, seven people in the treatment arm and 38 in the placebo arm developed COVID-19 within 2 to 8 months. George D. Yancopoulos, MD, PhD, president and chief scientific officer at Regeneron, said the data “add to the increasing body of evidence supporting the use of REGEN-COV to prevent COVID-19 in uninfected individuals.” “With infections still occurring despite widespread vaccination, the immunocompromised face an ongoing risk of encountering the virus during their daily lives,” Yancopoulos said in a statement. “We intend to rapidly share these additional data with regulatory authorities to help those in most need of protection from COVID-19.”

The FDA has expanded its EUA for Regeneron's COVID-19 drug as a preventative therapy for those who have been exposed to the disease and who are at high risk to progress to a severe case.  With its rapid mutations, the evolutionary process of the coronavirus makes it a moving target. And so it is with treatments for the disease, which can quickly become in vogue or obsolete.  Case in point for the former: Regeneron’s antibody cocktail REGEN-COV. Over the last few months, nearly every development in the COVID-19 antibody market has broken in favor of the treatment, a combination of casirivimab and imdevimab. On Friday, the FDA granted emergency use authorization to REGEN-COV as a preventative measure for those who have been exposed to COVID-19 and who are at high risk to progress to a severe case because they are not fully vaccinated or are not expected to mount an adequate antibody response to vaccination.  About 3% of the U.S. population won't respond fully to COVID-19 vaccines, including patients on chemotherapy, people with hematologic cancers and others, Regeneron says.

The FDA based its decision on a phase 3 trial, run jointly with the National Institutes of Health, which showed that REGEN-COV cut the risk of developing symptomatic COVID by 81% among healthy individuals who lived with an infected person. The study tested the med in 1,505 people who lived with an infected person within the prior four days. Those who received an infusion of REGEN-COV showed 72% efficacy against symptomatic COVID over the first week and 93% beyond the first week. Additionally, among those who developed symptoms, REGEN-COV recipients cleared the virus faster than those in the placebo group.  While vaccine recipients need time to build an effective antibody response, especially with a two-shot regimen, a direct injection of antibodies can offer more immediate protection.   The FDA granted REGEN-COV its initial EUA in November for patients with newly diagnosed COVID-19 who are at a high risk of progressing to severe disease. Since then, the drug Regeneron’s therapy has gained FDA nods for a subcutaneous injection and at a smaller dose. Regeneron's antibody trailed Eli Lilly's antibody onto the market, but it has since proven more resilient against mutations than its rival. Another antibody drug gained FDA approval two months ago. But sotrovimab, a joint effort from GlaxoSmithKline and Vir Biotechnology, has yet to secure a supply deal from the United States.

Regeneron cocktail reduces mortality by 20% in those who don’t produce antibodies themselves, RECOVERY trial shows. The world’s largest trial of COVID-19 therapeutics has for the first time produced convincing evidence that a therapy that directly attacks the virus can save hospitalized patients from death. A combination of antibodies called casirivimab and imdevimab, produced by Regeneron, did not lower mortality when all patients in the study were taken together, investigators of the United Kingdom’s Recovery trial announced today—but it reduced deaths by one-fifth among those who did not produce antibodies themselves. A paper with the results will be made available on the medRxiv preprint server later today, the researchers say. “Here you have really the first direct SARS-CoV-2 drug,” says Eric Topol, director of the Scripps Research Translational Institute. Two drugs previously shown to reduce mortality from COVID-19 were developed for other diseases and work by dampening an overactive immune response, which is “kind of an indirect strategy,” Topol says. But Regeneron’s antibodies, which attach to the receptor-binding domain of the spike protein and prevent the virus from entering cells, are expensive and not widely available, and quickly identifying patients that benefit from it may be a challenge.

Researchers have developed several monoclonal antibodies against SARS-CoV-2, with mixed results. Some, including Regeneron’s, have shown some positive effects on disease progression in outpatients, but none was demonstrated to save the lives of severely ill patients in the hospital. The Recovery trial started to evaluate Regeneron’s cocktail in mid-September 2020. By late May, 9785 patients had been randomly allocated to receive either the usual care in the United Kingdom or the usual care plus a one-time infusion of the two antibodies, a procedure that takes roughly 1 hour.  About one-third of the patients were seronegative when they entered the trial, meaning they did not produce antibodies themselves. That includes people with underlying health conditions that weaken their immune system, but also people who, for unclear reasons, are unable to produce antibodies early on. In this group, 30% of patients given standard care died, versus 24% of those who received the antibody cocktail. That translates to six lives saved for every 100 such patients treated with the drug. The Regeneron cocktail received a lot of attention when former U.S. President Donald Trump received it during his bout with COVID-19 in October 2020. Although it’s not clear whether Trump’s immune system produced antibodies, the new results suggest the treatment may have helped save his life, Topol says: “Who knows what might have happened at his age, with his morbid obesity and all the other risk factors that he had.”

Although it received an emergency use authorization from the U.S. Food and Drug Administration in November 2020—and the U.S. government bought 1.5 million doses— Regeneron’s therapy has not been widely used in the United States, Topol says. “This is just sitting on shelves,” he says. “I think [the Recovery trial] is going to wake people up as to the benefit.” But doctors will have to determine which patients fail to produce antibodies. “I think this isn’t a complicated test to run, it just needs to be done,” says Martin Landray of the University of Oxford, one of Recovery’s principal investigators. A bigger challenge may be cost. “We anticipate, but we don’t know this, that they may be around £1000 or £2000 per treatment,” Recovery co-investigator Peter Horby said at a press conference on Tuesday. That might put the therapy and many similar ones in the pipeline out of reach for most people living in developing countries, which also have far fewer COVID-19 vaccine doses than rich countries. Access to antibody drugs in general has been particularly unequal across the globe, says Lindsay Keir, a pediatrician who co-authored a Wellcome Trust report on global access to such treatments released last year. “Antibodies that we have benefited from in high-income countries for 20, 30 years, still aren’t available in many countries,” Keir says. The inequity is a “scandal,” Horby says. “There really must be an initiative to make these drugs accessible, and that requires two things: They have to be available, which means we have to scale up manufacturing, and they have to be affordable, which means we have to reduce the prices.”

Original findings available as preprint in medRxiV (June 16, 2021):

https://doi.org/10.1101/2021.06.15.21258542 

See Recovery trial press release (June 16, 2021):

https://www.recoverytrial.net/news/recovery-trial-finds-regeneron2019s-monoclonal-antibody-combination-reduces-deaths-for-hospitalised-covid-19-patients-who-have-not-mounted-their-own-immune-response-1 

Regeneron Pharmaceuticals is planning to ask the Food and Drug Administration (FDA) to allow its antibody cocktail to be used as a preventive treatment for COVID-19, the company said Monday.  New results from a clinical trial conducted with the National Institute of Allergy and Infectious Diseases found the drug reduced the risk of symptomatic infection by 81 percent in people who were not infected at the start of the trial, Regeneron said. The company has already received emergency use authorization from the FDA to use its antibody drugs to treat adults with mild to moderate COVID-19 and pediatric patients at least 12 years old who have tested positive for the virus and are at high risk of severe disease but are not yet hospitalized. The trial enrolled 1,505 people who were not infected with the virus but lived in the same household as someone who recently tested positive. The patients were randomized to receive either one dose of the antibody therapy or a placebo administered as injections. After 29 days, 11 people out of the 753 who received a single 1,200 mg dose of the treatment developed symptomatic COVID-19; 59 people who received a placebo out of 752 participants developed symptomatic COVID-19. 

The drug provided 72 percent protection against symptomatic infections in the first week and 93 percent protection in subsequent weeks, Regeneron said. The data has not yet been peer reviewed or published. Regeneron also said the trial found individuals treated with the therapy who experienced a symptomatic infection resolved their symptoms in one week, compared to three weeks with placebo.  Infected individuals also cleared the virus faster with the therapy, the company said. Adverse events occurred in 20 percent of patients who received the antibody drug and 29 percent of those who received a placebo, Regeneron said, but nobody withdrew from the trial because of them.  None of the participants who received the therapy were hospitalized or went to the ER because of COVID-19 over the course of 29 days; four in the placebo group did so.  There were four deaths in the trial — two in the therapy group and two in the placebo group — but none were reported due to COVID-19 or the drug. "With more than 60,000 Americans continuing to be diagnosed with COVID-19 every day, the REGEN-COV antibody cocktail may help provide immediate protection to unvaccinated people who are exposed to the virus, and we are also working to understand its potential to provide ongoing protection for immunocompromised patients who may not respond well to vaccines," George Yancopoulos, president and chief scientific officer at Regeneron, said in a statement.

Regeneron's Press Release (April 12, 2021):

https://investor.regeneron.com/news-releases/news-release-details/phase-3-prevention-trial-showed-81-reduced-risk-symptomatic-sars

The company believes its antibody could be an option not just to treat Covid-19 but to help prevent it in limited circumstances. Eli Lilly said Thursday that its monoclonal antibody prevented Covid-19 infections in nursing home residents and staff in a clinical trial, the first time such a treatment has been shown to prevent infection.  Lilly released the results in a press release, although it said that it would publish the data in a research paper as quickly as possible. In November, the antibody, bamlanivimab, was authorized for emergency use by the Food and Drug Administration in treating patients with Covid who are at risk of more severe disease. An antibody cocktail made by the biotechnology firm Regeneron has also been authorized.  But Lilly believes its antibody could be an option not just to treat Covid-19 but to help prevent it in limited circumstances. “Of course, I think the vaccines are more effective than prophylaxis and likely longer lasting,” Daniel Skovronsky, Eli Lilly’s chief scientific officer, said in an interview. “So this should not be seen in any way as competition to vaccines. It should be for when it’s too late, when there’s an outbreak and people are getting exposed and there’s not going to be time for a vaccine to work.”

The study, begun Aug. 3, was conducted with the National Institute of Allergy and Infectious Diseases. Lilly used an unusual strategy: a fleet of refitted recreational vehicles that could prepare study drug, do lab work, and pull trailers that could be used as on-site infusion clinics. That meant that when a nursing home or long-term care facility had an outbreak, an RV could be dispatched. Lilly developed the antibody in collaboration with Abcellera, a Vancouver biotech.  Lilly enrolled 1,097 participants in the study. Of these, 132 tested positive for the SARS-CoV-2 virus, which causes Covid-19, at the beginning of the study. Of the remaining participants, 300 were residents of long-term care facilities and the rest were facility staff, including health care workers.  Among these, 965, symptomatic Covid-19 infections were reduced by 57%. Among the 299 patients who were nursing home residents, the results were stronger still, reducing symptomatic Covid-19 cases by 80%. In both cases the result was statistically significant.  There were four deaths among the 965 patients, all of them in the placebo group. When the 132 who tested positive at the study’s beginning were included, there were another four deaths — again, only among patients who received placebo. All deaths were in residents, not staff.

Among the 299 nursing home residents, there were four deaths attributed to Covid-19, all in the placebo arm. Among the 41 nursing home residents who tested positive at the study’s beginning, there were four deaths, again in the bamlanivimab arm. In order to get a long duration of effect from the antibodies, Lilly used a dose of 4.2 grams, about six-fold higher than the dose authorized for use in patients with Covid-19. Bamlanivimab is given intravenously. Covid-19 vaccines have already been made available to patients in nursing homes, Skovronsky acknowledged. But he said the antibodies could still be useful if there are outbreaks in places the vaccines have not reached. Eli Lilly will discuss with the FDA whether a new emergency authorization is warranted. Regeneron is conducting its own Covid prevention study in households where one member was infected. Skovronsky said that he also hoped that the results would encourage people who develop Covid to receive antibody treatment. Use of the monoclonal antibodies has been more sporadic than expected, in part because of distribution problems and in part because doctors and patients don’t know to ask for them. The government has purchased large stocks of antibodies from both Lilly and Regeneron; whether the drugs are used more after governments purchase them makes no difference to the companies.

Lilly's Official Press Release (Jan. 21, 2021):

https://investor.lilly.com/news-releases/news-release-details/lillys-neutralizing-antibody-bamlanivimab-ly-cov555-prevented