Virus World

Covid-19 antibody drug developers have had a rough time. One by one, antibody medicines that reached the market under emergency use saw their authorized indications narrowed and then revoked by the FDA due to ineffectiveness against newer strains of the virus. By the end of last year, no Covid-19 antibody drugs remained authorized for use in the U.S. InflaRx is showing that Covid-19 antibody drug research is still alive. The FDA this week authorized the biotech’s antibody, vilobelimab, as a treatment for Covid-19 in hospitalized adults. The drug is meant for severe cases. The authorization specifies treatment must start within 48 hours of the patient receiving mechanical ventilation or artificial life support. Jena, Germany-based InflaRx will market its new product under the name “Gohibic.” The antibody drugs whose authorizations were revoked all targeted some part of SARS-CoV-2 in order to prevent it from infecting cells. InflaRx’s target isn’t on the virus. The biotech’s antibody addresses a part of the immune response believed to play a role in the inflammation that leads to Covid-19 progression. The drug targets C5a, a protein of the complement system, which is a part of the immune system.

Authorization of InflaRx’s drug provides an alternative to Olumiant, an Eli Lilly drug. Like Gohibic, Olumiant is also authorized for treating hospitalized patients within 48 hours of starting mechanical ventilation or artificial life support. This Lilly drug works by blocking JAK proteins associated with inflammation. But Olumiant is a small molecule made into a pill—a challenging formulation for patients receiving breathing assistance. Olumiant can be dissolved in water and swallowed or administered via a gastrointestinal tube. But InflaRx’s Gohibic provides yet another dosing option, as that drug is administered as an intravenous infusion. InflaRx initially developed its antibody as a treatment for hidradenitis suppurativa, a rare inflammatory skin disorder. In 2019, the antibody drug failed a Phase 2b test in that indication. With the onset of the pandemic the following year, InflaRx began a clinical trial testing the antibody in Covid-19 patients. The Gohibic EUA request was based on data from a placebo-controlled Phase 3 study that enrolled 369 mechanically ventilated patients in intensive care units. According to study results, after 28 days, the treatment group showed a 23.9% reduction in death from all causes compared to the placebo arm. The most common adverse reactions reported in the study included pneumonia, sepsis, delirium, and pulmonary embolism. The FDA also said serious infections have been reported in Covid-19 patients who received Gohibic. Now that InflaRx has emergency authorization for Gohibic, the company said it is communicating with the FDA about the next steps for a biologics license application seeking full regulatory approval. The company is having similar discussions with regulators in Europe.

FDA Press Release (April 4, 2023):

https://www.fda.gov/drugs/drug-safety-and-availability/fda-authorizes-gohibic-vilobelimab-injection-treatment-covid-19 

The FDA halted the use of two monoclonal antibody treatments for COVID-19 because they are not effective against the omicron variant of SARS-CoV-2, which now accounts for almost all U.S. cases. The FDA revised the emergency use authorizations for the two treatments bamlanivimab and etesevimab administered together, and the cocktail of casirivimab and imdevimab. Their use will now be limited to infections that are likely to have been caused by a variant that is susceptible to the treatments. “Because data show these treatments are highly unlikely to be active against the omicron variant, which is circulating at a very high frequency throughout the United States, these treatments are not authorized for use in any U.S. states, territories, and jurisdictions at this time,” Patrizia Cavazzoni, MD, director of the FDA’s Center for Drug Evaluation and Research, said in a press release. Cavazzoni said this will avoid exposing patients to side effects from treatments “that are not expected to provide benefit to patients who have been infected with or exposed to the omicron variant.” She said the treatments may be reauthorized in regions where patients are likely to be infected or exposed to a susceptible variant, or if they are proven affective against future variants. The FDA noted that there are several other therapies that are expected to work against omicron, including Paxlovid, sotrovimab, remdesivir and molnupiravir.

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 global spread of SARS-CoV-2/COVID-19 is devastating health systems and economies worldwide. Recombinant or vaccine-induced neutralizing antibodies are used to combat the COVID-19 pandemic. However, recently emerged SARS-CoV-2 variants B.1.1.7 (UK), B.1.351 (South Africa) and B.1.1.248 (Brazil) harbor mutations in the viral spike (S) protein that may alter virus-host cell interactions and confer resistance to inhibitors and antibodies. Here, using pseudoparticles, we show that entry of UK, South Africa and Brazil variant into human cells is susceptible to blockade by entry inhibitors. In contrast, entry of the South Africa and Brazil variant was partially (Casirivimab) or fully (Bamlanivimab) resistant to antibodies used for COVID-19 treatment and was less efficiently inhibited by serum/plasma from convalescent or BNT162b2 vaccinated individuals. These results suggest that SARS-CoV-2 may escape antibody responses, which has important implications for efforts to contain the pandemic.

Preprint available (Feb. 11. 2021):

https://doi.org/10.1101/2021.02.11.430787 

The authorization raised immediate questions about who would get access to the antibody treatments, which are in short supply. The Food and Drug Administration has granted emergency authorization of a Covid-19 antibody treatment made by Eli Lilly that is similar to a therapy given to President Trump shortly after he contracted the coronavirus. The decision, announced on Monday by the agency, is likely to be seen as a valuable tool to treat patients with Covid-19 at a time when the pandemic is raging across the United States, hospitals are overwhelmed and doctors have few options to treat the disease. Eli Lilly said that its treatment, called bamlanivimab, should be administered as soon as possible after a positive coronavirus test, and within 10 days of developing symptoms. The authorization applies only to people newly infected with the virus, and the agency said it should not be used in hospitalized patients. It is authorized for people who are 12 and older and at risk for developing a severe form of Covid-19 or being hospitalized for the condition. The F.D.A. said that included people who were over 65 and obese — a key group that early studies have shown can benefit the most from the treatment. “It’s a great day for science and medicine — sort of a feat of what’s possible,” said Dr. Daniel M. Skovronsky, the chief scientific officer of Eli Lilly. The company and its collaborators, including the National Institutes of Health, he said, were able “to create a new drug, manufacture it, test it in clinical trials, and get it authorized for use in just seven months.”

In October, the company announced that it had reached a $375 million deal to sell 300,000 doses of the treatment to the U.S. government. The emergency authorization for Eli Lilly raised immediate questions about who would get access to the treatment at a time when emergency authorizations for coronavirus vaccines might still be weeks or months away. The news came on the same day that Pfizer announced positive early results from its coronavirus vaccine trial. That vaccine might get emergency authorization sometime this year, but even then it would not be available to most Americans until well into 2021.  In a statement on Monday, Alex M. Azar II, the health secretary and a former executive at Eli Lilly, said the F.D.A.’s emergency authorization for bamlanivimab was a “step forward” in “bridging us to the rollout of safe and effective vaccines.” Eli Lilly has said that it expects to have enough doses to treat up to one million people by the end of the year, and that it will be able to significantly increase production thereafter. But that means that even in the best-case scenario, there won’t initially be enough to curb a virus that is now infecting more than 110,000 people a day in the United States. “It’s kind of the best times for these therapies to enter, because they can have an impact,” said Dr. Walid F. Gellad, who leads the Center for Pharmaceutical Policy and Prescribing at the University of Pittsburgh. “It’s also the worst time because we don’t have enough doses, and it’s going to add to the backlog of testing.”...

Lilly's press release (Nov. 9, 2020): 

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

FDA letter of authorization (Nov. 9, 2020):

https://www.fda.gov/media/143602/download

The U.S. Army will spend more than a half-billion dollars to procure two leading COVID-19 candidates—AstraZeneca’s vaccine AZD1222, co-developed with the University of Oxford and a spinout company; and Eli Lilly’s neutralizing antibody bamlanivimab (LY-CoV555). The U.S. Department of Defense (DoD) disclosed yesterday that the Army this week awarded firm-fixed-price contracts of $312.5 million with Lilly (W911QY-21-C-0016) on Tuesday, and more than $286.9 million with AstraZeneca (W15QKN-21-C-0003) on Wednesday. The contracts, awarded by U.S. Army Contracting Command, cover an unspecified quantity of bamlanivimab to be made at a Lilly production site in Indianapolis; and 200 million doses of AZD1222 to be produced at AstraZeneca sites in West Chester Township, OH, and Albuquerque, NM.

Funds for the Lilly contract will come from the Coronavirus Aid, Relief, and Economic Security (CARES) Act, enacted March 27. The AstraZeneca contract will be funded through “other procurement,” Army funds the service branch uses to finance the procurement, production, and modernization of equipment not otherwise provided for, under a fiscal year 2021 budget when that spending plan is finalized. AZD1222 is based on an adenovirus vaccine vector and the COVID-19 spike protein. After vaccination, the surface spike protein of the coronavirus is produced, which primes the immune system to attack the coronavirus if it later infects the body. Bamlanivimab is an anti-SAR-CoV-2 antibody first identified in a blood sample from a recovered COVID-19 patient, and discovered through the rapid pandemic response platform of partner AbCellera, in partnership with NIAID’s Vaccine Research Center. Both AZD1222 and bamlanivimab are among 19 “Front Runner” leading candidates among the more than 300 COVID-19 therapeutics under study in GEN’s updated and just-launched “COVID-19 Drug & Vaccine Candidate Tracker.”

Just on Wednesday, Lilly said that the U.S. government agreed to buy an initial 300,000 vials of bamlanivimab over the next two months for $375 million—$1,250 a vial—to be provided by the Biomedical Advanced Research and Development Authority (BARDA) partnered with the DoD Joint Program Executive Office for Chemical, Biological, Radiological and Nuclear Defense and Army Contracting Command. The contract is part of Operation Warp Speed, the Trump administration’s program designed to accelerate the development, manufacturing, and distribution of COVID-19 diagnostics, drugs, and 300 million doses of vaccines. The contract also includes an option for the federal government to buy another 650,000 vials from Lilly for up to an additional $812.5 million through the end of June 2021. In May, AstraZeneca was awarded up to $1.2 billion from BARDA toward development, production, and delivery of AZD1222. The development and production work to be funded by BARDA included the up-to-30,000-patient Phase III trial (NCT04516746) that is being resumed in the United States after a month-long pause in global patient recruitment, as well as another trial to evaluate the vaccine in children. Separately, AstraZeneca has received $509.65 million in Warp Speed funding toward development of another COVID-19 candidate, the monoclonal antibody combination therapy AZD7442. Most of that money, $486 million, will fund two Phase III trials and related development activities for AZD7442, a combination of AZD8895 and AZD1061.

The drugmaker’s experimental antibody treatment is similar to the one President Trump received from Regeneron. A government-sponsored clinical trial that is testing an antibody treatment for Covid-19 developed by the drugmaker Eli Lilly has been paused because of a “potential safety concern,” according to emails that government officials sent on Tuesday to researchers at testing sites. The company confirmed the pause. The news comes just a day after Johnson & Johnson announced the pause of its coronavirus vaccine trial because of a sick volunteer, and a month after AstraZeneca’s vaccine trial was halted over concerns about two participants who had fallen ill after getting the company’s vaccine. The Eli Lilly trial was designed to test the benefits of the antibody therapy on hundreds of people hospitalized with Covid-19, compared with a placebo. All of the study participants also received another experimental drug, remdesivir, which has become commonly used to treat coronavirus patients. It is unclear exactly what safety issues prompted the pause. In large clinical trials, pauses are not unusual, and declines in health in volunteers are not necessarily the result of the experimental drug or vaccine. Such halts are meant to allow an independent board of scientific experts to review the data and determine whether the event may have been related to the treatment or occurred by chance.

Enrollment for the Eli Lilly trial, which was sponsored by several branches of the National Institutes of Health and the Department of Veterans Affairs, among other organizations, had been continuing. But on Tuesday, multiple officials sent emails to researchers telling them to stop adding volunteers to the study out of an “abundance of caution.” In a statement, an N.I.H. spokeswoman said the trial, which had enrolled 326 Covid-19 patients, was paused when the independent safety board found that after five days of treatment, the group of patients who had received the antibodies showed a different “clinical status” than the group who had received a saline placebo — a difference that crossed a predetermined threshold for safety. The N.I.H. statement did not specify the nature of the participants’ conditions. But the so-called stopping rules for the trial lay out the conditions for “futility” — the idea that a treatment has a very low chance of working, based on the data so far. A trial could also be halted if there is evidence that patients in one group are faring much worse than those in the other. Given the ambiguity in the statements released on Tuesday, all scenarios remain possible, said Dr. Eric Topol, a clinical trials expert at the Scripps Research Institute. “It’s so amorphous,” Dr. Topol said...

Initial trial to determine if monoclonal antibodies can shorten severity of COVID-19 in outpatients. Study aims to determine safety and efficacy of experimental monoclonal antibodies. A Phase 2 clinical trial will evaluate the safety and efficacy of potential new therapeutics for COVID-19, including an investigational therapeutic based on synthetic monoclonal antibodies (mAbs) to treat the disease. Researchers sponsored by the National Institute of Allergy and Infectious Diseases (NIAID), part of the National Institutes of Health, are working with clinical sites to identify potential patient volunteers currently infected with SARS-CoV-2, the virus which causes COVID-19, who have mild to moderate disease not requiring hospitalization. They will be invited to take an experimental therapy or a placebo as part of a rigorously designed randomized clinical trial. The trial, which is known as ACTIV-2, also may investigate other experimental therapeutics later under the same trial protocol. If the investigational mAbs show promise, the study would expand from a Phase 2 to a Phase 3 trial to gather additional critical data from a larger pool of volunteers without delay. The trial will be led by the NIAID-funded AIDS Clinical Trials Group (ACTG) and will enroll participants at sites around the world.

ACTIV-2 was established as part of NIH’s Accelerating COVID-19 Therapeutic Interventions and Vaccines (ACTIV), a public-private partnership program instituted to speed development of the most promising treatments and vaccines. This study is also receiving support through Operation Warp Speed(link is external), the U.S. government’s multi-agency effort to develop, manufacture and distribute medical countermeasures to fight COVID-19. The design of the study is adaptive to enable maximum flexibility in the shortest time frame. If the experimental treatment appears effective in the first stage, the treatment can be advanced rapidly to testing in larger groups of volunteers. The study also can be adapted to test additional therapeutics. “We have seen encouraging, rapid results from other adaptive treatment trials for COVID-19,” said NIH Director Francis S. Collins, M.D., Ph.D. “Under ACTIV, specific therapeutics are being prioritized based on their likelihood for success. Prioritized therapeutics under ACTIV will use a master protocol that emphasizes flexibility, which enables these critical trials to be conducted without incurring delays when a treatment shows promise.”

The first therapeutic to be tested in this trial will be LY-CoV555, an investigational monoclonal antibody made by Eli Lilly and Company (Indianapolis, Indiana). LY-CoV555 emerged from Lilly’s collaboration with AbCellera Biologics (Vancouver, British Columbia). Antibodies are infection-fighting proteins produced by immune cells. So-called neutralizing antibodies target specific viruses or other pathogens. This antibody, which was discovered by AbCellera in collaboration with NIAID’s Vaccine Research Center, was isolated from a blood sample from a recovered COVID-19 patient. Copies of this antibody were then synthesized in a lab—the term “monoclonal” refers to these laboratory-manufactured antibodies. “Using an antibody generated by the immune system of a recovered COVID-19 patient gives us a jump start on finding a safe and effective therapeutic,” said NIAID Director Anthony S. Fauci, M.D. “Investigating a variety of different therapeutics, including monoclonal antibodies, will help ensure that we advance towards an effective treatment for people suffering from COVID-19 disease as quickly as possible.”...

The FDA has approved Eli Lilly’s new COVID-19 monoclonal antibody treatment bebtelovimab, granting it emergency authorization. Bebtelovimab can be used for the treatment of mild-to-moderate COVID-19 and has been shown to be effective against the omicron variant.  One day after the United States announced a supply deal for Eli Lilly’s new COVID-19 monoclonal antibody treatment, bebtelovimab, the FDA granted it emergency use authorization. Bebtelovimab can be used for the treatment of mild-to-moderate COVID-19 in adults and pediatric patients, age 12 and older, who are at high risk for progression to severe COVID-19. The treatment has been shown to be active against the omicron variant. Three weeks ago, Lilly’s antibody cocktail of bamlanivimab and etesevimab was banned by the FDA because it was shown to be ineffective against omicron. Regeneron’s antibody, REGEN-COV, also was grounded that day for the same reason. The authorized dose of bebtelovimab is 175 mg given as an intravenous injection over at least 30 seconds. The dosage is considerably smaller and quicker to administer than previous antibody treatments approved for COVID-19. “With the emergence of variants such as omicron, treatment options remain limited,” Daniel Skovronsky, M.D., Ph.D., Lilly's chief scientific and medical officer, said in an announcement of the approval. “Lilly is pleased to provide another treatment option to help address the ongoing needs of patients and healthcare providers, who continue to battle this pandemic.”  The endorsement is based on the analyses of the phase 2 BLAZE-4 trial of nonhospitalized patients who were treated with bebtelovimab alone or together with bamlanivimab and etesevimab. Pseudovirus and authentic virus testing showed that bebtelovimab retained full neutralizing activity against omicron. In addition, the drug demonstrated neutralization against all other known variants of interest including omicron’s emerging subvariant BA.2.

The U.S. has agreed to a $720 million deal for bebtelovimab. Lilly will supply 600,000 courses of the treatment—300, 000 this month and 300,000 by the end of next month. The U.S. will have the option to buy 500,000 more antibody courses to be delivered by July 31. “Should the BA.2 subvariant grow in proportion in the U.S., this potential treatment will help ensure that we can continue to offer a monoclonal antibody treatment that works against that strain of the virus,” the Department of Health & Human Services said in a statement announcing the deal. The HHS will provide the treatment for free, it said. Lilly has been stockpiling the treatment, CEO David Ricks said last month in an interview for Fierce JPM Week. Meanwhile, Lilly also is hoping for a full approval for baricitinib, also known as Olumiant, the company’s Incyte-partnered rheumatoid arthritis drug, which according to Ricks, has become the standard-of-care for late-stage patients on ventilators, as it reduces the risk of death by 46%. Earlier this month, Lilly announced COVID-19 antibody sales of $2.24 billion for 2021, with $1.06 billion coming in the fourth quarter.

Eli Lilly's Press Release (Feb. 11, 2022):

https://investor.lilly.com/news-releases/news-release-details/lillys-bebtelovimab-receives-emergency-use-authorization 

FDA Letter of EUA  (Feb. 11, 2022):

https://www.fda.gov/media/156151/download 

Doctors have a new option for the youngest patients who are vulnerable to the worst outcomes from Covid.  The Food and Drug Administration on Friday authorized Eli Lilly’s monoclonal antibody treatment for infants and children under age 12 with Covid-19 who are at high risk of becoming severely ill from the virus because they have a condition such as obesity or diabetes. Previously, high-risk Covid patients 12 or older had been eligible to get the drugs, which are typically administered intravenously at a clinic or hospital and have been shown to lower the risk of hospitalization and death. Until now, “we haven’t had something for young kids” with Covid that could keep them out of the hospital, said Dr. Walid F. Gellad, who is the director of the Center for Pharmaceutical Policy and Prescribing at the University of Pittsburgh’s School of Medicine. The authorization comes as fears are rising about a winter surge fueled by the new Omicron coronavirus variant, which appears to be spreading because of a mix of its contagiousness and its ability to dodge the body’s immune defenses. It is not yet known how Omicron may affect young children compared to other versions of the virus or whether Lilly’s antibody treatment may be less effective against it.

Hospitalizations of children with Covid soared over the summer during a surge in Delta cases. Among the states that report the data, between 0.1 percent and 1.9 percent of all confirmed cases of Covid in children have resulted in hospitalization, according to the American Academy of Pediatrics. The F.D.A. said that body-weight-adjusted doses of Lilly’s treatment, a cocktail of two antibody drugs, were studied in a safety trial that enrolled 125 pediatric patients. “Parents of young kids, especially high-risk young kids, have had a difficult time because even though their kids are at lower risk, the focus has not been on that age, until recently with the vaccinations,” Dr. Gellad said. “It’s always good to have another option, but it’s always worth reiterating it doesn’t take the place of vaccination.”

FDA Press Release (DEc. 3, 2021): https://www.fda.gov/news-events/press-announcements/fda-expands-authorization-two-monoclonal-antibodies-treatment-and-post-exposure-prevention-covid-19 

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.”

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

Clinical setbacks reported this past week by Regeneron Pharmaceuticals and Eli Lilly have raised questions about the effectiveness of antibody therapies in patients with severe COVID-19 compared to patients with mild-to-moderate forms of the virus. Regeneron said Friday it agreed to hold off on further enrollment of patients requiring high-flow oxygen or mechanical ventilation in the Phase II/III portion (NCT04426695) of an adaptive Phase I/II/III trial assessing its two-antibody “cocktail” REGN-COV2 in hospitalized adult patients with COVID-19. In pausing enrollment of the sickest patients, Regeneron said it is following the recommendation of the trial’s independent data monitoring committee (IDMC) “based on a potential safety signal and an unfavorable risk/benefit profile at this time.” Regeneron did not disclose the potential safety signal that triggered the pause in patient enrollment—but did say it would inform the FDA of its findings, since the agency is evaluating the company’s request for an emergency use authorization (EUA) of REGN-COV2 for in mild-to-moderate outpatients at high risk for poor outcomes. Regeneron is the second developer of a leading antibody candidate against COVID-19 to suffer a clinical setback this past week. On October 26, the NIH’s National Institute of Allergy and Infectious Diseases (NIAID) halted the up-to-10,000 patient Phase III ACTIV-3 trial (NCT04501978) it was conducting to assess the safety and effectiveness of Lilly’s LY-CoV555, recently renamed bamlanivimab, compared with Gilead Sciences’ Veklury™ (remdesivir) and placebo in people who have been hospitalized with COVID-19.

“Disappointing replication”

“A disappointing replication: monoclonal antibodies to #SARSCoV2 don’t provide benefit to hospitalized patients w/ moderate-severe illness,” tweeted Eric Topol, MD, founder and director of the Scripps Translational Research Institute, on Friday.  Topol, who is also professor, molecular medicine and executive vice president of Scripps Research, added that the Regeneron and Lilly disappointments reflected “the need to treat #COVID19 early or preventatively.” Florian Krammer, PhD, professor at the department of microbiology, Icahn School of Medicine at Mount Sinai, also noted in a Twitter thread that early in COVID-19, monoclonal antibodies and other antivirals are likely to help infected patients.  “Late in infection, our own immune system does the damage, and immunomodulatory drugs likely help at this stage (like dexamethasone),” Krammer said. “Using mAbs late (like in the trials stopped by Eli Lilly and Regeneron) was unlikely to work. But using them early is very promising.” Reflecting that promise, the IDMC in Regeneron’s hospitalized patient trial of REGN-COV2 also recommended continuing enrollment of the less severely injured hospitalized patients—namely those requiring either no or low-flow oxygen, “as the risk/benefit remains acceptable in these cohorts.” The trial has an estimated enrollment of 2,970 participants....

Eli Lilly & Co. is ending a clinical trial of its antibody drug bamlanivimab in hospitalized COVID-19 patients after federal researchers concluded the therapy produced no marked improvement.  The study of the monoclonal antibody called bamlanivimab was initially paused by the company on Oct. 13 out of "an abundance of caution," because of a potential safety concern. For this particular study the therapy was being used in combination with remdesivir, an antiviral with emergency use authorization for the virus. Remdesivir was among the medications President Trump received after contracting the coronavirus. 

On Monday, the National Institutes of Health, which sponsored the trial, found the antibody treatment posed no significant safety risks for patients. However, researchers said, "bamlanivimab is unlikely to help hospitalized COVID-19 patients recover from this advanced stage of their disease." The decision to end this study does not put an end to Lilly's investment in the experimental therapy. Company officials said they "remain confident ... that bamlanivimab monotherapy may prevent progression of disease for those earlier in the course of COVID-19." The company and the NIH are pursuing several additional trials involving the antibody, which is designed to stop the virus from infecting cells. The trials target patients with less advanced stages of the disease.

Lilly's public release (October 26, 2020) available at: 

https://www.lilly.com/news/stories/statement-activ3-clinical-trial-nih-covid19

Patients admitted with COVID-19 at select hospitals may now volunteer to enroll in a clinical trial to test the safety and efficacy of a potential new treatment for the disease. The Phase 3 randomized, controlled trial is known as ACTIV-3, and as a “master protocol,” it is designed to expand to test multiple different kinds of monoclonal antibody treatments. It also can enroll additional volunteers in the middle of the trial, if a specific investigational treatment shows promise. The new study is one of four ongoing or planned trials in the National Institutes of Health’s. Accelerating COVID-19 Therapeutic Interventions and Vaccines (ACTIV) program, a public-private partnership to speed development of the most promising treatments and vaccine candidates. It also is receiving support through Operation Warp Speed(link is external), the U.S. government’s multi-agency effort to develop, manufacture and distribute medical countermeasures to fight COVID-19.

The trial will take place at select hospitals around the world that are part of existing clinical trial networks. They include the lead network, the International Network of Strategic Initiatives in Global HIV Trials (INSIGHT), operated by the National Institute of Allergy and Infectious Diseases (NIAID), a part of the National Institutes of Health. Collaborating clinical trial networks include the Prevention and Early Treatment of Acute Lung Injury network (PETAL) and Cardiothoracic Surgical Trials Network (CTSN), supported by the NIH’s National Heart, Lung and Blood Institute through the Collaborating Network of Networks for Evaluating COVID-19 and Therapeutic Strategies (CONNECTS) program, and the U.S. Department of Veterans Affairs Medical Centers. ACTIV-3 uses an adaptive two-stage Phase 3 protocol design. The ACTIV-3 trial can be modified to test additional experimental therapeutics and flexibly allow novel therapeutics to enter at either stage 1 or stage 2. In addition, if a treatment appears to be safe and effective in the initial stage after review by an independent data and safety monitoring board (DSMB), the investigational therapeutic proceeds to stage 2 testing, where more volunteers are enrolled. If an investigational therapeutic is unsafe or not likely to be effective, it will be dropped...

The initial stage of the ACTIV-3 clinical trial aims to enroll approximately 300 volunteers who have been hospitalized with mild to moderate COVID-19 with fewer than 13 days of symptoms. Once their COVID-19 infections have been confirmed and they have consented to take part in the study, participants will be randomly assigned to receive either an intravenous (IV) infusion of LY-CoV555 or a saline placebo infusion. Participants also will receive standard care for COVID-19, including the antiviral remdesivir. After five days, participants’ symptoms will be assessed, as will their need for supplemental oxygen, mechanical ventilation, or other supportive care. Volunteers will be followed for 90 days after enrollment and will receive regular examinations and have blood samples taken periodically during this time to analyze their response to the investivational therapeutic. Data collected on the fifth day of the volunteers’ participation will determine whether the investigational therapeutic will be administered to a larger group of volunteers. If LY-CoV555 appears to be safe and appears to be effective, the trial will enroll an additional 700 participants. It also will begin enrolling more severely ill participants, such as those with organ failure requiring mechanical support, or COVID-19-associated dysfunction of organs other than the lungs. The primary endpoint of the trial is the participants’ sustained recovery for 14 days after release from the hospital. The principal investigator of ACTIV-3 is Jens Lundgren, M.D., of the University of Copenhagen and Rigshospitalet. Leads of the participating networks include James Neaton, Ph.D., of the INSIGHT network, Taylor Thompson, M.D., of the PETAL network, Annetine Gelijns, Ph.D., and Alan Moskowitz, M.D., of the CTSN, and Rachel Ramoni, D.M.D., Sc.D., of the U.S. Department of Veterans Affairs. To ensure that the trial is being conducted in a safe and effective manner, an independent DSMB will oversee the trial and conduct periodic reviews of the accumulating data...