Virus World

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

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

Lilly, which is developing the drug with the biotechnology firm Abcellera, tested three doses of its antibody against placebo. A drug being developed by Eli Lilly helped sick patients rid their systems of the virus that causes Covid-19 sooner and may have prevented them from landing in the hospital, according to newly released data. The drug is what is known as a monoclonal antibody, which experts view as being among the most likely technologies to help treat Covid-19. It’s a manufactured version of the antibodies that the body uses as part of its response to a virus.  “This is a good start,” said Eric Topol, the director and founder of the Scripps Research Translational Institute. “A lot is pinned not only on Lilly but on the whole family of these [monoclonal antibodies], because even though they’re expensive and they’re not going to make a gajillion doses, they could make a big difference in the whole landscape of the pandemic.” Lilly, which is developing the drug with the biotechnology firm Abcellera, tested three doses of its antibody against placebo in a trial enrolling about 450 patients recently diagnosed with mild to moderate Covid-19. The middle dose, 2,800 mg, met the trial’s primary goal of significantly reducing patients’ levels of SARS-CoV-2 after 11 days. But other doses of the drug did not meet that goal, including a higher dose of 7,000 mg and a lower one of 700 mg. That could raise the risk that the benefit was due to chance, because normally one expects a medicine to become more effective as the dose increases, known as a dose response.

In a statement, Lilly said the problem may have stemmed from how the study chose to assess how much virus was detectable after 11 days. Most patients, including those who received placebo, had almost no virus at that time point. The company said that an analysis at day three showed the lower viral levels among those who received the antibody. In a more tantalizing finding, the medicine also appeared to reduce patients’ odds of ending up in the hospital. Just 1.7% of patients who received the drug, called LY-CoV555, eventually went to the emergency room or were hospitalized, compared with 6% of those who took placebo. That amounts to 72% relative reduction in risk. Those hospitalization data, though, are from a small number of patients, again increasing the odds that the finding won’t hold up with further study. Five of 302 patients on LY-CoV555 were hospitalized, compared to nine of 150 patients who received placebo. Lilly declined to confirm the difference is statistically significant, citing the need for full publication of the results.

“This is extremely exciting, and maybe a pivotal moment in the fight against Covid-19, said Daniel Skovronsky, Lilly’s chief scientific officer. “I think this should give us confidence that neutralizing antibodies are going to be an important part of the solution for ours and other companies, and that  we will win the fight against Covid-19 through medicine and innovation.” Skovronsky noted that studies of the antibody began only six months ago, and said that, although two doses missed on the 11-day endpoint, the antibody’s impact on symptoms and hospitalization gave him confidence in the result. He said that Lilly will share the results with regulators such as the Food and Drug Administration, and hoped to have discussions about a possible emergency use authorization (EUA). “We will be discussing with regulators what the appropriate next steps are,” Skovronsky said. “So, of course, those discussions will include additional clinical trials as well as other options such as EUA. It’s a small dataset for sure, we we have 450 patients in this data set, but the magnitude of the impact on a hard end point years is very exciting and potentially meaningful for patients.”..

Company's Release available in this site (Sept. 16, 2020):

https://investor.lilly.com/node/43721/pdf

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 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

A new antibody-based drug shows promise in treating outpatients who have mild to severe COVID-19, according to initial results of research conducted in part at Cook County Health and Northwestern University. Patients given the drug were hospitalized or visited the emergency room less often than those given a placebo, Cook County Health officials said. The patients receiving the drug also showed improvement within two to six days, a shorter disease course that is not only good for patients but also may reduce the amount of time a person is infectious, helping protect other people. The drug, manufactured by Eli Lilly and AbCellera Biologics Inc., was tested on 452 outpatients at 24 medical institutions across the country, including Cook County’s vast public health system and the Northwestern University Feinberg School of Medicine. Most of the 14 patients who took part at Cook County Health were Latino or Black, populations that have been hit especially hard by the disease. The results of the continuing study, which is being run by Eli Lilly, were published Wednesday by the New England Journal of Medicine.

The drug, administered through a one-time infusion, includes the replicated antibodies of one of the first patients in the United States to survive COVID-19. It’s classified as a monoclonal antibody treatment, the same type of medication given to President Donald Trump after he was diagnosed with the disease and which he described as “a cure.” The drug in the Eli Lilly trial was formulated using a single antibody. The drug Trump received was made by Regeneron and involves two antibodies. 

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...