Virus World

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

The world's largest randomised trial of potential medicines for COVID-19 is to add Regeneron's experimental antiviral antibody cocktail REGN-COV2 to the drugs it is testing in patients hospitalised with the disease. The UK RECOVERY trial, which has been testing a range of potential COVID-19 treatments since it began in April, will compare the effects of adding REGN-COV2 - a lab-manufactured monoclonal antibody - to standard care. “This is the first drug actually designed for this disease,” said Martin Landray, a professor of medicine & epidemiology at Oxford University who is co-leading the trial. “There are lots of good reasons for thinking this might be really quite a powerful treatment,” he told Reuters in an interview. The addition of Regeneron’s drug to the RECOVERY trial comes amid growing hopes that monoclonal antibodies may emerge as effective ways to treat COVID-19.  Until now, the RECOVERY trial had mostly been studying whether existing drugs could be re-purposed to tackle the new disease, and it has already found answers on a number of them.

In June and September, trial results showed that widely used steroids such as dexamethasone and hydrocortisone were able to reduce death rates among severely-ill COVID-19 patients.  Also in June, RECOVERY trial results showed that the anti-malarial drug hydroxychloroquine, once touted by U.S. President Donald Trump as a potential “game changer” in the pandemic, was of no benefit in treating COVID-19 patients.  Regeneron’s REGN-COV2 cocktail, which the company is already testing in late-stage clinical trials in people, combines one Regeneron-made antibody and a second antibody isolated from people who have recovered after being infected with COVID-19.  The combination is designed to bind to the spike protein used by the new coronavirus to gain access to human cells, limiting the virus’s ability to escape.  Regeneron developed the biological drug before linking up with Roche ROG.S to expand its manufacturing capacity in hopes of meeting global demand, should the medicine prove effective. Regeneron would handle U.S. sales, with Roche selling the medicine around the world.

Landray said his team had secured enough supply of the drug so that up to “several thousand” patients could be given it in the trial and compared with several thousand controls. “Given that the second phase (of COVID-19 infections in the UK) seems to be coming now, it is a really good time to be starting this,” he said. The United States already has a $450 million deal for the cocktail in place, under the terms of which Regeneron will sell it around 70,000 to 300,000 potential treatment doses or 420,000 to 1.3 million prevention doses of REGN-COV2. Data is due later this month, Regeneron has said.  Alongside Regeneron, Eli Lilly LLY.N, working with biotech firm AbCellera, is seen as a leading contender in the antibody race. In August it started testing whether its antibody can prevent COVID-19 infections in nursing homes. A separate trial testing the compound on recently diagnosed COVID patients may yield initial data in September or shortly after. GlaxoSmithKline GSK.L and partner Vir Biotechnology VIR.O also began testing an experimental antibody on newly diagnosed COVID-19 patients late last month. AstraZeneca AZN.L is for now testing its antibody-based cocktail on healthy volunteers for tolerability.

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.”...

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

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...