Candidate: Etesevimab (LY-CoV016 or JS016)
Type: Recombinant fully human monoclonal neutralizing antibody, which specifically binds to the SARS-CoV-2 surface spike protein receptor binding domain with high affinity and can block the binding of the virus to the ACE2 host cell surface receptor, as point mutations were introduced into the native human IgG1 antibody to mitigate effector function.
2022 Status: FDA LIMITS EUA—The FDA on January 24 limited the Emergency Use Authorization for etesevimab, as well as Lilly’s bamlanivimab and Regeneron Pharmaceuticals’ REGEN-COV (co-marketed by Roche as Ronapreve in some nations) to no longer authorize its use as a treatment for the Omicron variant of SARS-CoV-2 in any U.S. states, territories, and jurisdictions “at this time.”
“In the future, if patients in certain geographic regions are likely to be infected or exposed to a variant that is susceptible to these treatments, then use of these treatments may be authorized in these regions,” the FDA added.
The FDA added that several other therapies are expected to work against Omicron, citing Pfizer’s Paxlovid™ (nirmatrelvir; PF-07321332), GlaxoSmithKline and Vir Biotechnology’s sotrovimab, and Merck & Co. and Ridgeback Therapeutics’ molnupiravir (MK-4482, EIDD-2801) as treatments for the Omicron variant.
2021 Status: EUA EXPANDED TO HIGH-RISK CHILDREN <12–The FDA on December 3 expanded the Emergency Use Authorization (EUA) for the combination of etesevimab and bamlanivimab to include high-risk pediatric patients under age 12, Eli Lilly said. The expansion allows the combination to be administered in high-risk pediatric patients for the treatment of mild to moderate COVID-19 as well as post-exposure prophylaxis.
Lilly said the expanded authorization was based on safety and efficacy data of pediatric and infant patients in the Phase II/III BLAZE-1 trial studying etesevimab and bamlanivimab administered together for the treatment of mild to moderate COVID-19 and who are at high risk for severe disease progression. The median time to complete symptom resolution was 7 days for subjects treated with bamlanivimab 700 mg and etesevimab 1,400 mg, and 5 days for subjects treated with weight-based dosing of etesevimab and bamlanivimab. No pediatric subject died or required hospitalization due to COVID-19.
As of December 3, Lilly said, more than 700,000 patients had been treated with bamlanivimab or the combination of etesevimab and bamlanivimab, potentially preventing more than 35,000 hospitalizations and at least 14,000 deaths.
220,000 DOSES FOR EU—AbCellera, Eli Lilly’s partner in developing Bamlanivimab, said September 21 that Lilly and the European Commission had agreed to supply up to 220,000 doses of etesevimab together with bamlanivimab to treat confirmed COVID-19 in patients aged 12 years and older that do not require supplemental oxygen for COVID-19 and who are at increased risk of progressing to severe COVID-19.
No value was disclosed for the Joint Procurement Agreement, which is designed to enable participating countries in the European Union (EU) and European Economic Area (EEA) to purchase the products directly from Lilly following national approval for emergency use or marketing authorization at the EU level.
As of September 21, Lilly said, bamlanivimab alone and together with etesevimab had been used to treat more than 535,000 patients in the U.S., potentially keeping more than 25,000 patients out of the hospital and saving more than 10,000 lives.
FDA EXPANDS EUA—The FDA on September 16 expanded the Emergency Use Authorization (EUA) granted to Eli Lilly for the combination of bamlanivimab and etesevimab by allowing its use for post-exposure prophylaxis (PEP) in high-risk individuals 12 years of age and older who have not been fully vaccinated against COVID-19 or are not expected to mount an adequate immune response to complete vaccination, and have been exposed to someone infected with SARS-CoV-2 or who are at high risk of exposure in an institutional setting, including a nursing home or prison.
Lilly said the expanded authorization was based on data from the Phase III BLAZE-2 trial (NCT04497987), which showed that bamlanivimab 4200 mg reduced the risk of contracting symptomatic COVID-19 by up to 80% in nursing home residents, and up to 57% among residents and staff of long-term care facilities. BLAZE-2 was conducted by Lilly with the NIH’s National Institute of Allergy and Infectious Diseases (NIAID), and the COVID-19 Prevention Network (CoVPN).
According to the company, over 535,000 treatment courses of bamlanivimab or bamlanivimab and etesevimab together have been administered to patients as of September 16.
$330M U.S. Gov’t Purchase—The U.S. government will purchase an additional 388,000 doses of etesevimab, Lilly said September 15, in a deal expected to generate $330 million in the second half of 2021. Approximately 200,000 doses are expected to ship during Q3 and the rest in Q4. The doses will complement doses of bamlanivimab previously purchased by the government, according to Lilly.
Antibody Combination Distribution Resumed— On September 2, the FDA and the U.S. Assistant Secretary for Preparedness and Response (ASPR) announced the authorization of the use of etesevimab and bamlanivimab, administered together, in allU.S. states, territories, and U.S. jurisdictions where recent data has shown the combined frequency of variants resistant to the combination was less than or equal to 5%.
Upon that basis, such authorization had been granted August 27 for use of the combination in 22 U.S. states: Colorado, Connecticut, Illinois, Indiana, Iowa, Kansas, Maine, Massachusetts, New Hampshire, Michigan, Minnesota, Missouri, Montana, Nebraska, North Dakota, Ohio, Rhode Island, South Dakota, Utah, Vermont, Wisconsin, and Wyoming.
Shelf Life Extension—On August 20, the FDA and ASPR extended from 12 months to 18 months the shelf life of bamlanivimab under its Emergency Use Authorization for the combination with etesevimab.
Antibody Combination Distribution Halted—The FDA and the U.S. Assistant Secretary for Preparedness and Response (ASPR) said June 25 they immediately paused all nationwide distribution of Eli Lilly’s antibody combination of etesevimab and bamlanivimab.
ASPR said the combination showed itself “not active” against two COVID-19 variants. P.1/Gamma (first identified in Brazil) and B.1.351/Beta (first identified in South Africa) have shown significantly reduced susceptibility against etesevimab-bamlanivimab, the FDA acknowledged in its “Fact Sheet” for healthcare providers of detailed instructions for administering the antibody combination.
The FDA recommended that healthcare providers nationwide use two other monoclonal antibody therapies that have been granted EUAs—Regeneron Pharmaceuticals’ two-antibody “cocktail” or combination REGEN-COV™; and Sotrovimab (formerly VIR-7831), which is being developed by GlaxoSmithKline (GSK) and Vir Biotechnology.
Eli Lilly said March 10 that its antibody combination of bamlanivimab (LY-CoV555) 700 mg and etesevimab (LY-CoV016) 1400 mg—already FDA-authorized for emergency use—generated additional positive Phase III results, slashing by 87% the risk of COVID-19 related hospitalizations and deaths in high-risk patients recently diagnosed with the virus.
Four hospitalizations and deaths, or “events,” occurred in patients 29 days after treatment with the bamlanivimab-etesevimab combination, compared with 15 reported in patients given placebo in the randomized, double-blind, placebo-controlled BLAZE-1 Phase III trial (NCT04427501), Lilly said.
The data came from a newly reported cohort of 769 high-risk patients aged 12 and older with mild to moderate COVID-19. Of those patients, 511 were randomized to therapy, and the other 258 to placebo. The study’s key endpoint was the percentage of participants who experience COVID-related hospitalizations or death from any cause by day 29.
Lilly added that bamlanivimab and etesevimab together also showed statistically significant improvements on key secondary endpoints—defined as change from baseline to day 7 in SARS-CoV-2 viral load, persistently high SARS-CoV-2 viral load on day 7, time to sustained symptom resolution, and COVID-related hospitalization, ER visit, or death from any cause from baseline by day 29. Additional endpoints in BLAZE-1 included change from baseline in viral load at other time points, symptom improvement, symptom resolution, as well as safety.
Positive CHMP opinion—The European Medicines Agency’s Committee for Medicinal Products for Human Use (CHMP) on March 5 issued a positive opinion on bamlanivimab administered together with etesevimab as well as on bamlanivimab alone. Both options can be used for the treatment of confirmed COVID-19 in patients aged 12 years and older that do not require supplemental oxygen for COVID-19 and who are at high risk of progressing to severe COVID-19, the CHMP advised.
The CHMP based its opinion on results from the Phase II and Phase III portions of the BLAZE-1 trial (NCT04427501), which showed in part that bamlanivimab and etesevimab together reduced the risk of COVID-19 hospitalizations and death by 70% in non-hospitalized high-risk patients with mild to moderate COVID-19.
100,000 Doses of Combo for $210M—Lilly said February 26 that the U.S. government agreed to purchase a minimum of 100,000 doses of the combination therapy of bamlanivimab (LY-CoV555) and etesevimab (LY-CoV016) for $210 million, with doses set to be delivered through March 31, 2021. The U.S. government will have the option to purchase up to an additional 1.1 million doses of the combination through November 25, 2021, under the same terms as the base agreement and subject to agreement from Lilly, product availability and the medical need in the U.S.
The government has already committed to purchase a total of 1.45 million doses of bamlanivimab alone, which includes more than 1 million doses that have been delivered, and an agreement to deliver 450,000 additional doses by March 31. The government has promised to provide neutralizing antibodies at no out-of-pocket cost to patients, while acknowledging that healthcare facilities may charge a fee for the product’s administration.
Emergency Use with Etesevimab Authorized—The FDA on February 9 granted Emergency Use Authorization (EUA) for bamlanivimab (LY-CoV555) 700 mg in combination with etesevimab (LY-CoV016) 1400 mg for the treatment of mild to moderate COVID-19 in patients aged 12 and older who are at high risk for progressing to severe COVID-19 and/or hospitalization.
The FDA also authorized infusion times of 16 minutes for bamlanivimab and 21 minutes for the bamlanivimab-etesevimab combination—compared with the previously authorized time of 60 minutes. Lilly said it reduced the infusion times in response to feedback received from nurses and doctors administering the infusions.
The EUA is based on Phase III data from the Phase III BLAZE-1 trial (NCT04427501), which demonstrated bamlanivimab and etesevimab together reduced the risk of COVID-19 hospitalizations and death by 70%. These data replicate earlier results published in JAMA in a much larger group of patients. Lilly said the outcomes seen with bamlanivimab and etesevimab together were consistent with the reduction in risk of hospitalization or ER visits seen with bamlanivimab alone. The most common adverse event more often reported for patients receiving bamlanivimab and etesevimab together vs. placebo was nausea on the day of infusion.
Lilly said January 26 its authorized bamlanivimab (LY-CoV555), in combination with another of its antibody candidates, etesevimab (LY-CoV016), met the primary endpoint of the Phase III BLAZE-1 trial (NCT04427501) by significantly reducing COVID-19-related hospitalizations and deaths in high-risk patients recently diagnosed with COVID-19.
Of the 10 patients who died during the study, all were randomized to placebo, Lilly added.
Lilly reported 11 events (2.1%) in patients receiving its antibody combination, compared with 36 events (7%) in placebo patients—a 70% risk reduction among the study’s 1,035 patients. That decrease was consistent with the reduction in risk of hospitalization or ER visits seen with bamlanivimab alone in the Phase II portion of BLAZE-1, the company said.
The bamlanivimab-etesevimab combo also showed statistically significant improvements on all four key secondary endpoints—the change from baseline to day 7 in SARS-CoV-2 viral load, persistently high SARS-CoV2 viral load on day 7, time to sustained symptom resolution, and COVID-related hospitalization, ER visit or death from any cause from baseline by day 29.
Bamlanivimab was 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.
Etesevimab is licensed by Lilly from Junshi Biosciences after it was jointly developed by Junshi Biosciences and Institute of Microbiology, Chinese Academy of Science (IMCAS). Junshi Biosciences leads development of etesevimab in Greater China, while Lilly leads development in the rest of the world.
2020 Status: Junshi Biosciences said July 12 that it completed enrollment in a Phase I trial (NCT04441918) of JS016, which according to the company is the first COVID-19 neutralizing antibody to enter clinical trials in China, and the first neutralizing antibody entering clinical trial in healthy subjects in the world. During the second quarter, JS016 entered into U.S. clinical trials that were overseen by Eli Lilly.
The Phase I trial is a randomized, double-blind, placebo-controlled study designed to investigate the safety and tolerability of a single dose JS016 intravenous injection in 40 healthy subjects in four dosing groups. The first patient was enrolled on June 7 at Huashan Hospital Affiliated to Fudan University in China. Junshi said no dose-limiting events had been observed as of July 12.
Junshi said it plans to initiate a Phase Ib trial in non-severe COVID-19 patients and Phase II/III trials in severe and critical patients “soon.” Simultaneously, the company disclosed plans to investigate the prophylactic potential of JS016 in high-risk populations.
The antibody treatment is being co-developed by the companies, with Junshi leading development in Greater China, and Lilly holding rights in the rest of the world—including the U.S., where it plans to begin dosing the first patient in a complementary clinical trial. Both studies aim to assess the safety, tolerability, pharmacokinetics, and immunogenicity of JS016 in healthy participants not been diagnosed with COVID-19.
JS016 is part of Lilly’s COVID-19 clinical development program, through which the pharma is creating a portfolio of monotherapy and combination or “cocktail” antibody regimens that could combine JS016 with LY-CoV555, being codeveloped with AbCellera, and additional antibodies now in preclinical development.
JS016 was jointly developed by Junshi with the Institute of Microbiology, Chinese Academy of Science (IMCAS). According to Junshi, preclinical research has shown JS016 to express extremely high specific affinity (on a level of nM) to the SARS-CoV-2 receptor-binding domain on the spike protein blocking the virus from invading host cells. A study published in Nature showed JS016 protected rhesus monkeys from COVID-19 infection, suggesting a potential for prophylactic use in humans.
COVID-19: 200 Candidates and Counting
To navigate through the >200 potential therapeutic and vaccine options for COVID-19, GEN has grouped the candidates into four broad categories based on their developmental and (where applicable) clinical progress:
● FRONT RUNNER – the most promising therapeutics/vaccines based on clinical progress, favorable data or both.
● DEFINITELY MAYBE – earlier phases with promising partners, or more advanced candidates in development that have generated uneven data.
● KEEPING AN EYE ON… – interesting technology, attracting notable partners, or both, but preliminary data.
● TOO SOON TO TELL – longshots pending additional experimental and/or clinical data.
GEN has also tagged the most common treatment types: