In November 2021, Elli Lilly and Company informed the EMA to end the rolling review of bamlanivimab in combination with etesevimab for the treatment of COVID-19 infections, as the company is withdrawing it from the process. At the time of the company’s withdrawal, EMA had received non-clinical (laboratory) data, data from clinical studies, data on the quality and manufacturing process of the antibodies and the risk management plan (RMP). The withdrawal was a decision by the company and it retains the right to request another rolling review or submit a marketing authorisation application in the future  . In March 2021, CHMP started a ‘rolling review’ of data on the antibodies bamlanivimab and etesevimab to be used in combination for the treatment of COVID-19 infections. The review will also look at bamlanivimab used alone  . Earlier, in March 2021, the European Medicines Agency's (EMA) Committee for Medicinal Products for Human Use (CHMP) issued a positive scientific opinion for bamlanivimab alone and bamlanivimab administered together with etesevimab [see Adis Insight Drug profile 800058525]. The opinion recommended administration of bamlanivimab alone and combination of bamlanivimab with etesevimab will be used for the treatment of confirmed COVID-2019 infection in patients, aged 12 years and older that do not require supplemental oxygen for COVID-2019 and who are at high risk of progressing to severe COVID-2019 infections. The CHMP opinion was based from the phase II and phase III BLAZE-1 trials [see below]  . Earlier, in February 2021, the bamlanivimab plus etesevimab [see Adis Insight Drug profile 800058525] regimen was authorized for use in Italy, for the treatment of mild to moderate COVID-2019 infections  . In the same month, the European Medical Agency's (EMA) human medicines committee (CHMP) initiated a rolling review of data on the use of bamlanivimab alone and in combination with etesevimab for the treatment of COVID-2019 infection in patients who do not require oxygen supplementation and who are at high risk of progressing to severe COVID-2019. The CHMP decision to start rolling review based on preliminary results from a study indicates that reduced the viral load in the back of the nose and throat of non hospitalized patients with COVID-19 who do not need supplementation oxygen  .
In April 2021, the US FDA revoked the emergency use authorisation (EUA) of bamlanivimab 700 mg alone, for the treatment of mild-to-moderate COVID-2019 infection in adults and certain paediatric patients, as the criteria for issuance of an authorisation were not met. The decision was made based on the scientific data, which included sustained increase of SARS-CoV-2 viral variants that were resistant to bamlanivimab alone which resulted in the increased risk for treatment failure  . In the same month, Eli Lilly and Company had requested the US FDA to revoke the Emergency Use Authorization (EUA). The request was made due to the evolving variant landscape in the US and the full availability of bamlanivimab and etesevimab [see Adis Insight Drug profile 800058525] together. This request was not due to any new safety concern. This was taken as a final step in Lilly's transition to only supply bamlanivimab and etesevimab together for administration in the US for the treatment of COVID-2019 infection– as planned with the US FDA – following the modification of contracts with the US government to ensure adequate supply of etesevimab to be used together with bamlanivimab  . Previously in November 2020, AbCellera had announced that bamlanivimab 700 mg received an emergency use authorization (EUA) from the US FDA. Bamlanivimab is authorised for the treatment of mild to moderate COVID-19 in adults and paediatric patients 12 years and older with positive results of direct SARS-CoV-2 viral testing, who weigh at least 40 kg and are at high risk for progressing to severe COVID-19 and/or hospitalisation. The EUA is based on data from the two randomised trials namely; BLAZE-1 and BLAZE-2 [see below]. In February 2021, the infusion time was authorized at 16 minutes, significantly reduced from the previously approved time of 60 minutes. As of October 2020, Eli Lilly and Company submitted an initial request for emergency use authorization (EUA) to US FDA for bamlanivimab (LY CoV555) monotherapy in higher-risk patients who have been recently diagnosed with mild-to-moderate COVID-19 infection, based on the combination therapy data   .
In September 2021, AbCellera announced that, the US FDA has expanded the Emergency Use Authorization (EUA) for bamlanivimab administered with etesevimab [see Adis Insight Drug profile800058525] to include post-exposure prophylaxis (PEP) to prevent COVID-2019 infection. The expanded EUA is based on data from the phase 3 BLAZE-2 trial [See below]   .
In February 2021, the US FDA granted Emergency Use Authorization (EUA) for etesevimab [see Adis Insight Drug profile 800058525] and bamlanivimab combination therapy, for the treatment of mild to moderate COVID-2019 infection in high-risk patients aged 12 years and older who are high risk for progressing to severe COVID-2019 and/or hospitalization. The therapies are indicated to be infused together in a single IV infusion, as soon as possible after a positive test and within 10 days of symptom onset. The infusion time has been authorized at 21 minutes. The EUA request was submitted by Eli Lilly, in November 2020, based on the phase II/III BLAZE-1 trial data [see below]    .
In November 2020, Health Canada granted authorisation to bamlanivimab under the interim order respecting the importation, sale and advertising of drugs for use in relation to COVID-19, as a treatment for adults and paediatric patients 12 years of age or older with mild to moderate COVID-19 who weigh at least 40 kg and are at high risk of progressing to severe COVID-19 illness and/or hospitalisation. This authorisation was based on data from BLAZE-1 trial [see below]  .
As of March 2021, Bamlanivimab alone is authorisd under special/emergency pathways in Czech Republic, Germany, Israel, Italy, Hungary, Sweden, Panama, Kuwait and UAE. In addition, bamlanivimab alone has been authorised for emergency use in Rwanda and Morocco, and through Lilly's work with the Bill & Melinda Gates Foundation, as company is providing doses of the medicine free of charge in these countries   .
As of November 2020, Eli Lilly was in discussions with global regulators including from India, Brazil, Russia and Europe for pursuing authorisation of bamlanivimab for COVID-2019 infections  .
In August 2020, National Institute of Allergy and Infectious Diseases initiated a phase III TICO (ACTIV-3) trial to evaluate the safety and efficacy of multiple investigational agents (either LY 3819253, remdesivir, VIR 7831, BRII 196/BRII 198, AZD 7442 and ensovibep) plus standard of care for the treatment of COVID-19 positive adults in the hospitalised setting (014 / ACTIV-3; NCT04501978; EudraCT2020-003278-37). The trial is designed as part of the National Institutes of Health’s (NIH) Accelerating COVID-19 Therapeutic Interventions and Vaccines (ACTIV) public-private partnership. The randomised trial intends to enrol 10000 patients in Hungary, Netherlands, Denmark, Greece, Poland, Singapore, Spain, Switzerland, Sweden, Uganda, United Kingdom and the US and may expand to India  .
In December 2020, Eli Lilly and company in collaboration with UnitedHealth Group, initiated the pragmatic UNITED trial to assess the efficacy and safety of bamlanivimab versus a propensity matched cohort for the treatment of symptomatic, high-risk COVID-2019 patients in the outpatient setting (2020-0081; NCT04639479). Trial participants will track for symptom development and in-home SARS-CoV-2 testing. If positive, the patients will receive a one-time at-home infusion of bamlanivimab, 700mg. The primary objective is to determine the incidence of COVID-2019 related hospitalisation at day 28 among bamlanivimab-treated participants relative to external, propensity-matched controls. The trial will also evaluate the incidence of COVID-related mortality at day 28, as well as safety of bamlanivimab. The trial is intended to enroll up to 500 000 patients, with at least 5 000 expected to receive bamlanivimab therapy   .
In November 2020, Eli Lilly and company completed an expanded access programme for COVID-2019 infections in the US. In October 2020, Eli Lilly Company initiated an expanded access programme for COVID-2019 infections in the US (18165; J2X-MC-Y001; NCT04603651)  .
In August 2020, National Institute of Allergy and Infectious Diseases and Eli Lilly initiated the phase II/III Adapt Out COVID trial to evaluate the safety and efficacy of bamlanivimab (LY CoV 555, LY 3819253), as compared with a placebo constituted of a 0.9% sodium chloride solution, for the treatment of COVID-19 infections (NCT04518410; ACTIV-2; ACTIV2; A5401; 38742; DAIDS-ES). The randomised trial intends to enrol 2 000 patients in the US and Puerto Rico  .
In August 2020, National Institute of Allergy and Infectious Diseases initiated phase III TICO trial to evaluate the safety and efficacy of bamlanivimab and standard of care drug remdesivir [see Adis Insight Drug profile800043325] for the treatment of COVID-19 infections (NCT04501978; ACTIV-3; 014; 014ACTIV3). The primary endpoint of the trial is sustained recovery of the participants for 14 days, following release from the hospital. The randomised, blinded, controlled, multicentre trial intends to enrol 10 000 patients in USA  . In October 2020, Independent data safety monitoring board (DSMB) recommended to pause enrolment in its ongoing phase III trial  .
In May 2021, Eli Lilly, in collaboration with AbCellera Biologics and National Institute of Allergy and Infectious Diseases, completed a phase III BLAZE-2 trial that evaluated bamlanivimab alone and in combination with etesevimab (LY 3832479/LY CoV016) [see Adis Insight Drug profile800058525] to prevent COVID-2019 infections (NCT04497987; 18063; J2X-MC-PYAD; CoVPN #3501). The randomised study was initiated in August 2020 and enrolled 1374 participants in the US. The study was run jointly with the National Institute of Allergy and Infectious Diseases (NIAID), part of the National Institutes of Health (NIH). In August 2020, National Institute of Allergy and Infectious Diseases reported that enrollment of healthy adults who are at risk of infection due to close contact at work or home to persons with SARS-CoV-2 infection in the trial has been initiated in the US    . In January 2021, results from the trial were released by the company   . In January 2021, efficacy data from a trial in COVID-2019 infections was released by Eli Lilly and Company. In March 2021, Eli Lilly and Company presented safety and efficacy data from a phase III trial at the 28th Conference on Retroviruses and Opportunistic Infections (CROI-2021)   .
In June 2021, Eli Lilly and Company in collaboration with AbCellera Biologics completed the phase II BLAZE-5 trial which evaluated the real-world effectiveness of bamlanivimab in patients with mild-to-moderate COVID-2019 infections (NCT04701658; J2X-MC-PYAJ; 18216). The open-label, prospective cohort trial was initiated in February 2021 and enrolled 3000 patients in the US  .
In October 2020, Eli Lilly and Company initiated a phase II BLAZE-4 trial to evaluate the efficacy and safety of etesevimab (LY 3832479/LY CoV016) [see Adis Insight Drug profile800058525] and bamlanivimab (LY 3819253/LY CoV555) as monotherapy and combination therapy in patients with mild to moderate COVID-2019 infections (NCT04634409; J2X-MC-PYAH). The randomised, placebo-controlled trial is designed to enrol approximately 1782 patients in the US, Argentina and Puerto Rico   . In January 2021, Eli Lilly expanded the trial to evaluate bamlanivimab in combination with sotrovimab [see Adis Insight Drug profile800058114] in patients with mild to moderate COVID-2019 infections. Subsequently, first patient was dosed in the trial  . In March 2021, Eli lilly and company reported that the BLAZE-4 trial met primary end point in which combination of bamlanivimab, 700mg with sotrovimab, 500mg showed significant reduction in high viral load by 70% (> 5.27; cycle threshold value < 27.5) at day 7 compared with placebo   . In September 2021, Eli Lilly reported that the trial has completed patient enrollment  .
In January 2021, the phase II/III BLAZE-1 trial met the primary and secondary endpoints of the study by significantly reducing viral load and accelerated symptom resolution with the combination therapy of bamlanivimab and etesevimab, in patients with COVID-2019 infections (17947; J2W-MC-PYAB; NCT04427501). In June 2020, Eli Lilly, in collaboration with AbCellera Biologics, initiated the trial to evaluate safety and efficacy of bamlanivimab alone and in combination with etesevimab [see Adis Insight Drug profile 800058525]. The randomised, double-blind, placebo-controlled trial intends to enrol approximately 3 300 patients in the US and Puerto Rico  . In September 2020, interim safety and efficacy results from the trial were released by the company  . In October 2020, the company released the interim analysis of the trial  . In January and March 2021, the company released additional data from the trial. In March 2021, Eli Lilly and Company released efficacy and adverse events data from a phase II/III trial at the 28th Conference on Retroviruses and Opportunistic Infections (CROI-2021)   .
In August 2020, Eli Lilly completed a phase I trial that evaluated safety, tolerability, pharmacokinetics, and pharmacodynamics of bamlanivimab in patients with COVID-2019 infections (17823; J2W-MC-PYAA; NCT04411628). The randomised, double-blind placebo-controlled trial was initiated in May 2020 and enrolled approximately 24 patients in the US  . As of July 2020, dosing has been completed in the trial. In September 2020, Eli Lilly has successfully completed enrollment in the trial and primary safety assessments of LY CoV 555    .
In December 2020, Eli Lilly and Company completed a phase I trial that evaluated the pharmacokinetics, safety, and tolerability of bamlanivimab, administered subcutaneously in healthy volunteers (NCT04537910; 18124; J2X-MC-PYAG). The randomised, placebo-controlled, double-blind study was initiated in September 2020,and enrolled approximately 25 volunteers in the US  .
In April 2021, AbCellera reported results from the preclinical studies  .
As of March 2020, early research development for COVID-2019 treatment is underway in Canada  .
In October 2020, Eli Lilly and Company entered into an agreement with Bill & Melinda Gates Foundation, as part of the COVID-19 Therapeutics Accelerator, to provide access to future Lilly therapeutic antibodies under development for the prevention and treatment of COVID-19 infections, to benefit low and middle-income countries  .
In preclinical studies, all resistant viruses, except the Q493R variant were neutralised by bamlanivimab and etesevimab [see Adis Insight Drug profile 800058525] combination therapy. Neutralisation and binding assessments also confirmed reduced susceptibility of the variants to the single selecting mAb with 50-fold or greater reductions in potency  .
In February 2021, Junshi Biosciences and Eli Lilly and Company entered into a supply agreement with the US government for purchase of minimum of 100,000 doses of etesevimab (JS016 or LY-CoV016) 1400 mg [see Adis Insight Drug profile800058525] and bamlanivimab (LY-CoV555) 700 mg together. The agreement is for $210 million and 450,000 doses will be delivered through March 31, 2021. The U.S. government will have the option to purchase up to an additional 1,100,000 doses 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 US   .
In October 2020, Eli Lilly and Company entered into a supply agreement with the US government to meet Operation Warp Speed goals. As per agreement Lilly will supply 300,000 vials of bamlanivimab 700mg for COVID-19 for $US375 million. The initial agreement is for delivery over the two months following an Emergency Use Authorization (EUA) by the US Food and Drug Administration and also provides the option for the US government to purchase up to an additional 650,000 vials through June 30, 2021, under the same terms as the base agreement and subject to agreement from Lilly, product availability and the medical need in the US. Lilly is partnering with Operation Warp Speed and a national distributor to finalise distribution plans and shipping preparations. Lilly is also working with Operation Warp Speed to assist US federal and state agencies in the identification and creation of options for locations where patients can receive this medication that are accessible and minimise infection transmission  .