Swiss pharma giant Roche announced Tuesday promising results from clinical trials of an anti-COVID cocktail developed with US biotech firm Regeneron.
The results of the Phase 3 trial showed that the combination of the antibodies casirivimab and imdevimab “reduced hospitalisation or death by 70 percent in non-hospitalised patients with COVID-19,” it said in a statement.
The cocktail also “significantly shortened the duration of symptoms by four days,” from 14 to 10.
Roche said the tests were carried out on people believed to be at higher risk of contracting a severe COVID-19 infection, typically the elderly and those with underlying serious health conditions.
Several pharmaceutical companies have been developing antibody treatments which prevent the virus from replicating in the body, in the hope of finding an effective treatment to go alongside vaccines to combat emerging variants.
Roche noted that the treatment is the only monoclonal antibody combination which remains effective when confronted with the major variants, some of which are more infectious and cause more serious illness.
Levi Garraway, Roche’s chief medical officer and head of global product development, said “new infections continue to rise globally with over three million reported cases last week.
“This investigational antibody cocktail may offer hope as a potential new therapy to high-risk patients—particularly in light of recent evidence showing that casirivimab and imdevimab together retain activity against key emerging variants,” Garraway said in a statement.
The results will now be passed on to regulators and submitted for peer review.
COVID-19 antibody therapeutics in late-stage studies
COVID-19 is characterized by cytokine storm-induced acute respiratory distress syndrome, moderate to severe pneumonia, tissue damage resulting from hyper-inflammation, and abnormal clotting. In particular, complement 5, interleukin (IL)-1, IL-6, interferon (IFN), and granulocyte-macrophage colony-stimulating factor (GM-CSF) have been implicated in the pathology of the disease.
As the pandemic began to spread in early 2020, over 60 antibody therapeutics already in clinical studies or marketed for other indications with similar pathology were repurposed as possible COVID-19 interventions. As of November 2020, late-stage clinical studies for numerous repurposed antibody therapeutics (Table 1) were recruiting patients, and emergency use authorizations (EUAs) had been requested or granted for 3, anti-IL-6 receptor levilimab, anti-CD6 itolizumab, and anti-C-C chemokine receptor type 5 (CCR5) leronlimab.
Table 1. – Monoclonal antibodies undergoing late-stage clinical studies or authorized for COVID-19*
|Primary sponsoring company||INN or code name||Molecular format||Target(s)||Most advanced phase for COVID-19||Phase 2/3 or 3 clinical study conditions|
|Biocon, Equillium||Itolizumab#||Humanized IgG1||CD6||EUA in India||Hospitalized Patients With COVID-19 (NCT04605926 pending)|
|Biocad||Levilimab#||Human IgG1||IL-6 R||EUA in Russia||Severe COVID-19 (NCT04397562)|
|AbCellera / Eli Lilly and Company||Bamlanivimab (LY-CoV555, LY3819253)||Human IgG1||SARS-CoV-2||EUA in US||Preventing SARS-CoV-2 Infection and COVID-19 (NCT04497987); Inpatients With COVID-19 (NCT04501978); Outpatients With COVID-19 (NCT04518410)|
|Regeneron Pharmaceuticals, Inc.||Casirivimab and imdevimab (REGN-COV2; REGN10933 + REGN10987)||Human IgG1 mAbs||SARS-CoV-2||EUA in US||Ambulatory Adult Patients With COVID-19 (NCT04425629); Hospitalized Adult Patients With COVID-19 (NCT04426695); Preventing SARS-CoV-2 Infection in Household Contacts of Individuals Infected With SARS-CoV-2 (NCT04452318)|
|CytoDyn||Leronlimab||Humanized IgG4||CCR5||EUA requested in US||Severe or Critical COVID-19 (pivotal Phase 2 NCT04347239); Mild to moderate COVID-19 (pivotal Phase 2 NCT04343651)|
|InflaRx GmbH||Vilobelimab (IFX-1, CaCP29)||Chimeric IgG4||C5||Phase 2/3||Severe COVID-19 Pneumonia (NCT04333420)|
|Alexion Pharmaceuticals||Ravulizumab-cwvz#||Humanized IgG2/4||C5||Phase 3||Hospitalized adults with severe pneumonia or acute respiratory distress syndrome (NCT04369469)|
|Jiangsu Pacific Meinuoke Bio Pharmaceutical Co Ltd||Meplazumab||Humanized IgG2||CD147||Phase 2/3 pending||Hospitalized Adults With COVID-19 (NCT04586153)|
|Humanigen, Inc.||Lenzilumab||Human IgG1||GM-CSF||Phase 3||COVID-19 Pneumonia (NCT04351152)|
|Kiniksa Pharmaceuticals, Ltd.||Mavrilimumab||Human IgG4||GM-CSFR||Phase 2/3||COVID-19 Pneumonia and Hyper-inflammation (NCT04447469)|
|Swedish Orphan Biovitrum||Emapalumab#||Human IgG1||IFN|
|Phase 2/3||Hyper-inflammation and Respiratory Distress in Patients With SARS-CoV-2 Infection (NCT04324021)|
|R-Pharm JSC, Cromos Pharma||Olokizumab#||Humanized IgG4||IL-6||Phase 2/3||Severe COVID-19 (NCT04380519, NCT04452474 pending)|
|Hoffmann-La Roche||Tocilizumab#||Humanized IgG1||IL-6 R||Phase 3||Hospitalized Patients With COVID-19 Pneumonia (NCT04372186, NCT04409262)|
|Sinocelltech Ltd.||SCTA01||Humanized mAb||SARS-CoV-2||Phase 2/3 pending||Hospitalized Patients With Severe COVID-19 (NCT04644185)|
|Vir Biotechnol./GlaxoSmithKline||VIR-7831/GSK4182136||Human mAb||SARS-CoV-2||Phase 2/3||Early Treatment of COVID-19 in Outpatients (NCT04545060)|
|Celltrion||CT-P59||Human mAb||SARS-CoV-2||Phase 2/3||Mild to Moderate COVID-19 (NCT04602000)|
|AstraZeneca||AZD7442 (AZD8895 + AZD1061)||Human mAbs||SARS-CoV-2||Phase 3||Pre-exposure Prophylaxis (NCT04625725); Post-exposure Prophylaxis (NCT04625972)|
#Product previously approved for a disease other than COVID-19 in at least one country.
Table notes: Table 1 includes only monoclonal antibodies evaluated in commercially sponsored, late-stage clinical studies that are listed on clinicaltrials.gov.
Abbreviations: COVID-19, coronavirus disease 2019; EUA, emergency use authorization; IFN, interferon; IL, interleukin; GM-CSF, granulocyte-macrophage colony-stimulating factor; SARS-CoV-2, severe acute respiratory syndrome coronavirus 2.
Also, in early 2020, over 100 organizations sought to discover new antibodies that bind the SARS-CoV-2 Spike protein, and thereby block viral entry into host cells by disrupting interactions of the Spike protein with the cellular angiotensin-converting enzyme 2 (ACE2) receptor. As of November 2020, details for over 120 anti-SARS-CoV-2 antibody therapeutics sponsored by commercial firms have been publicly disclosed (data available at www.antibodysociety.org/covid-19-biologics-tracker).
In the remarkably short period of ~10 months, five advanced to late-stage clinical studies (Table 1), and the study results for two of these bamlanivimab (LY-CoV555) and casirivimab and imdevimab (REGN-COV2) were sufficiently positive that EUAs were granted by the US Food and Drug Administration (FDA). A Phase 2/3 study for another, SCTA01, is pending. All of these antibodies target the spike protein of the virus.
AZD7442 (AstraZeneca) is a combination of two monoclonal antibodies (mAbs) derived from convalescent patients with SARS-CoV-2 infection. Discovered at Vanderbilt University Medical Center and licensed to AstraZeneca in June 2020, the mAbs were optimized by AstraZeneca with half-life extension (YTE modification; half-life 70–100 d) and reduced Fc receptor binding (L234F/L235E/P331S triple mutations).
A Phase 1 study (NCT04507256) in healthy adults was started in August 2020, and Phase 3 trials are due to start in mid-November. The Phase 3 studies will evaluate AZD7442 in pre-exposure (PROVENT study, NCT04625725) and post-exposure (STORMCHASER study, NCT04625972) use, as well as outpatient treatment.
CT-P59 (Celltrion) is being evaluated in a placebo-controlled, Phase 2/3 study (NCT04602000) of outpatients with SARS-CoV-2 infection. The estimated enrollment is 1020 participants. This study started in late September 2020 but has a primary completion date in December 2020. Results for a Phase 1 study (NCT04593641) evaluating the safety, tolerability and virology of CT-P59 in patients with mild symptoms of SARS-CoV-2 infection were reported at the 2020 fall Conference of the Korean Society of Infectious Diseases on November 5, 2020.14 This study enrolled a total of 18 patients, 15 of which were randomized into three cohorts that received CT-P59 at 20 mg/kg, 40 mg/kg or 80 mg/kg, respectively. Three patients received matching placebo. Patients treated with CT-P59 experienced about 44% reduced mean clinical recovery time compared to the average for patients who received placebo. Celltrion expects to apply for an EUA, conditional on the results for the Phase 2/3 study of CT-P59.
VIR-7831 (also known as GSK4182136; Vir Biotechnology, GlaxoSmithKline) is being evaluated in a Phase 2/3 study (NCT04545060) as an early treatment of COVID-19 in patients who are at high risk of hospitalization. This study has an estimated enrollment of 1360 participants and a primary completion date in January 2021.
SCTA01 (Sinocelltech Ltd.) is being evaluated in a Phase 1 study (NCT04483375) of healthy subjects that started in July 2020, and a Phase 2/3 study is due to start in February 2021. The placebo-controlled Phase 2/3 trial (NCT04644185) will evaluate the efficacy and safety of SCTA01 in hospitalized patients with severe COVID-19.
Bamlanivimab (also known as LY-CoV555 and LY3819253; Eli Lilly and Company) is being evaluated for several types of patients (outpatient and hospitalized) and uses (prophylaxis and treatment). Results of an interim analysis of Phase 2 BLAZE-1 study (NCT04427501) involving outpatients with recently diagnosed mild or moderate COVID-19 were recently reported.15 Patients received intravenous (IV) administration of 700 mg, 2800 mg, or 7000 mg LY-CoV555 or placebo.
The change from baseline to Day 11 in viral load was the primary outcome measure. These values were −0.20 (95% confidence interval [CI], −0.66 to 0.25; P = .38), −0.53 (95% CI, −0.98 to −0.08; P = .02), and 0.09 (95% CI, −0.37 to 0.55; P = .70) for the 700 mg, 2400 mg, and 7000 mg doses, respectively. However, the authors noted that the endpoint did not appear to be clinically meaningful because the viral load was substantially reduced at Day 11 for most patients. This outcome is consistent with the infection’s natural progression. The percentage of patients who were hospitalized on Day 29 was lower among those who received LY-CoV555 vs. placebo (1.6% vs. 6.3%, respectively), in particular for patients in high-risk subgroups (4.2% vs. 14.6%, respectively).
LY-CoV555 is being evaluated in Phase 3 BLAZE-2 trial (NCT04497987), which will assess the ability of the antibody to prevent SARS-CoV-2 infection and COVID-19 in residents and staff at nursing and assisted living facilities. It is also being evaluated in 2 Phase 2/3 platform studies (ACTIV-2 (NCT04518410) and ACTIV-3 (NCT04501978)) sponsored by the National Institute of Allergy and Infectious Diseases that will compare the effects of LY-CoV555 vs. placebo in outpatients with COVID-19 (ACTIV-2) or vs. remdesivir in hospitalized patients (ACTIV-3).
Casirivimab and imdevimab (also known as REGN-COV2 and REGN10933+ REGN10987; Regeneron) is being evaluated in multiple late-stage clinical studies. REGN-COV2 is a cocktail of two human antibodies derived from parallel efforts using both transgenic mice and B cells from recovered COVID-19 patients. Like LY-CoV555, REGN-COV2 is being evaluated in both outpatient and hospitalized patients, and for both prophylaxis and treatment.
Results from the ongoing Phase 1/2/3 seamless trial (NCT04425629) evaluating high (8 g) and low (2.4 g) doses of REGN-COV2 in ambulatory adult patients with COVID-19 were announced in late October 2020.16 The study’s primary and key secondary endpoints, which assessed virologic endpoints based on viral load, seronegative status and dose group, and COVID-19-related medically attended visits in patients who had laboratory-confirmed COVID-19 at baseline, were met. No significant difference in virologic or clinical efficacy between the two doses was observed.
REGN-COV2 is also being evaluated in a seamless Phase 1/2/3 study (NCT04426695) of hospitalized COVID-19 patients. Prophylactic use of the cocktail is being evaluated in an ongoing Phase 3 study (NCT04452318), which will determine how well REGN-COV2 prevents SARS-CoV-2 infection in household contacts of individuals infected with SARS-CoV-2.
Antibody therapeutics under review or authorized for COVID-19 in the US
As of November 20, 2020, an EUA request for leronlimab for the treatment of COVID-19 had been submitted to the FDA, and both bamlanivimab and REGN-COV2 were authorized for emergency use by the FDA. Bamlanivimab and REGN-COV2 target the SARS-CoV-2 virus and thus reduce the viral load, while leronlimab targets CCR5 and is intended to treat symptoms of COVID-19.
Bamlanivimab (Eli Lilly and Company)
Lilly announced they had submitted an EUA request for bamlanivimab monotherapy in higher-risk patients on October 7, 2020, and on November 9, 2020, the FDA authorized its emergency use. The agency stated that “it is reasonable to believe that bamlanivimab may be effective for the treatment of mild to moderate COVID-19 in adults and pediatric patients with positive results of direct SARS-CoV-2 viral testing who are 12 y of age and older weighing at least 40 kg, and who are at high risk for progressing to severe COVID-19 and/or hospitalization, and that, when used under the conditions described in this authorization, the known and potential benefits of bamlanivimab when used to treat COVID-19 in such patients outweigh the known and potential risks of such product.”17
The EUA was based on review of the topline data from the planned interim analysis of BLAZE-1 (NCT04427501), which is ongoing. The EUA letter indicates that distribution of the authorized bamlanivimab (700 mg/20 mL vial) will be controlled by the United States Government for use consistent with the terms and conditions of the EUA, and that the EUA is effective only while circumstances exist justifying the authorization of emergency use during the COVID-19 pandemic. The recommended dose is 700 mg and the recommended concentration for infusion is 700 mg/200 mL, with a minimum infusion rate of 200 mL/h (i.e., 1-h total infusion time).
Lilly has an agreement with the US government to supply 300,000 vials of 700 mg doses of LY-CoV555 for 375 USD million.18 According to Lilly, up to 1 million doses may be available in Q4 2020. The price per vial has been set at 1,250 USD for wealthy countries, with one vial representing a full course of treatment. Tiered pricing for LY-Cov555 monotherapy will apply to middle- and low-income countries.19
Lilly is also pursuing development of a cocktail comprising LY-Cov555 and LYCoV016 (also known as JS016, LY3832479, CB6-LALA). LYCoV016 is a human anti-SARS-CoV-2 antibody with an Fc portion that was modified to include Leu234Ala and Leu235Ala (LALA) mutations, which disrupt effector functions.20 The two antibodies bind complementary regions of the SARS-CoV-2 spike protein. The company anticipates submission of an EUA request for combination therapy by the end of 2020 and may have data to support a biologics license application (BLA) submission for combination therapy as early as Q2 2021.
Casirivimab and imdevimab (Regeneron)
In early October 2020, Regeneron announced that they requested an EUA for casirivimab and imdevimab (REGN-COV2), and on November 20, 2020, the FDA authorized its emergency use.21 After reviewing the analysis of Phase 1 and 2 data from the ongoing Phase 1/2/3 NCT04425629 study, the agency concluded that “it is reasonable to believe that casirivimab and imdevimab, administered together, may be effective for the treatment of mild to moderate COVID-19 in adults and pediatric patients (12 y of age and older weighing at least 40 kg) with positive results of direct SARS-CoV-2 viral testing, and who are at high risk for progressing to severe COVID-19 and/or hospitalization, and that, when used under the conditions described in this authorization, the known and potential benefits of casirivimab and imdevimab, administered together, outweigh the known and potential risks of such product.”
The EUA letter further states that distribution of REGN-COV2 will be directed by the US government, and its EUA will be effective until the declaration that circumstances exist justifying the authorization of the emergency use of drugs and biological products during the COVID-19 pandemic is terminated or the EUA is revoked. The authorized dosage is 1,200 mg of casirivimab and 1,200 mg of imdevimab administered together as a single IV infusion over at least 60 min via pump or gravity as soon as possible after positive viral test for SARS-CoV-2 and within 10 d of symptom onset.
Regeneron was granted a 450 USD million contract to manufacture and supply REGN-COV2 by the US government, which has committed to making the doses available to Americans for free. The agreement covers a fixed number of bulk lots, as well as fill/finish and storage activities. Delivery of REGN-COV2 drug product started during the third quarter of 2020, and the company expects to have ~80,000 doses available by the end of November, ~200,000 total doses ready by the first week of January 2021, and ~300,000 total doses ready by the end of January 2021.
Leronlimab (Cytodyn Inc.)
Leronlimab is a humanized anti-CCR5 IgG4 antibody developed for a variety of indications, including HIV, stroke, graft-vs.-host disease (GvHD), triple-negative breast cancer (TNBC), as well as COVID-19. Among other roles, CCR5 modulates immune cell trafficking to sites of inflammation. Data from COVID-19 patients (n = 23) receiving 700 mg leronlimab on an open-label compassionate use basis have suggested that the drug may improve outcomes.22
CytoDyn completed a Phase 2 clinical trial (NCT04343651, CD10) that compared the efficacy and safety of leronlimab vs. placebo for mild to moderate COVID-19. Patients are being recruiting for a Phase 2b/3 trial (CD12, NCT04347239) to evaluate the efficacy and safety of leronlimab for patients with severe or critical COVID-19. In this adaptive-design multicenter study, patients are randomized to receive weekly doses of 700 mg leronlimab, or placebo, which are each administered via subcutaneous (SC) injection.
Cytodyn disclosed in an investment community conference call that they requested an EUA from FDA for leronlimab for mild to moderate COVID-19 based on data from the Phase 2 CD10 study. Top-level results of the study showed that, in patients with Total Clinical Symptom Scores of ≥4 at baseline (higher scores equate to poorer health state), at Day 3, more subjects treated with leronlimab reported improvement in total clinical symptom score compared to the placebo group (90% on leronlimab arm vs. 71% on placebo).23
reference link : https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7833761/