Phase 3 program in hospitalized patients to continue based on passing futility analysis on ability to reduce incidence of death or mechanical ventilation
As in earlier outpatient trial, immune status when patients entered the trial was a strong predictor of viral load and clinical outcomes
First antibody therapy to demonstrate anti-viral effect in patients hospitalized with COVID-19
TARRYTOWN, NY, USA I December 29, 2020 I Regeneron Pharmaceuticals, Inc. (NASDAQ: REGN) today announced encouraging initial data from an ongoing Phase 1/2/3 clinical trial of the Regeneron antibody cocktail, casirivimab and imdevimab, in hospitalized COVID-19 patients requiring low-flow oxygen. The analysis was prospectively designed to focus on patients who had not yet mounted their own immune response to SARS-CoV-2 (i.e., did not have antibodies at baseline: seronegative), as prior evidence suggested these patients were at greater risk. The primary clinical objective of this initial analysis was to determine if there was sufficient efficacy in these patients to warrant continuing the trial (i.e., futility analysis). The results passed the futility analysis (p<0.3 one-sided), as seronegative patients treated with the antibody cocktail had a lower risk of death or receiving mechanical ventilation (HR: 0.78; 80% CI: 0.51-1.2). The benefit was driven by results starting one week post-treatment, when the risk of death or receiving mechanical ventilation was reduced by approximately half with antibody cocktail treatment, based on a post-hoc analysis.
Seronegative patients (n=217) had much higher viral loads than those who had already developed their own antibodies (seropositive) to SARS-CoV-2 at the time of randomization. In seronegative patients, the antibody cocktail reduced the time-weighted average daily viral load through day 7 by -0.54 log10 copies/mL, and through day 11 by -0.63 log10 copies/mL (nominal p=0.002 for combined doses). At day 5, the relative reduction compared to placebo was -1.1 log10 copies/mL (nominal p=0.002 for combined doses). As expected, in seropositive patients (n=270) the clinical and virologic benefit of the antibody cocktail was limited (clinical endpoint HR: 0.98; time-weighted average viral load reduction by day 7 of -0.20 log10 copies/mL for combined doses).
“These preliminary results in hospitalized patients, as well as data from the previously announced outpatient trial, indicate that antibodies produced by a patient’s own immune response are important to control COVID-19 infection. In this trial, patients who had not yet mounted their own immune response had much higher viral loads and much worse clinical outcomes; for example in the placebo group, seronegative patients were almost three-times more likely to die compared to seropositive patients,” said George D. Yancopoulos, M.D., Ph.D., President and Chief Scientific Officer at Regeneron. “Moreover, the data from these trials in hospitalized and non-hospitalized patients suggest that Regeneron’s antibody cocktail may compensate for an inadequate endogenous antibody response by reducing viral levels and the risk of adverse clinical outcomes. It is important to remember that while the virology results from this analysis of hospitalized patients were robust, the clinical efficacy data are based on a small data set of events and cannot be viewed as conclusive at this stage. A much larger trial will be required to rigorously characterize this effect and we believe the ongoing UK-based RECOVERY trial will provide those answers. It has already enrolled more than 2,000 hospitalized patients in the part of the trial evaluating adding the antibody cocktail to standard-of-care compared to standard-of-care alone.”
The clinical and virological analyses include data from the Regeneron-sponsored trial evaluating hospitalized patients who were on low-flow oxygen (defined as maintaining oxygen saturation of >93% via nasal cannula, simple facemask, or similar device), including 217 who were seronegative when they entered the trial and 270 who were seropositive; although seronegative patients comprised less than half of the trial population, based on placebo rates they account for approximately two-thirds of the deaths in the absence of antibody cocktail treatment. Patients were randomized to receive the antibody cocktail (either 8,000 mg high dose or 2,400 mg low dose) or placebo, in addition to standard-of-care therapies, with 67% receiving remdesivir and 74% receiving systemic corticosteroids. Similar clinical and virologic efficacy was observed for the high and low doses of the antibody cocktail.
Both antibody cocktail doses were well-tolerated. In the overall trial population, the incidence of serious adverse events was 21% for high dose, 20% for low dose and 24% for placebo. Infusion reactions were more common with the high dose of the antibody cocktail (2.7% high dose, 0.9% low dose, 1.4% placebo) and there were 2 discontinuations due to infusion-related reactions, both of which occurred in the high dose group.
In November, the Regeneron antibody cocktail was granted an Emergency Use Authorization (EUA) by the U.S. Food and Drug Administration (FDA) in high-risk patients who have confirmed COVID-19 but are not currently hospitalized. The EUA is temporary and does not take the place of a formal biologics license application (BLA) submission review and approval process and the use of the antibody cocktail remains investigational. Evaluation of its safety and efficacy is ongoing in multiple clinical trials.
“We appreciate the continued support of patients and investigators around the world who are working to advance Regeneron’s antibody cocktail trials under very challenging circumstances,” said David Weinreich, M.D., Senior Vice President and Head of Global Clinical Development at Regeneron. “Hospitalizations due to COVID-19 are increasing around the globe and have devastating consequences for these patients, their families and those who care for them, highlighting the need for effective therapeutics. We plan to share these most recent data with regulatory authorities.”
Regeneron announced in October that the hospitalized trial would be modified to no longer enroll the most critical patients requiring high-flow oxygen or mechanical ventilation at baseline, following a recommendation by the Independent Data Monitoring Committee. The UK RECOVERY trial continues to recruit all hospitalized patients regardless of the degree of severity, based on a recommendation from its Independent Data Monitoring Committee.
In addition to the two hospitalized patient trials (company-sponsored and UK-based RECOVERY trial), the antibody cocktail is currently being studied in a Phase 3 trial for the treatment of non-hospitalized patients, and a Phase 3 trial for the prevention of COVID-19 in household contacts of infected individuals.
Under an agreement with the U.S. government, Regeneron is producing approximately 300,000 doses (2,400 mg) for outpatient use under the EUA. The company expects to complete the manufacture of these doses on schedule in January 2021 and is in discussions with the U.S. government regarding additional doses.
In the U.S., outside of clinical trials casirivimab and imdevimab are not authorized for use in patients who are hospitalized or require oxygen therapy due to COVID-19, or for people currently using chronic oxygen therapy because of an underlying comorbidity who require an increase in baseline oxygen flow rate due to COVID-19.
About the Regeneron Trial in Hospitalized Patients
The analysis includes patients enrolled in the Phase 1/2 portions of the trial, which was designed to evaluate clinical outcomes, safety and anti-viral activity with the casirivimab and imdevimab antibody cocktail for COVID-19. Patients were randomized 1:1:1 to receive a one-time infusion of 8,000 mg of the antibody cocktail (high dose), 2,400 mg of the antibody cocktail (low dose) or placebo. All patients entering the trial were hospitalized with laboratory-confirmed COVID-19 requiring low-flow oxygen, and all received other background standard-of-care as required.
All patients were characterized for their serology at baseline: approximately 50% of patients were seropositive, 40% were seronegative and 10% were categorized as “other” due to unclear or unknown serology status. Approximately 24% were Hispanic and 14% were African American. On average, patients were 62 years of age. In total, 53% of participants were male and 47% were female.
About Regeneron Antibody Cocktail
Casirivimab and imdevimab is a cocktail of two monoclonal antibodies (also known as REGN10933 and REGN10987, respectively) and was designed specifically to block infectivity of SARS-CoV-2, the virus that causes COVID-19.
On November 21, 2020, the casirivimab and imdevimab antibody combination received EUA from the FDA for the treatment of mild to moderate COVID-19 in adults, as well as in pediatric patients at least 12 years of age and weighing at least 40 kg, who have received positive results of direct SARS-CoV-2 viral testing and are at high risk for progressing to severe COVID-19 and/or hospitalization. The clinical evidence from Regeneron’s outpatient trial suggests that monoclonal antibodies such as casirivimab and imdevimab have the greatest benefit when given early after diagnosis and in patients who are seronegative and/or who have high viral load. The criteria for ‘high-risk’ patients are described in the Fact Sheet for Healthcare Providers.
To develop this novel medicine, Regeneron scientists evaluated thousands of fully-human antibodies produced by the company’s VelocImmune® mice, which have been genetically modified to have a human immune system, as well as antibodies identified from humans who have recovered from COVID-19. The two potent, virus-neutralizing antibodies that form the cocktail bind non-competitively to the critical receptor binding domain of the virus’s spike protein, which diminishes the ability of mutant viruses to escape treatment and protects against spike variants that have arisen in the human population, as detailed in Science.
The development and manufacturing of the antibody cocktail has been funded in part with federal funds from the Biomedical Advanced Research and Development Authority (BARDA), part of the U.S. Department of Health and Human Services (HHS), Office of the Assistant Secretary for Preparedness and Response, under OT number: HHSO100201700020C. Regeneron continues to increase in-house production of casirivimab and imdevimab, and the company has partnered with Roche to increase the global supply beginning in 2021. If the therapy proves safe and effective in clinical trials and regulatory approvals are granted, Regeneron will manufacture and distribute it in the U.S. and Roche will develop, manufacture and distribute it outside the U.S. Once both companies are at full manufacturing capacity in 2021, there are expected to be at least 2 million treatment doses available annually.
About Regeneron
Regeneron (NASDAQ: REGN) is a leading biotechnology company that invents life-transforming medicines for people with serious diseases. Founded and led for over 30 years by physician-scientists, our unique ability to repeatedly and consistently translate science into medicine has led to eight FDA-approved treatments and numerous product candidates in development, all of which were homegrown in our laboratories. Our medicines and pipeline are designed to help patients with eye diseases, allergic and inflammatory diseases, cancer, cardiovascular and metabolic diseases, pain, infectious diseases and rare diseases.
Regeneron is accelerating and improving the traditional drug development process through our proprietary VelociSuite® technologies, such as VelocImmune, which uses unique genetically-humanized mice to produce optimized fully-human antibodies and bispecific antibodies, and through ambitious research initiatives such as the Regeneron Genetics Center, which is conducting one of the largest genetics sequencing efforts in the world.
For additional information about the company, please visit www.regeneron.com or follow @Regeneron on Twitter.
SOURCE: Regeneron Pharmaceuticals
Post Views: 23
Phase 3 program in hospitalized patients to continue based on passing futility analysis on ability to reduce incidence of death or mechanical ventilation
As in earlier outpatient trial, immune status when patients entered the trial was a strong predictor of viral load and clinical outcomes
First antibody therapy to demonstrate anti-viral effect in patients hospitalized with COVID-19
TARRYTOWN, NY, USA I December 29, 2020 I Regeneron Pharmaceuticals, Inc. (NASDAQ: REGN) today announced encouraging initial data from an ongoing Phase 1/2/3 clinical trial of the Regeneron antibody cocktail, casirivimab and imdevimab, in hospitalized COVID-19 patients requiring low-flow oxygen. The analysis was prospectively designed to focus on patients who had not yet mounted their own immune response to SARS-CoV-2 (i.e., did not have antibodies at baseline: seronegative), as prior evidence suggested these patients were at greater risk. The primary clinical objective of this initial analysis was to determine if there was sufficient efficacy in these patients to warrant continuing the trial (i.e., futility analysis). The results passed the futility analysis (p<0.3 one-sided), as seronegative patients treated with the antibody cocktail had a lower risk of death or receiving mechanical ventilation (HR: 0.78; 80% CI: 0.51-1.2). The benefit was driven by results starting one week post-treatment, when the risk of death or receiving mechanical ventilation was reduced by approximately half with antibody cocktail treatment, based on a post-hoc analysis.
Seronegative patients (n=217) had much higher viral loads than those who had already developed their own antibodies (seropositive) to SARS-CoV-2 at the time of randomization. In seronegative patients, the antibody cocktail reduced the time-weighted average daily viral load through day 7 by -0.54 log10 copies/mL, and through day 11 by -0.63 log10 copies/mL (nominal p=0.002 for combined doses). At day 5, the relative reduction compared to placebo was -1.1 log10 copies/mL (nominal p=0.002 for combined doses). As expected, in seropositive patients (n=270) the clinical and virologic benefit of the antibody cocktail was limited (clinical endpoint HR: 0.98; time-weighted average viral load reduction by day 7 of -0.20 log10 copies/mL for combined doses).
“These preliminary results in hospitalized patients, as well as data from the previously announced outpatient trial, indicate that antibodies produced by a patient’s own immune response are important to control COVID-19 infection. In this trial, patients who had not yet mounted their own immune response had much higher viral loads and much worse clinical outcomes; for example in the placebo group, seronegative patients were almost three-times more likely to die compared to seropositive patients,” said George D. Yancopoulos, M.D., Ph.D., President and Chief Scientific Officer at Regeneron. “Moreover, the data from these trials in hospitalized and non-hospitalized patients suggest that Regeneron’s antibody cocktail may compensate for an inadequate endogenous antibody response by reducing viral levels and the risk of adverse clinical outcomes. It is important to remember that while the virology results from this analysis of hospitalized patients were robust, the clinical efficacy data are based on a small data set of events and cannot be viewed as conclusive at this stage. A much larger trial will be required to rigorously characterize this effect and we believe the ongoing UK-based RECOVERY trial will provide those answers. It has already enrolled more than 2,000 hospitalized patients in the part of the trial evaluating adding the antibody cocktail to standard-of-care compared to standard-of-care alone.”
The clinical and virological analyses include data from the Regeneron-sponsored trial evaluating hospitalized patients who were on low-flow oxygen (defined as maintaining oxygen saturation of >93% via nasal cannula, simple facemask, or similar device), including 217 who were seronegative when they entered the trial and 270 who were seropositive; although seronegative patients comprised less than half of the trial population, based on placebo rates they account for approximately two-thirds of the deaths in the absence of antibody cocktail treatment. Patients were randomized to receive the antibody cocktail (either 8,000 mg high dose or 2,400 mg low dose) or placebo, in addition to standard-of-care therapies, with 67% receiving remdesivir and 74% receiving systemic corticosteroids. Similar clinical and virologic efficacy was observed for the high and low doses of the antibody cocktail.
Both antibody cocktail doses were well-tolerated. In the overall trial population, the incidence of serious adverse events was 21% for high dose, 20% for low dose and 24% for placebo. Infusion reactions were more common with the high dose of the antibody cocktail (2.7% high dose, 0.9% low dose, 1.4% placebo) and there were 2 discontinuations due to infusion-related reactions, both of which occurred in the high dose group.
In November, the Regeneron antibody cocktail was granted an Emergency Use Authorization (EUA) by the U.S. Food and Drug Administration (FDA) in high-risk patients who have confirmed COVID-19 but are not currently hospitalized. The EUA is temporary and does not take the place of a formal biologics license application (BLA) submission review and approval process and the use of the antibody cocktail remains investigational. Evaluation of its safety and efficacy is ongoing in multiple clinical trials.
“We appreciate the continued support of patients and investigators around the world who are working to advance Regeneron’s antibody cocktail trials under very challenging circumstances,” said David Weinreich, M.D., Senior Vice President and Head of Global Clinical Development at Regeneron. “Hospitalizations due to COVID-19 are increasing around the globe and have devastating consequences for these patients, their families and those who care for them, highlighting the need for effective therapeutics. We plan to share these most recent data with regulatory authorities.”
Regeneron announced in October that the hospitalized trial would be modified to no longer enroll the most critical patients requiring high-flow oxygen or mechanical ventilation at baseline, following a recommendation by the Independent Data Monitoring Committee. The UK RECOVERY trial continues to recruit all hospitalized patients regardless of the degree of severity, based on a recommendation from its Independent Data Monitoring Committee.
In addition to the two hospitalized patient trials (company-sponsored and UK-based RECOVERY trial), the antibody cocktail is currently being studied in a Phase 3 trial for the treatment of non-hospitalized patients, and a Phase 3 trial for the prevention of COVID-19 in household contacts of infected individuals.
Under an agreement with the U.S. government, Regeneron is producing approximately 300,000 doses (2,400 mg) for outpatient use under the EUA. The company expects to complete the manufacture of these doses on schedule in January 2021 and is in discussions with the U.S. government regarding additional doses.
In the U.S., outside of clinical trials casirivimab and imdevimab are not authorized for use in patients who are hospitalized or require oxygen therapy due to COVID-19, or for people currently using chronic oxygen therapy because of an underlying comorbidity who require an increase in baseline oxygen flow rate due to COVID-19.
About the Regeneron Trial in Hospitalized Patients
The analysis includes patients enrolled in the Phase 1/2 portions of the trial, which was designed to evaluate clinical outcomes, safety and anti-viral activity with the casirivimab and imdevimab antibody cocktail for COVID-19. Patients were randomized 1:1:1 to receive a one-time infusion of 8,000 mg of the antibody cocktail (high dose), 2,400 mg of the antibody cocktail (low dose) or placebo. All patients entering the trial were hospitalized with laboratory-confirmed COVID-19 requiring low-flow oxygen, and all received other background standard-of-care as required.
All patients were characterized for their serology at baseline: approximately 50% of patients were seropositive, 40% were seronegative and 10% were categorized as “other” due to unclear or unknown serology status. Approximately 24% were Hispanic and 14% were African American. On average, patients were 62 years of age. In total, 53% of participants were male and 47% were female.
About Regeneron Antibody Cocktail
Casirivimab and imdevimab is a cocktail of two monoclonal antibodies (also known as REGN10933 and REGN10987, respectively) and was designed specifically to block infectivity of SARS-CoV-2, the virus that causes COVID-19.
On November 21, 2020, the casirivimab and imdevimab antibody combination received EUA from the FDA for the treatment of mild to moderate COVID-19 in adults, as well as in pediatric patients at least 12 years of age and weighing at least 40 kg, who have received positive results of direct SARS-CoV-2 viral testing and are at high risk for progressing to severe COVID-19 and/or hospitalization. The clinical evidence from Regeneron’s outpatient trial suggests that monoclonal antibodies such as casirivimab and imdevimab have the greatest benefit when given early after diagnosis and in patients who are seronegative and/or who have high viral load. The criteria for ‘high-risk’ patients are described in the Fact Sheet for Healthcare Providers.
To develop this novel medicine, Regeneron scientists evaluated thousands of fully-human antibodies produced by the company’s VelocImmune® mice, which have been genetically modified to have a human immune system, as well as antibodies identified from humans who have recovered from COVID-19. The two potent, virus-neutralizing antibodies that form the cocktail bind non-competitively to the critical receptor binding domain of the virus’s spike protein, which diminishes the ability of mutant viruses to escape treatment and protects against spike variants that have arisen in the human population, as detailed in Science.
The development and manufacturing of the antibody cocktail has been funded in part with federal funds from the Biomedical Advanced Research and Development Authority (BARDA), part of the U.S. Department of Health and Human Services (HHS), Office of the Assistant Secretary for Preparedness and Response, under OT number: HHSO100201700020C. Regeneron continues to increase in-house production of casirivimab and imdevimab, and the company has partnered with Roche to increase the global supply beginning in 2021. If the therapy proves safe and effective in clinical trials and regulatory approvals are granted, Regeneron will manufacture and distribute it in the U.S. and Roche will develop, manufacture and distribute it outside the U.S. Once both companies are at full manufacturing capacity in 2021, there are expected to be at least 2 million treatment doses available annually.
About Regeneron
Regeneron (NASDAQ: REGN) is a leading biotechnology company that invents life-transforming medicines for people with serious diseases. Founded and led for over 30 years by physician-scientists, our unique ability to repeatedly and consistently translate science into medicine has led to eight FDA-approved treatments and numerous product candidates in development, all of which were homegrown in our laboratories. Our medicines and pipeline are designed to help patients with eye diseases, allergic and inflammatory diseases, cancer, cardiovascular and metabolic diseases, pain, infectious diseases and rare diseases.
Regeneron is accelerating and improving the traditional drug development process through our proprietary VelociSuite® technologies, such as VelocImmune, which uses unique genetically-humanized mice to produce optimized fully-human antibodies and bispecific antibodies, and through ambitious research initiatives such as the Regeneron Genetics Center, which is conducting one of the largest genetics sequencing efforts in the world.
For additional information about the company, please visit www.regeneron.com or follow @Regeneron on Twitter.
SOURCE: Regeneron Pharmaceuticals
Post Views: 23
