PHASE 3 TRIAL SHOWS REGEN-COV? (CASIRIVIMAB WITH IMDEVIMAB) ANTIBODY COCKTAIL REDUCED HOSPITALIZATION OR DEATH BY 70% IN NON-HOSPITALIZED COVID-19 PATIENTS
REGEN-COV also significantly shortened the duration of symptoms by 4 days
All doses (8,000 mg, 2,400 mg and 1,200 mg) had similar efficacy across all endpoints
Companion dose-ranging Phase 2 trial showed significant and comparable viral reductions for all REGEN-COV doses tested, including as low as 300 mg
FDA recently updated?U.S.?EUA fact sheets for all authorized monoclonal antibody treatments, indicating that REGEN-COV is the only one to retain potency against key emerging variants
Regeneron will share new data with regulatory authorities immediately and request that a lower 1,200 mg dose be added to EUA
Regeneron Pharmaceuticals, Inc.?(NASDAQ:?REGN) today announced positive topline results from the largest trial to date assessing a COVID-19 treatment in infected non-hospitalized patients (n=4,567). This definitive Phase 3 outcomes trial in high-risk non-hospitalized COVID-19 patients ("outpatients") met its primary endpoint, showing the investigational REGEN-COV? (casirivimab with imdevimab) significantly reduced the risk of hospitalization or death by 70% (1,200 mg intravenous [IV]) and 71% (2,400 mg IV) compared to placebo.
"This is a landmark moment in the fight against COVID-19 as this large well-controlled trial provides conclusive results demonstrating that REGEN-COV can dramatically reduce the risk of hospitalization and death in the outpatient setting," said?Suraj Saggar, D.O., trial investigator and Chief of Infectious Disease at?Holy Name Medical Center?in?Teaneck, New Jersey. "With so many people still getting infected, as well as recent data showing that REGEN-COV addresses emerging variants, these data underscore the need to rapidly adopt REGEN-COV as standard-of-care to offer high-risk patients their best chance to reduce serious consequences like hospitalization or death."
REGEN-COV also met all secondary endpoints in the Phase 3 outcomes trial, including the ability to reduce symptom duration. In addition, a companion Phase 2 trial showed that even the lowest doses tested (IV: 300 mg; subcutaneous [SC]: 600 mg) had significant viral load reductions over the first 7 study days, comparable to the 2,400 mg and 1,200 mg IV doses.
"With approximately 60,000 newly diagnosed individuals in the?U.S.?every day and 40,000 still in the hospital because of COVID-19, we are committed to working with the government, healthcare providers and others to support rapid and widespread adoption of REGEN-COV in appropriate patients," said?George D. Yancopoulos, M.D., Ph.D., President and Chief Scientific Officer at Regeneron. "We will discuss the new data with regulatory authorities and request that the 1,200 mg dose be rapidly added to the?U.S.?Emergency Use Authorization, in order for the anticipated REGEN-COV supply to be available to treat even more patients. These Phase 3 data will also form the basis of a full Biologics License Application."
A safety assessment was conducted on all available patient data up to day 169, and identified no new safety signals. Serious adverse events (SAEs) were largely related to COVID-19 and occurred in 1.1% of patients in the 1,200 mg group, 1.3% in the 2,400 mg group and 4.0% in the placebo group. There was 1 death in the 1,200 mg group (n=827), 1 death in the 2,400 mg group (n=1,849) and 5 deaths in the placebo groups (n=1,843).
All patients in this analysis had at least one risk factor, including obesity (58%), age ?50 years (51%) and cardiovascular disease, including hypertension (36%). Approximately 35% of patients were Latino/Hispanic, 5% were Black/African American?and the median age was 50 years (range: 18-96 years).
Dose-ranging Virology Trial
A companion dose-ranging Phase 2 trial of 803 outpatient COVID-19 patients was conducted to evaluate the antiviral effect of several different REGEN-COV doses (IV: 2,400 mg, 1,200 mg, 600 mg and 300 mg; SC: 1,200 mg and 600 mg). All tested doses met the primary endpoint, rapidly and significantly reducing patients' viral load (log10?copies/mL) compared to placebo (p?0.001). Each dose demonstrated similar efficacy, including the lowest doses tested (IV: 300 mg; SC: 600 mg).
"These encouraging results confirm the rapid and significant antiviral effects of REGEN-COV, even at much lower and subcutaneous doses," said?David Weinreich, M.D., Executive Vice President and Head of?Global Clinical Development?at Regeneron. "We are grateful to all patients and investigators who participated in these and other ongoing REGEN-COV trials. We will share both our Phase 3 outcomes data and our Phase 2 virology data with regulatory authorities to discuss next steps, including the possibility of utilizing lower doses and more convenient subcutaneous administration."
Detailed results from both trials will be shared with regulatory authorities and submitted for peer review as soon as possible. REGEN-COV continues to be evaluated in clinical trials in multiple settings for COVID-19: in non-hospitalized and certain hospitalized patients, including the open-label RECOVERY trial of hospitalized patients in the?UK, and a trial for the prevention of COVID-19 in household contacts of infected individuals. As of?March 2021, more than 25,000 people have participated in clinical trials involving REGEN-COV.
The development and manufacturing of REGEN-COV have 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,?Office of the Assistant?Secretary for Preparedness and Response, under OT number: HHSO100201700020C.
FDA Updates to Fact Sheets
To address SARS-CoV-2 variants,?last week the?U.S. Food and Drug Administration?(FDA)?authorized?revisions to the fact sheets for monoclonal antibodies currently under emergency use authorization (EUA). The REGEN-COV?fact sheet?(see table below), notes that it retains potency against the main variants of concern known to be circulating within the?U.S.?In contrast, multiple variant strains had reduced susceptibility to the other two FDA-authorized monoclonal antibodies (fact sheets are available?here?and?here).
Supply and Distribution Update
REGEN-COV is available throughout the?U.S.?without restriction ? information on availability in your area is available from the?Department of Health and Human Services?and the?National Infusion Center Association.
Regeneron anticipates recording approximately?$260?million?in REGEN-COV?U.S.?net product sales to the?U.S.?government in the first quarter of 2021, representing final deliveries from the?initial agreement?with the?U.S.?government. Sales under the?second?U.S.?government agreement?are now expected to begin in the second quarter of 2021. The company expected to provide approximately 750,000 doses at the 2,400 mg dose level, but now anticipates being able to provide approximately 1.25 million doses if the 1,200 mg dose is added to the EUA. Due to the pandemic, many organizations are currently utilizing the same limited manufacturing resources including external fill and finish capacity, and this may impact the timing of final delivery of doses. The government is obligated to purchase all finished doses supplied by?June 30, 2021, up to 1.25 million doses total, and may accept doses after this date at its discretion.
Roche, which is responsible for REGEN-COV outside the?U.S., continues to work with the?European Medicines Agency, governments and other health authorities across the globe to bring this antibody cocktail to as many patients as possible.
About the REGEN-COV Antibody Cocktail
REGEN-COV (casirivimab with imdevimab) is a cocktail of two monoclonal antibodies (also known as REGN10933 and REGN10987) that was designed specifically to block infectivity of SARS-CoV-2, the virus that causes COVID-19, using Regeneron's proprietary?VelocImmune??and?VelociSuite??technologies. 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.
Under an EUA?issued?by the FDA, REGEN-COV is currently available in the?U.S.?to treat 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.
REGEN-COV is currently authorized and available in a 2,400 mg IV dose, with infusion times as short as 20 minutes. The criteria for 'high-risk' patients are described in the?Fact Sheet for Healthcare Providers. In the?U.S., REGEN-COV is not authorized for use in patients who are hospitalized due to COVID-19 or require oxygen therapy, 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.
Regeneron is?collaborating?with Roche to increase global supply of REGEN-COV. Regeneron is responsible for development and distribution of the treatment in the?U.S., and Roche is primarily responsible for development and distribution outside the?U.S.?The companies share a commitment to making the antibody cocktail available to COVID-19 patients around the globe and will support access in low- and lower-middle-income countries through drug donations to be made in partnership with public health organizations.
About Regeneron's?VelocImmune?Technology
Regeneron's?VelocImmune?technology utilizes a proprietary genetically engineered mouse platform endowed with a genetically humanized immune system to produce optimized fully human antibodies. When Regeneron's co-Founder, President and Chief Scientific Officer?George D. Yancopoulos?was a graduate student with his mentor?Frederick W. Alt?in 1985, they were the first to?envision?making such a genetically humanized mouse, and Regeneron has spent decades inventing and developing?VelocImmune?and related?VelociSuite?technologies.?Dr. Yancopoulos?and his team have used?VelocImmune?technology to create approximately a quarter of all original, FDA-approved fully human monoclonal antibodies currently available. This includes REGEN-COVTM?(casirivimab with imdevimab), Dupixent??(dupilumab), Libtayo??(cemiplimab-rwlc), Praluent??(alirocumab), Kevzara??(sarilumab), Evkeeza? (evinacumab-dgnb) and Inmazeb? (atoltivimab, maftivimab and odesivimab-ebgn).
AUTHORIZED USE AND IMPORTANT SAFETY INFORMATION
Authorized Emergency Use
REGEN-COV, (casirivimab with imdevimab to be administered together) is authorized for the treatment of mild to moderate coronavirus disease 2019 (COVID-19) in adults and pediatric patients (12 years 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. [see Limitations of Authorized Use]
TABLE 1: Key Results from Phase 3 Outpatient Trial1-3 | ||||
1,200 mg IV | Placebo | 2,400 mg IV | Placebo | |
n=736 | n=748 | n=1,355 | n=1,341 | |
Patients with??1 COVID-19-related hospitalization or death through day 29 | ||||
Risk reduction | 70% (p=0.0024) | 71% (p<0.0001) | ||
# of patients with events | 7 (1.0%) | 24 (3.2%) | 18 (1.3%) | 62 (4.6%) |
Time to COVID-19 symptom resolution | ||||
Median (days) | 10 | 14 | 10 | 14 |
Median reduction (days) | 4 (p<0.0001) | 4 (p<0.0001) |
1. | Based on the modified Full Analysis Set population, which includes all randomized patients with a positive SARS-CoV-2 RT-qPCR test from nasopharyngeal swabs at randomization and ?1 risk factor for severe COVID-19. |
2. | The formal hierarchical analysis first evaluated the 2,400 mg dose vs. concurrent placebo and then evaluated the 1,200 mg dose vs. concurrent placebo. |
3. | Based on Phase 1/2 analyses showing that the 8,000 mg and 2,400 mg doses were indistinguishable, the Phase 3 protocol was amended to compare the 2,400 mg and 1,200 mg doses vs. placebo, and the 8,000 mg data were converted to a descriptive analysis. |
TABLE 2: Pseudovirus Neutralization Data for SARS-CoV-2 Variant Substitutions with casirivimab and imdevimab Together | ||
Lineage with Spike Protein Substitution | Key Substitutions Tested | Fold Reduction in Susceptibility |
B.1.1.7 (UK?origin) | N501Ya | no changec |
B.1.351 (South Africa?origin) | K417N, E484K, N501Yb | no changec |
P.1 (Brazil?origin) | K417T + E484K | no changec |
B.1.427/B.1.429 (California?origin) | L452R | no changec |
B.1.526 (New York?origin)d | E484K | no changec |
a. | Pseudovirus expressing the entire variant spike protein was tested. The following changes from wild-type spike protein are found in the variant: del69-70, del145, N501Y, A570D, D614G, P681H, T716I, S982A, D1118H. |
b. | Pseudovirus expressing the entire variant spike protein was tested. The following changes from wild-type spike protein are found in the variant: D80Y, D215Y, del241-243, K417N, E484K, N501Y, D614G, A701V. |
c. | No change: < 2-fold reduction in susceptibility. |
d. | Not all isolates of the?New York?lineage harbor the E484K substitution (as of February 2021). |
- REGEN-COV has not been approved, but has been authorized for emergency use by FDA
- This use is authorized only for the duration of the declaration that circumstances exist justifying the authorization of the emergency use under section 564(b)(1) of the Act, 21 U.S.C. ? 360bbb-3(b)(1), unless the authorization is terminated or revoked sooner
- Healthcare providers should review the?Fact Sheet for Healthcare Providers?for information on the authorized use of REGEN-COV and mandatory requirements of the EUA and must comply with the requirements of the EUA. The?FDA Letter of Authorization?is available for reference,?as well as the?Dear Healthcare Provider Letter?and?Patient Fact Sheet
- REGEN-COV (casirivimab with imdevimab) is not authorized for use in patients
- who are hospitalized due to COVID-19, OR
- who require oxygen therapy due to COVID-19, OR
- who require an increase in baseline oxygen flow rate due to COVID-19 in those on chronic oxygen therapy due to underlying non-COVID-19 related comorbidity
- Benefit of treatment with REGEN-COV has not been observed in patients hospitalized due to COVID-19. Monoclonal antibodies, such as REGEN-COV, may be associated with worse clinical outcomes when administered to hospitalized patients with COVID-19 requiring high flow oxygen or mechanical ventilation.
- Have a body mass index (BMI) =35
- Have chronic kidney disease
- Have diabetes
- Have immunosuppressive disease
- Are currently receiving immunosuppressive treatment
- Are =65 years of age
- Are =55 years of age AND have
- cardiovascular disease, OR
- hypertension, OR
- chronic obstructive pulmonary disease/other chronic respiratory disease.
- Are 12 ? 17 years of age AND have
- BMI =85th percentile for their age and gender based on?CDC?growth charts,?https://www.cdc.gov/growthcharts/clinical_charts.htm,OR
- sickle cell disease, OR
- congenital or acquired heart disease, OR
- neurodevelopmental disorders (e.g., cerebral palsy), OR
- a medical-related technological dependence, for example, tracheostomy, gastrostomy, or positive pressure ventilation (not related to COVID-19), OR
- asthma, reactive airway or other chronic respiratory disease that requires daily medication for control.
- Hypersensitivity Including Anaphylaxis and Infusion-Related Reactions:?There is a potential for serious hypersensitivity reaction, including anaphylaxis, with administration of REGEN-COV. If signs or symptoms of a clinically significant hypersensitivity reaction or anaphylaxis occur, immediately discontinue administration and initiate appropriate medications and/or supportive therapy. Infusion-related reactions have been observed with administration of REGEN-COV.
- Signs and symptoms of infusion related reactions may include?fever, difficulty breathing, reduced oxygen saturation, chills, nausea, arrythmia (e.g., atrial fibrillation, tachycardia, bradycardia), chest pain or discomfort, weakness, altered mental status, headache, bronchospasm, hypotension, hypertension, angioedema, throat irritation, rash including urticaria, pruritus, myalgia, dizziness, fatigue and diaphoresis. If an infusion-related reaction occurs, consider slowing or stopping the infusion and administer appropriate medications and/or supportive care.
- Clinical Worsening After REGEN-COV Administration: Clinical worsening of COVID-19 after administration of REGEN-COV has been reported and may include signs or symptoms of fever, hypoxia or increased respiratory difficulty, arrythmia (e.g., atrial fibrillation, tachycardia, bradycardia), fatigue, and altered mental status. Some of these events required hospitalization. It is not known if these events were related to REGEN-COV use or were due to progression of COVID-19.
- Limitations of Benefit and Potential for Risk in Patients with Severe COVID-19:?Benefit of treatment with REGEN-COV has not been observed in patients hospitalized due to COVID-19. Monoclonal antibodies, such as REGEN-COV, may be associated with worse clinical outcomes when administered to hospitalized patients with COVID-19 requiring high-flow oxygen or mechanical ventilation. Therefore, REGEN-COV is not authorized for use in patients who are hospitalized due to COVID-19, OR who require oxygen therapy due to COVID-19, OR who require an increase in baseline oxygen flow rate due to COVID-19 in those on chronic oxygen therapy due to underlying non-COVID-19 related comorbidity.
- Serious adverse events (SAEs) were reported in 4 (1.6%) patients in REGEN-COV 2,400 mg group, 2 (0.8%) patients in REGEN-COV 8,000 mg group and 6 (2.3%) patients in the placebo group. None of the SAEs were considered to be related to study drug. SAEs that were reported as Grade 3 or 4 adverse events were pneumonia, hyperglycemia, nausea and vomiting (2,400 mg REGEN-COV), intestinal obstruction and dyspnea (8,000 mg REGEN-COV) and COVID-19, pneumonia and hypoxia (placebo).?REGEN-COV is?not authorized at the 8,000 mg dose (4,000 mg casirivimab and 4,000 mg imdevimab).
- One anaphylactic reaction was reported in the clinical program. The event began within 1 hour of completion of the infusion, and required treatment including epinephrine. The event resolved. Infusion-related reactions, of Grade 2 or higher severity, were reported in 4 subjects (1.5%) in the 8,000 mg (4,000 mg casirivimab and 4,000 mg imdevimab) arm. These infusion-related reactions events were moderate in severity; and include pyrexia, chills, urticaria, pruritus, abdominal pain, and flushing. One infusion-related reaction (nausea) was reported in the placebo arm and none were reported in the 2,400 mg (1,200 mg casirivimab and 1,200 mg imdevimab) arm. In two subjects receiving the 8,000 mg dose of REGEN-COV, the infusion-related reactions (urticaria, pruritus, flushing, pyrexia, shortness of breath, chest tightness, nausea, vomiting) resulted in permanent discontinuation of the infusion. All events resolved.
- Pregnancy:?There is currently limited clinical experience in the use of REGEN-COV in COVID-19 patients who are pregnant. REGEN-COV therapy should be used during pregnancy only if the potential benefit justifies the potential risk for the mother and the fetus.
- Lactation:?There is currently no clinical experience in use of REGEN-COV in COVID-19 patients who are breastfeeding. The development and health benefits of breastfeeding should be considered along with the mother's clinical need for REGEN-COV and any potential adverse effects on the breastfed child from REGEN-COV or from the underlying maternal condition.