Justification for Emergency Use of Drugs During the COVID-19 Pandemic

There is currently an outbreak of Coronavirus Disease 2019 (COVID-19) caused by SARS-CoV-2, a novel coronavirus. The Secretary of HHS has declared that:

• A public health emergency related to COVID-19 has existed since January 27, 2020.
• Circumstances exist justifying the authorization of emergency use of drugs and biological products during the COVID-19 pandemic (March 27, 2020 declaration).

An EUA is a FDA authorization for the emergency use of an unapproved product or unapproved use of an approved product (i.e., drug, biological product, or device) in the United States under certain circumstances including, but not limited to, when the Secretary of HHS declares that there is a public health emergency that affects the national security or the health and security of United States citizens living abroad, and that involves biological agent(s) or a disease or condition that may be attributable to such agent(s). Criteria for issuing an EUA include:

• The biological agent(s) can cause a serious or life-threatening disease or condition;
• Based on the totality of the available scientific evidence (including data from adequate and well-controlled clinical trials, if available), it is reasonable to believe that
  • the product may be effective in diagnosing, treating, or preventing the serious or life-threatening disease or condition; and
  • The known and potential benefits of the product - when used to diagnose, prevent, or treat such disease or condition - outweigh the known and potential risks of the product, taking into consideration the material threat posed by the biological agent(s);
• There is no adequate, approved, and available alternative to the product for diagnosing, preventing, or treating the serious or life-threatening disease or condition.

Information Regarding Available Alternatives for the EUA Authorized Use

Veklury (remdesivir) is FDA-approved for the treatment of 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, who are not hospitalized and have mild-to-moderate COVID-19, and who are at high risk for progression to severe COVID-19, including hospitalization or death. Veklury is administered via intravenous infusion for a total treatment duration of 3 days.

Although Veklury is an approved alternative treatment of mild-to-moderate 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 progression to severe COVID-19, including hospitalization or death, FDA does not consider Veklury to be an adequate alternative to bebtelovimab for this authorized use because it may not be feasible or practical for certain patients (e.g., it requires a 3-day treatment duration).

Other therapeutics are currently authorized for the same use as bebtelovimab. For additional information on all products authorized for treatment or prevention of COVID-19, please see https://www.fda.gov/emergency-preparedness-and-response/mcm-legal-regulatory-and-policy-framework/emergency-use-authorization.

For information on clinical studies of bebtelovimab and other therapies for the treatment of COVID-19, see www.clinicaltrials.gov.

2.1 Dosage

The dosage in adults (18 years and older) and pediatric patients (≥12 years of age and weighing at least 40 kg) is bebtelovimab 175 mg.

Administer bebtelovimab as soon as possible after positive results of direct SARS-CoV-2 viral testing and within 7 days of symptom onset.

Bebtelovimab must be administered as a single intravenous injection over at least 30 seconds.

2.2 Dosage Adjustment in Specific Populations

No dosage adjustment is recommended in pregnant or lactating individuals, in geriatrics, in individuals with renal impairment, or in individuals with mild hepatic impairment [see Clinical Pharmacology (12.3)].

2.3 Dose Preparation and Administration

General Information

• Bebtelovimab should be prepared by a qualified healthcare professional using aseptic technique.
• Inspect bebtelovimab vial visually for particulate matter and discoloration. Bebtelovimab is clear to opalescent and colorless to slightly yellow to slightly brown solution. Discard the vial if the solution is cloudy, discolored or visible particles are observed.
• Bebtelovimab may only be administered in settings in which healthcare providers have immediate access to medications to treat a severe infusion reaction, such as anaphylaxis, and the ability to activate the emergency medical system (EMS), as necessary.
• Clinically monitor patients for possible infusion-related reactions during administration and observe patients for at least 1 hour after injection is complete.

Materials Needed for Administration

• 1 bebtelovimab vial (175 mg/2 mL)
• 1 disposable polypropylene dosing syringe capable of holding 2 mL
• 0.9% Sodium Chloride Injection for flushing
• Optional: 1 syringe extension set made of polyethylene or polyvinylchloride with or without di-ethylhexylphthalate (DEHP)

Preparation

• Remove bebtelovimab vial from refrigerated storage and allow to equilibrate to room temperature for approximately 20 minutes before preparation. Do not expose to direct heat. Do not shake vial. Inspect the vial.
• Withdraw 2 mL from the vial into the disposable syringe.
• Discard any product remaining in the vial.
• This product is preservative-free and therefore, should be administered immediately.
  • If immediate administration is not possible, store the syringe for up to 24 hours at refrigerated temperature (2°C to 8°C [36°F to 46°F]) and up to 7 hours at room temperature (20°C to 25°C [68°F to 77°F]). If refrigerated, allow the prepared syringe to equilibrate to room temperature for approximately 20 minutes prior to administration.
• If used, attach and prime the syringe extension set.
• Administer the entire contents of the syringe via IV injection over at least 30 seconds.
• After the entire contents of the syringe have been administered, flush the injection line with 0.9% Sodium Chloride to ensure delivery of the required dose.

5.1 Hypersensitivity Including Anaphylaxis and Infusion-Related Reactions

Serious hypersensitivity reactions, including anaphylaxis, have been observed with administration of other SARS-CoV-2 monoclonal antibodies and could occur with administration of bebtelovimab. If signs and symptoms of a clinically significant hypersensitivity reaction or anaphylaxis occur, immediately discontinue administration and initiate appropriate medications and/or supportive care.

Infusion-related reactions, which may occur up to 24 hours after the injection, have been observed in clinical trials of bebtelovimab when administered with other monoclonal antibodies and may occur with use of bebtelovimab alone. These reactions may be severe or life threatening.

Signs and symptoms of infusion-related reactions may include:

• fever, difficulty breathing, reduced oxygen saturation, chills, fatigue, arrhythmia (e.g., atrial fibrillation, sinus tachycardia, bradycardia), chest pain or discomfort, weakness, altered mental status, nausea, headache, bronchospasm, hypotension, hypertension, angioedema, throat irritation, rash including urticaria, pruritus, myalgia, vasovagal reactions (e.g., pre-syncope, syncope), dizziness and diaphoresis.

Administer appropriate medications and/or supportive care if an infusion-related reaction occurs.

Hypersensitivity reactions occurring more than 24 hours after the injection have also been reported with the use of SARS-CoV-2 monoclonal antibodies under Emergency Use Authorization.

5.2 Clinical Worsening After SARS-CoV-2 Monoclonal Antibody Administration

Clinical worsening of COVID-19 after administration of SARS-CoV-2 monoclonal antibody treatment has been reported and may include signs or symptoms of fever, hypoxia or increased respiratory difficulty, arrhythmia (e.g., atrial fibrillation, sinus tachycardia, bradycardia), fatigue, and altered mental status. Some of these events required hospitalization. It is not known if these events were related to SARS-CoV-2 monoclonal antibody use or were due to progression of COVID-19.

5.3 Limitations of Benefit and Potential for Risk in Patients with Severe COVID 19

Treatment with bebtelovimab has not been studied in patients hospitalized due to COVID-19. Monoclonal antibodies, such as bebtelovimab, may be associated with worse clinical outcomes when administered to hospitalized patients with COVID-19 requiring high flow oxygen or mechanical ventilation. Therefore, bebtelovimab is not authorized for use in patients, regardless of age, who:

• are hospitalized due to COVID-19, OR
• require oxygen therapy and/or respiratory support due to COVID-19, OR
• require an increase in baseline oxygen flow rate and/or respiratory support due to COVID-19 and are on chronic oxygen therapy and/or respiratory support due to underlying non-COVID-19 related comorbidity.

6.1 Adverse Reactions from Clinical Studies

The following adverse reactions have been observed in the clinical studies of bebtelovimab that supported the EUA. The adverse reaction rates observed in these clinical studies cannot be directly compared to rates in the clinical studies of other products and may not reflect the rates observed in clinical practice. Additional adverse events associated with bebtelovimab may become apparent with more widespread use.

The safety of bebtelovimab is primarily based on exposure of 602 ambulatory (non-hospitalized) subjects who received doses of bebtelovimab, alone or in combination with bamlanivimab and etesevimab, in the phase 1 and phase 2 portions of BLAZE-4, a randomized, single-dose clinical trial.

The following adverse reactions (i.e., adverse events assessed as causally related) have been observed in those who have received bebtelovimab, alone or in combination with bamlanivimab and etesevimab, at the authorized dose or higher:

• Infusion-related reactions (n=2, 0.3%)
• Pruritus (n=2, 0.3%)
• Rash (n=5, 0.8%)

The most common treatment-emergent adverse events observed in subjects treated with bebtelovimab, alone or in combination with bamlanivimab and etesevimab, at the authorized dose or higher, included nausea (0.8%) and vomiting (0.7%).

6.4 Required Reporting for Serious Adverse Events and Medication Errors

The prescribing healthcare provider and/or the provider's designee is/are responsible for mandatory reporting of all serious adverse events* and medication errors potentially related to bebtelovimab within 7 calendar days from the healthcare provider's awareness of the event, using FDA Form 3500 (for information on how to access this form, see below). The FDA requires that such reports, using FDA Form 3500, include the following:

• Patient demographics and baseline characteristics (e.g., patient identifier, age or date of birth, gender, weight, ethnicity, and race)
• A statement "Bebtelovimab use for COVID-19 under Emergency Use Authorization (EUA)” under the “Describe Event, Problem, or Product Use/Medication Error” heading
• Information about the serious adverse event or medication error (e.g., signs and symptoms, test/laboratory data, complications, timing of drug initiation in relation to the occurrence of the event, duration of the event, treatments required to mitigate the event, evidence of event improvement/disappearance after stopping or reducing the dosage, evidence of event reappearance after reintroduction, clinical outcomes).
• Patient's preexisting medical conditions and use of concomitant products
• Information about the product (e.g., dosage, route of administration, NDC #).

Submit adverse event and medication error reports, using Form 3500, to FDA MedWatch using one of the following methods:

• Complete and submit the report online: www.fda.gov/medwatch/report.htm
• Complete and submit a postage-paid FDA Form 3500 (https://www.fda.gov/media/76299/download) and return by:
  • Mail to MedWatch, 5600 Fishers Lane, Rockville, MD 20852-9787, or
  • Fax to 1-800-FDA-0178, or
• Call 1-800-FDA-1088 to request a reporting form

In addition, please provide a copy of all FDA MedWatch forms to:

 

Eli Lilly and Company, Global Patient Safety

 

Fax: 1-317-277-0853

 

E-mail: mailindata_gsmtindy@lilly.com

 

Or call Eli Lilly and Company at 1-855-LillyC19 (1-855-545-5921) to report adverse events.

The prescribing health care provider and/or the provider's designee is/are responsible for mandatory responses to requests from FDA for information about adverse events and medication errors following receipt of bebtelovimab.

*Serious adverse events are defined as:

• Death;
• A life-threatening adverse event;
• Inpatient hospitalization or prolongation of existing hospitalization;
• A persistent or significant incapacity or substantial disruption of the ability to conduct normal life functions;
• A congenital anomaly/birth defect;
• Other important medical event, which may require a medical or surgical intervention to prevent death, a life-threatening event, hospitalization, disability, or congenital anomaly.

8.1 Pregnancy

8.2 Lactation

8.4 Pediatric Use

Bebtelovimab is not authorized for use in pediatric individuals under 12 years of age or weighing less than 40 kg. The safety and effectiveness of bebtelovimab have not been assessed in pediatric patients. The recommended dosing regimen in patients 12 years to less than 18 years of age, weighing at least 40 kg, is expected to result in comparable serum exposures of bebtelovimab as those observed in adults.

8.5 Geriatric Use

Of the 602 patients receiving bebtelovimab in BLAZE-4, 10.5% were 65 years of age and older and 3.3% were 75 years of age and older. Based on population PK analyses of samples from 573 patients over an age range of 14 to 89 years, there was no impact of age on PK. Therefore, there is no difference in the PK of bebtelovimab in geriatric patients compared to younger patients.

12.1 Mechanism of Action

Bebtelovimab is a recombinant neutralizing human IgG1λ monoclonal antibody (mAb) to the spike protein of SARS-CoV-2 and is unmodified in the Fc region. Bebtelovimab binds the spike protein with a dissociation constant KD = 0.046 to 0.075 nM and blocks spike protein attachment to the human ACE2 receptor with an IC50 value of 0.39 nM (0.056 mcg/mL).

12.2 Pharmacodynamics

The exposure-response relationships of bebtelovimab for viral loads and clinical outcomes are unknown.

12.3 Pharmacokinetics

A summary of PK parameters of bebtelovimab following administration of a single dose of 175 mg bebtelovimab is provided in Table 1.

12.4 Microbiology

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenesis, mutagenesis, and reproductive toxicology studies with bebtelovimab have not been conducted.

13.2 Animal Toxicology and/or Pharmacology

In toxicology studies, bebtelovimab had no adverse effects when administered intravenously to rats.

In tissue cross reactivity studies using human adult and fetal tissues, no binding of clinical concern was detected for bebtelovimab.

14.1 Phase 2 Data from the Placebo-Controlled Portion of BLAZE-4 (Low Risk Subjects; Treatment Arms 9-11)

In this portion of the trial, adult subjects were treated with a single infusion of bamlanivimab 700 mg, etesevimab 1,400 mg, and bebtelovimab 175 mg (N=127), 175 mg bebtelovimab alone (N=125), or placebo (N=128). The majority (96.8%) of the subjects enrolled in these treatment arms did not meet the criteria for high-risk.

At baseline, median age was 35 years (with 1 placebo subject aged 65 or older); 56% of subjects were female, 79% were White, 36% were Hispanic or Latino, and 19% were Black or African American. Subjects had mild (74%) to moderate (26%) COVID-19; the mean duration of symptoms was 3.6 days; mean viral load by cycle threshold (CT) was 24.63 at baseline. The baseline demographics and disease characteristics were well balanced across treatment arms with the exception of baseline serology status. A higher percentage of subjects in the placebo arm were positive for baseline serology (15% vs. 9% for bamlanivimab, etesevimab, and bebtelovimab together, and 7% for bebtelovimab alone). Participants enrolled in these treatment arms had not received SARS-CoV-2 vaccine at baseline.

The primary endpoint was the proportion of subjects with persistently high viral load (PHVL) by Day 7. PHVL occurred in 26 subjects treated with placebo (21%) as compared to 16 (13%) subjects treated with bamlanivimab 700 mg, etesevimab 1,400 mg, and bebtelovimab 175 mg together [p=0.098], and 17 (14%) subjects treated with bebtelovimab 175 mg alone [p=0.147], a 38% (95% CI: -9%, 65%) and 34% (95% CI: -15%, 62%) relative reduction, respectively.

Secondary endpoints included mean change in viral load from baseline to Day 3, 5, 7, and 11 (Figure 1).

Figure 1: SARS-CoV-2 Viral Load Change from Baseline (Mean ± SE) by Visit from the Placebo-Controlled Portion of BLAZE-4 in Low Risk Adults (700 mg bamlanivimab, 1,400 mg etesevimab, 175 mg bebtelovimab together and 175 mg bebtelovimab alone).

For the secondary endpoint of COVID-19 related hospitalization (defined as ≥24 hours of acute care) or death by any cause by Day 29, these events occurred in 2 (1.6%) subjects treated with placebo as compared with 3 (2.4%) events in subjects treated with bamlanivimab 700 mg, etesevimab 1,400 mg, and bebtelovimab 175 mg together and 2 (1.6%) events in subjects treated with bebtelovimab 175 mg alone. There was 1 subject treated with bamlanivimab 700 mg, etesevimab 1,400 mg, and bebtelovimab 175 mg together who died on Day 5. Conclusions are limited as COVID-19 related hospitalization and death rates are expected to be low in a low risk population.

The median time to sustained symptom resolution as recorded in a trial specific daily symptom diary was 7 days (95%CI: 6, 8 days) for subjects treated with bamlanivimab 700 mg, etesevimab 1,400 mg, and bebtelovimab 175 mg together [p=0.289] and 6 days (95% CI: 5, 7 days) for subjects treated with bebtelovimab 175 mg alone [p=0.003] as compared with 8 days (95% CI: 7, 9 days) for subjects treated with placebo. Symptoms assessed were cough, shortness of breath, feeling feverish, fatigue, body aches and pains, sore throat, chills, and headache. Sustained symptom resolution was defined as absence of any of these symptoms, except for allowance of mild fatigue and cough, in two consecutive assessments.

14.2 Phase 2 Data from the Randomized, Open-Label Portion of BLAZE-4 (High Risk Subjects; Treatment Arms 12-13)

In this portion of the trial, subjects were treated with a single infusion of bamlanivimab 700 mg, etesevimab 1,400 mg, and bebtelovimab 175 mg (N=50) or 175 mg bebtelovimab alone (N=100). The majority (91.3%) of the subjects enrolled in these dose arms meet the criteria for high-risk.

At baseline, median age was 50 years (with 28 subjects aged 65 or older); 52% of subjects were female, 75% were White, 18% were Hispanic or Latino, and 18% were Black or African American. Subjects had mild (75%) to moderate (25%) COVID-19; the mean duration of symptoms was 4.7 days; mean viral load by cycle threshold (CT) was 26.66 at baseline; and 20.7% of subjects had at least one dose of a COVID-19 vaccine. There were 2 pediatric patients enrolled (ages 14 and 17), one in each treatment arm. The baseline demographics and disease characteristics were well balanced across treatment groups.

The primary objective for these treatment arms was to characterize the safety profile of bebtelovimab 175 mg by evaluating adverse events and serious adverse events. Efficacy endpoints included the proportion of subjects with COVID-19 related hospitalization or death by any cause by Day 29, mean change in viral load from baseline to Days 3, 5, 7, and 11 and time to sustained symptom resolution.

The proportion of subjects with COVID-19 related hospitalization (defined as ≥24 hours of acute care) or death by any cause was assessed by Day 29. Events occurred in 2 (4%) subjects treated with bamlanivimab 700 mg, etesevimab 1,400 mg, and bebtelovimab 175 mg together and 3 (3%) subjects treated with bebtelovimab 175 mg alone. There was 1 subject treated with bebtelovimab 175 mg alone who died on Day 34.

Mean changes in viral load from baseline to Day 3, 5, 7, and 11 are shown in Figure 2.

Figure 2: SARS-CoV-2 Viral Load Change from Baseline (Mean ± SE) by Visit from the Open-Label Portion of BLAZE-4 (700 mg bamlanivimab, 1,400 mg etesevimab, 175 mg bebtelovimab together and 175 mg bebtelovimab alone).

The median time to sustained symptom resolution as recorded in a trial specific daily symptom diary was 7 days for subjects treated with bebtelovimab 175 mg alone.

14.3 Phase 2 Data from the Non-Randomized, Open-Label Portion of BLAZE-4 (High Risk Subjects; Treatment Arm 14)

In this portion of the trial, subjects were treated with a single infusion of bamlanivimab 700 mg, etesevimab 1,400 mg, and bebtelovimab 175 mg (N=176). The majority (97.7%) of the subjects enrolled meet the criteria for high-risk.

At baseline, median age was 51 years (with 35 subjects aged 65 or older); 56% of subjects were female, 80% were White, 28% were Hispanic or Latino, and 16% were Black or African American. Subjects had mild (73%) to moderate (27%) COVID-19; the mean duration of symptoms was 4 days; mean viral load by cycle threshold (CT) was 23.45 at baseline; and 31% of subjects had at least one dose of a COVID-19 vaccine. There were 2 pediatric patients enrolled (ages 14 and 15).

The primary objective for this treatment arm was to characterize the safety profile of bamlanivimab 700 mg, etesevimab 1,400 mg, and bebtelovimab 175 mg by evaluating adverse events and serious adverse events. Efficacy endpoints included the proportion of subjects with COVID-19 related hospitalization or death by any cause by Day 29, mean change in viral load from baseline to Days 3, 5, 7, and 11, and time to sustained symptom resolution.

The proportion of subjects with COVID-19 related hospitalization (defined as ≥24 hours of acute care) or death by any cause was assessed by Day 29. Events occurred in 3 subjects (1.7%), and no subjects died.

Mean changes in viral load from baseline to Day 3, 5, 7, and 11 were -1.4, -3.1, -4.0, and -5.4, respectively.

The median time to sustained symptom resolution as recorded in a trial specific daily symptom diary was 8 days.

14.4. Overall Benefit-Risk Assessment and Limitations of Data Supporting the Benefits of the Product

Based on the data from BLAZE-4, bebtelovimab has been shown to improve symptoms in patients with mild-to-moderate COVID-19. Additionally, a reduction in SARS-CoV-2 viral load on Day 5 was observed relative to placebo, though the clinical significance of this is unclear. The placebo-controlled phase 2 data are limited by enrollment of only subjects without risk factors for progression to severe COVID-19, and the trial was not powered or designed to determine a difference in the clinical outcomes of hospitalization or death between the placebo and bebtelovimab treatment arms [see Clinical Studies (14.1)]. Bebtelovimab has been studied in individuals who have risk factors for progression to severe COVID-19, but the efficacy analyses are limited due to the lack of a concurrent placebo control arm for this population [see Clinical Studies (14.2, 14.3)].

However, based on the totality of scientific evidence available, including the available Phase 2 and pharmacokinetic data, along with the nonclinical viral neutralization data for Omicron and other variants of concern, it is reasonable to believe that bebtelovimab may be effective for the treatment of patients with mild-to-moderate COVID-19 to reduce the risk of progression to hospitalization or death. In addition, the mechanism of action for bebtelovimab is similar to other neutralizing SARS-CoV-2 monoclonal antibodies, including bamlanivimab and etesevimab, that have data from Phase 3 clinical trials showing a reduction in hospitalization or death in high risk patients infected with other SARS-CoV-2 variants. The safety profile of bebtelovimab is acceptable with monitorable risks and is comparable to other SARS-CoV-2 monoclonal antibodies, including bamlanivimab and etesevimab. Considered together, these data support that the known and potential benefits of treatment with bebtelovimab outweigh the known and potential risks 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 progression to severe COVID-19, including hospitalization or death, and for whom alternative COVID-19 treatment options approved or authorized by FDA are not accessible or clinically appropriate.

Clinical data summarized above were similar for bebtelovimab alone as compared to the combination of bamlanivimab, etesevimab and bebtelovimab administered together. Bebtelovimab retains activity against currently circulating variants [see Microbiology (12.4)].

How Supplied

Bebtelovimab injection is a sterile, preservative-free clear to opalescent and colorless to slightly yellow to slightly brown solution supplied in a single-dose vial.

Storage and Handling

Bebtelovimab is preservative-free. Discard unused portion.

Store unopened vials in a refrigerator at 2°C to 8°C (36°F to 46°F) in the original carton to protect from light.

DO NOT FREEZE, SHAKE, OR EXPOSE TO DIRECT LIGHT.