Bebtelovimab: Package Insert and Label Information (Page 4 of 5)

13 NONCLINICAL TOXICOLOGY

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.

Antiviral Activity In Vivo

Prophylactic administration of bebtelovimab to male Syrian golden hamsters (n=5 to 8 per group) resulted in 2 to 4 log10 decreases in viral genomic RNA and viral replication (subgenomic RNA) from lung tissue, as well as decreases in lung weight and improvements in body weight compared to controls.

The applicability of these findings to a treatment setting is not known.

14 CLINICAL STUDIES

The data supporting this EUA for treatment of mild-to-moderate COVID-19 are primarily based on analyses of data from the Phase 2 portion of the BLAZE-4 trial (NCT04634409) that enrolled both low risk and high risk subjects (treatment arms 9-14). This trial evaluated the clinical efficacy data from subjects receiving 175 mg bebtelovimab alone and together with 700 mg bamlanivimab and 1,400 mg of etesevimab.

BLAZE-4 is a Phase 1/2, randomized, single-dose clinical trial evaluating treatment of subjects with mild-to-moderate COVID-19 (subjects with COVID-19 symptoms who are not hospitalized). Efficacy of bebtelovimab, alone and together with bamlanivimab and etesevimab, was evaluated in low risk adults (i.e., those not at high-risk to progress to severe COVID-19) in a randomized part of the trial which included a placebo control arm (treatment arms 9-11). Low risk adults were randomized with a 1:1:1 ratio. High-risk adults and pediatric subjects (12 years of age and older weighing at least 40 kg) received open-label active treatments. One cohort of high risk subjects was randomized with 2:1 ratio (treatment arms 12 and 13). Another cohort of high risk subject was enrolled with no randomization (treatment arm 14). The trial enrolled subjects who were not hospitalized and had 1 or more COVID-19 symptoms that were at least mild in severity. Treatment was initiated within 3 days of obtaining the clinical sample for the first positive SARS-CoV-2 viral infection determination.

BLAZE-4 was conducted prior to the emergence of the Omicron variant. No subject in BLAZE-4 was infected with virus of the Omicron lineage or sub-lineages. The majority of participants in the trial were infected with Delta (49.8%) and Alpha (28.6%).

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
(click image for full-size original)

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
(click image for full-size original)

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)].

16 HOW SUPPLIED/STORAGE AND HANDLING

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.

Antibody Concentration Package Size NDC
Bebtelovimab 175 mg/2 mL (87.5 mg/mL) One vial per carton 0002-7589-01

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.

17 PATIENT COUNSELING INFORMATION

As a healthcare practitioner, you must communicate to the patient and/or caregiver information consistent with the “FACT SHEET FOR PATIENTS, PARENTS AND CAREGIVERS” and provide them with a copy of this Fact Sheet prior to administration of bebtelovimab. However, if providing this information will delay the administration of bebtelovimab to a degree that would endanger the life of a patient, the information must be provided to the parent and/or caregiver as soon as feasible after bebtelovimab administration.

Remind patients treated with bebtelovimab that they should continue to self-isolate and use infection control measures (e.g., wear mask, isolate, social distance, avoid sharing personal items, clean and disinfect “high touch” surfaces, and frequent handwashing) according to CDC guidelines.

For additional information visit: www.LillyAntibody.com/bebtelovimab

If you have questions, please contact: 1-855-LillyC19 (1-855-545-5921)

18 MANUFACTURER INFORMATION

Eli Lilly and Company, Indianapolis, IN 46285, USA

Copyright © 2022, Eli Lilly and Company. All rights reserved.

Literature revised August 23, 2022

BEB-0007-EUA HCP-20220823

Fact Sheet for Patients, Parents, and Caregivers

Emergency Use Authorization (EUA) of Bebtelovimab for Coronavirus Disease 2019(COVID-19)

You are being given this Fact Sheet because your healthcare provider believes it is necessary to provide you or your child with bebtelovimab for the treatment of mild-to-moderate coronavirus disease 2019 (COVID-19) in adults and children (12 years of age and older weighing at least 88 pounds [40 kg]) with positive results of direct severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) viral testing, and who are at high risk for progression to severe COVID-19, including hospitalization or death, and for whom other COVID-19 treatment options approved or authorized by FDA are not available or clinically appropriate. This Fact Sheet contains information to help you understand the potential risks and potential benefits of receiving bebtelovimab, which you or your child have received or may receive.

The U.S. Food and Drug Administration (FDA) has issued an Emergency Use Authorization (EUA) to make bebtelovimab available during the COVID-19 pandemic (for more details about an EUA please see “What is an Emergency Use Authorization?” at the end of this document). Bebtelovimab is not an FDA-approved medicine in the United States. Read this Fact Sheet for information about bebtelovimab. Talk to your healthcare provider about your options or if you have any questions. It is your choice for you or your child to receive bebtelovimab or stop it at any time.

What is COVID-19?

COVID-19 is caused by a virus called a coronavirus (SARS-CoV-2). You can get COVID-19 through contact with another person who has the virus.

COVID-19 illnesses have ranged from very mild (including some with no reported symptoms) to severe, including illness resulting in death. While information so far suggests that most COVID-19 illness is mild, serious illness can happen and may cause some of your or your child’s other medical conditions to become worse. Older people and people of all ages with severe, or long lasting (chronic) medical conditions like heart disease, lung disease, diabetes, and obesity, for example, seem to be at higher risk of being hospitalized for COVID-19. Older age, with or without other conditions, also places people at higher risk of being hospitalized for COVID-19.

What is bebtelovimab?

Bebtelovimab is an investigational medicine used for the treatment of mild-to-moderate coronavirus disease 2019 (COVID-19) in adults and children (12 years of age and older weighing at least 88 pounds [40 kg]):

  • with positive results of direct SARS-CoV-2 viral testing, and
  • who are at high risk 3 for progression to severe COVID-19, including hospitalization or death, and
  • for whom other COVID-19 treatment options approved or authorized by FDA are not available or clinically appropriate.

There is limited information known about the safety and effectiveness of using bebtelovimab for the treatment of mild-to-moderate COVID-19.

For more information on EUA, see the “What is an Emergency Use Authorization (EUA)?” section at the end of this Fact Sheet.

Bebtelovimab is not authorized for use in people who:

  • are likely to be infected with a SARS-CoV-2 variant that is not able to be treated by bebtelovimab based on the circulating variants in your area (ask your health care provider about FDA and CDC’s latest information on circulating variants by geographic area), or
  • 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.

What should I tell my healthcare provider before I or my child receive bebtelovimab?

Tell your healthcare provider about all your or your child’s medical conditions including if you or your child:

  • Have any allergies
  • Are pregnant or plan to become pregnant
  • Are breastfeeding or plan to breastfeed
  • Have any serious illnesses
  • Are taking any medicines (prescription, and over-the-counter, vitamins, or herbal products)

How will I or my child receive bebtelovimab?

Bebtelovimab will be given as an injection through a vein (intravenously or IV) over at least 30 seconds. You will be observed by your healthcare provider for at least 1 hour after you receive bebtelovimab.

What are the important possible side effects of bebtelovimab?

  • Allergic reactions. Allergic reactions can happen during and after injection with bebtelovimab. Tell your healthcare provider right away if you or your child develop any of the following signs and symptoms of allergic reaction: fever, difficulty breathing, low oxygen level in your blood, chills, tiredness, fast or slow heart rate, chest discomfort or pain, weakness, confusion, nausea, headache, shortness of breath, low or high blood pressure, wheezing, swelling of your lips, face, or throat, rash including hives, itching, muscle aches, dizziness, feeling faint, and sweating. These reactions may be severe or life threatening.

The side effects of receiving any medicine by vein may include brief pain, bleeding, bruising of the skin, soreness, swelling, and possible infection at the injection site.

These are not all the possible side effects of bebtelovimab. Not many people have received bebtelovimab. Serious and unexpected side effects may happen. All of the risks are not known at this time.

It is possible that bebtelovimab could interfere with your body’s own ability to fight off a future infection of SARS-CoV-2. Similarly, bebtelovimab may reduce the body’s immune response to a vaccine for SARS-CoV-2. Talk to your healthcare provider if you have any questions.

What other treatment choices are there?

Veklury (remdesivir) is FDA-approved for the treatment of mild-to-moderate COVID-19 in certain adults and pediatric patients. Talk with your doctor to see if Veklury is appropriate for you.

Like bebtelovimab, FDA may allow for the emergency use of other medicines to treat people with COVID-19. Go to https://www.fda.gov/emergency-preparedness-and-response/mcm-legal-regulatory-and-policy-framework/emergency-use-authorization for information on the emergency use of other medicines that are authorized by FDA to treat people with COVID-19. Your healthcare provider may talk with you about clinical trials for which you may be eligible.

It is your choice for you or your child to be treated or not to be treated with bebtelovimab. Should you decide not to receive it or for your child to not receive it, it will not change your or your child’s standard medical care.

What if I am pregnant or breastfeeding?

There is limited experience treating pregnant women or breastfeeding mothers with bebtelovimab. Severe allergic reactions have been observed with administration of bebtelovimab, including in pregnant patients.

For a mother and unborn baby, the benefit of receiving bebtelovimab may be greater than the risk from the treatment. If pregnant or breastfeeding, discuss your options and specific situation with your healthcare provider.

How do I report side effects with bebtelovimab?

Contact your healthcare provider if you have any side effects that bother you or do not go away.

Report side effects to FDA MedWatch at www.fda.gov/medwatch, or call 1-800-FDA-1088 or to Eli Lilly and Company, Inc. as shown below.

Email Fax Number Telephone Number
mailindata_gsmtindy@lilly.com 1-317-277-0853 1-855-LillyC19 (1-855-545-5921)

How can I learn more about COVID-19?

  • Ask your healthcare provider
  • Visit https://www.cdc.gov/COVID19
  • Contact your local or state public health department

What is an Emergency Use Authorization?

The United States FDA has made bebtelovimab available under an emergency access mechanism called an Emergency Use Authorization (EUA). The EUA is supported by a Secretary of Health and Human Service (HHS) declaration that circumstances exist to justify the emergency use of drugs and biological products during the COVID-19 pandemic.

Bebtelovimab for the treatment of mild-to-moderate COVID-19 in adults and children (12 years of age and older weighing at least 88 pounds [40 kg]) and who are at high risk of developing severe COVID-19, including hospitalization or death, and for whom other COVID-19 treatment options approved or authorized by FDA are not available or clinically appropriate has not undergone the same type of review as an FDA-approved product. In issuing an EUA under the COVID-19 public health emergency, the FDA has determined, among other things, that based on the total amount of scientific evidence available, including data from adequate and well-controlled clinical trials, it is reasonable to believe that the product may be effective for diagnosing, treating, or preventing COVID-19, or a serious or life-threatening disease or condition caused by COVID-19; that the known and potential benefits of the product, when used to diagnose, treat, or prevent such disease or condition, outweigh the known and potential risks of such product; and that there are no adequate, approved and available alternatives.

All of these criteria must be met to allow for the product to be used in the treatment of patients during the COVID-19 pandemic. The EUA for bebtelovimab is in effect for the duration of the COVID-19 declaration justifying emergency use of bebtelovimab, unless terminated or revoked (after which bebtelovimab may no longer be used under the EUA).

Additional Information

For general questions, visit the website or call the telephone number provided below.

Website Telephone Number
www.LillyAntibody.com/bebtelovimab 1-855-LillyC19(1-855-545-5921)

Literature revised May 17, 2022

Eli Lilly and Company, Indianapolis, IN 46285, USA Copyright © 2022, Eli Lilly and Company. All rights reserved.

BEB-0002-EUA PAT-20220517

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