A Comparison Of Bamlanivimab Versus Bamlanivimab-Etesevimab

In this article an infectious diseases pharmacist provides a comparison of bamlanivimab versus bamlanivimab-etesevimab.

Authored By: Timothy P. Gauthier, Pharm.D., BCPS, BCIDP

16 April 2021 – Important Note

Today the FDA revoked the EUA for bamlanivimab monotherapy. The EUA for bamlanivimab-etesivimab remained standing.

22 January 2022 – Important Note 2

Today the FDA revoked the EUA for bamlanivimab-etesevimab due to lack of activity versus the Omicron variant.

Date Published: 15 March 2021

Update added: 24 March 2021

Bamlanivimab and etesevimab are monoclonal antibodies produced by Eli Lilly. Both bamlanivimab and bamlanivimab-etesevimab have active FDA Emergency Use Authorizations at the time of writing this article.

As the combination therapy has recently become available for use, I thought it might be a worthwhile endeavor to contrast the monotherapy versus the combination therapy options. The information here is current as of the Fact Sheets for Healthcare Providers available 14 March 2021. The content at the other end of these links may be updated after this review, but the Fact Sheet can be accessed here for bamlanivimab monotherapy and here for bamlanivimab-etesevimab combination therapy. This is not an exhaustive review of all details related these therapies.

As part of this learning process I thought it might be fun to pause and learn about where the difficult to pronounce name “etesevimab” came from. I asked Dr. Boden from Kaleio Brands (a drug naming company) and he was kind enough to provide the following two paragraphs:

Etesevimab was named at the special INN meeting for COVID medicinal substances that was held August 20-21, 2020. The official definition of the antibody is, immunoglobulin G1-kappa, anti-[Homo sapiens severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike (S) protein, receptor binding domain (RBD)], Homo sapiens monoclonal antibody.

Monoclonal antibodies all end with the common stem, –mab, and make use of defining infixes to specify the target (e.g. –tamab for tumor-targeted antibodies; –vimab for antiviral antibodies; –limab for immunomodulating antibodies). As an anti-spike protein antibody (antiviral), the name makes use of the –vimab suffix. The fantasy prefix is etese-, which is supposed to be devoid of meaning. It is notable that “-sev- is imbedded in the name which alludes to the antibody’s use to treat severe acute respiratory syndrome. It isn’t known if this was done intentionally by Lilly when they suggested names on their application, but it is a happy coincidence if not strategically intended. The ete- prefix sounds somewhat like “anti,” so all told, it sounds like the name figuratively says “anti-SARS-CoV-2 antibody.” A good name!

I found that extremely interesting and hope you did too. Let’s move on with our comparison. These next two paragraphs are taken directly from the Fact Sheets referenced above:

“Bamlanivimab and etesevimab are different in their mechanisms of action. Bamlanivimab is a recombinant neutralizing human IgG1κ monoclonal antibody (mAb) to the spike protein of SARS-CoV-2 and is unmodified in the Fc region. Bamlanivimab binds the spike protein with a dissociation constant KD = 0.071 nM and blocks spike protein attachment to the human ACE2 receptor with an IC50 value of 0.17 nM (0.025 μg/mL). Meanwhile, etesevimab is a recombinant neutralizing human IgG1κ mAb to the spike protein of SARS-CoV-2, with amino acid substitutions in the Fc region (L234A, L235A) to reduce effector function. Etesevimab binds the spike protein with a dissociation constant KD = 6.45 nM and blocks spike protein attachment to the human ACE2 receptor with an IC50 value of 0.32 nM (0.046 μg/mL).

Bamlanivimab and etesevimab bind to different but overlapping epitopes in the receptor binding domain (RBD) of the S-protein. Using both antibodies together is expected to reduce the risk of viral resistance.”

The EUA Criteria for bamlanivimab monotherapy are the same as for bamlanivimab-etesevimab combotherapy. Here are the details captured from the bamlanivimab-etesevimab Fact Sheet for Healthcare Providers. Of note the EUAs do not allow use in patients hospitalized for COVID-19, but the products may be given to patients hospitalized for reasons other than COVID-19. Both products should be given as soon as possible after symptom onset if the other necessary criteria are met.

The following is a brief table contrasting the two therapies. Note how there are few differences…

Item	Bamlanivimab	Bamlanivimab + Etesevimab
Investigational Names	LY3819253 or LY-CoV555	LY3819253 or LY-CoV555 + LY3832479 or LY-CoV016
Brand Name	None (yet)	None (yet)
Date of EUA Approval	11/9/2020	2/9/2021
Date EUA Revoked	4/16/2021	EUA Still Active
EUA Criteria	Same, see EUA	Same, see EUA
Dose EUA Approved	700 mg	700 mg + 1400 mg
Number of Drug Vials	1 vial	1 vial + 2 vials
Drug volume	20 mL	20 mL + 40 mL
Lowest Total Volume	70 mL	110 mL
Fastest Infusion Rate	270 mL/hr	310 mL/hr
Fastest Infusion Time	16 minutes	21 minutes
Expiration Room Temp (including infusion time)	7 hours	7 hours
Expiration Refrigerated (including infusion time)	24 hours	24 hours
Diluent	NS only	NS only
Post-Infusion Monitoring	1-hour	1-hour
Listed Potential Infusion-Related Reactions	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, dizziness, and diaphoresis	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, dizziness and diaphoresis.
FDA MedWatch Reporting of Serious Adverse Events	Required	Required
Patient Fact Sheet	Required	Required

Variant Considerations (section added 3/24/2021)

You can access the information for activity versus the different variants in the Fact Sheet for Healthcare Providers for each of the below products available here. Variant prevalence in the US and by state is available here. NIH COVID-19 Guideline recommendations are here, low-level and high-level designation are used here for simplicity sake.

	Bamlanivimab	Bamlanivimab + Etesevimab	Cariviumab + Imdevimab	Rate in US (3/13/2021)
Manufacturer	Eli Lilly	Eli Lilly	Regeneron	–
Variant B.1.1.7 (UK origin)	Effective	Effective	Effective	9.5%
Variant B.1.351 (S. African origin)	Ineffective	Ineffective	Effective	0.4%
Variant P.1 (Brazil origin)	Ineffective	Ineffective	Effective	0.1%
Variant B.1.347/B.1.429 (California origin)	Ineffective	Reduced Efficacy	Effective	9.1%
Variant B.1526 (New York origin)	Ineffective	Reduced Efficacy	Effective	3.4%
NIH Guideline Recommendation	Low-Level	High-Level	Low-Level	–
Shipping in US as of 3/24/2021	No	Yes	Yes	–

Quick Clinical Data Review

March 2021
- NIH COVID-19 Guideline Statement:
  - “The EUA for bamlanivimab plus etesevimab for the treatment of outpatients with mild to moderate COVID-19 who are at high risk of progressing to severe COVID-19 and/or hospitalization is based on data from several studies, including the Blocking Viral Attachment and Cell Entry With SARS-CoV-2 Neutralizing Antibodies (BLAZE)-1 and BLAZE-4 trials. In particular, the supporting data is from BLAZE-1, a Phase 3 trial that included more than 1,000 randomized high-risk participants with almost 50 primary outcome clinical events (i.e, hospitalization or death). The number of clinical events reported for this study supporting the EUA for bamlanivimab plus etesevimab is greater than that currently reported for Phase 2 studies of bamlanivimab monotherapy or the casirivimab plus imdevimab combination (see here). Furthermore, the clinical events reported in the bamlanivimab monotherapy and the casirivimab plus imdevimab studies included emergency department visits, as well as hospitalizations and deaths. Based on the larger sample size and greater number of clinical events in the BLAZE-1 Phase 3 trial, the Panel has greater confidence in the currently available evidence for the clinical efficacy of the bamlanivimab plus etesevimab combination than in the evidence for the other monoclonal antibody options. For this reason, when available, bamlanivimab plus etesevimab should be used for high-risk outpatients according to the EUA. The Panel’s recommendations on the use of bamlanivimab monotherapy and casirivimab plus imdevimab can be found here.”
- Details from CROI provided by Dr. Paul Sax’s NEJM Journal Watch blog post. Registration is needed to access the details.
  - A single infusion of bamlanivimab and etesevimab given to outpatients with COVID-19 at high risk for severe disease reduced the risk of clinical progression (hospitalization or death). There were no deaths in the treatment arm, 10 in placebo. Viral load decline and clinical recovery were also faster with treatment.
  - Banlanivimab was effective in preventing COVID-19 in skilled nursing facilities. Those who did get COVID-19 despite treatment had lower viral loads and more rapid resolution of symptoms compared to the placebo group. While vaccination will undoubtedly be the mainstay of preventive strategies for COVID-19, in certain settings monoclonal antibodies may have a role.
- ACTIV-3/TICO LY-CoV555 Study Group. A Neutralizing Monoclonal Antibody for Hospitalized Patients with Covid-19. N Engl J Med 2021; 384:905-914.
  - Monoclonal antibody LY-CoV555, when coadministered with remdesivir, did not demonstrate efficacy among hospitalized patients who had Covid-19 without end-organ failure.
January 2021
- Gottlieb RL, et al. Effect of Bamlanivimab as Monotherapy or in Combination With Etesevimab on Viral Load in Patients With Mild to Moderate COVID-19A Randomized Clinical Trial. JAMA. 2021; 325 (7): 632-644. (BLAZE-1 data)
  - In the phase 2 portion of a randomized phase 2/3 clinical trial with 577 patients, there was no significant difference in change in viral load with 3 different doses of bamlanivimab monotherapy compared with placebo; treatment with a combination of bamlanivimab and etesevimab significantly decreased SARS-CoV-2 log viral load at day 11 compared with placebo (between-group difference, –0.57 [95% CI, –1.00 to –0.14], P = .01).
- Chen P, et al. SARS-CoV-2 Neutralizing Antibody LY-CoV555 in Outpatients with Covid-19. N Engl J Med 2021; 384:229-237. (BLAZE-1 data)
  - In this interim analysis of a phase 2 trial, one of three doses of neutralizing antibody LY-CoV555 appeared to accelerate the natural decline in viral load over time, whereas the other doses had not by day 11.

There are several news releases from Lilly, but those should be interpreted with caution until full data sets are available.

Closing Comments

To close out, it may be helpful to know that HHS has published this COVID antibody locator for people seeking access to therapy.

Additionally, the NIH COVID-19 Guideline is an excellent resource for discussion on the place of bamlanivimab monotherapy and bamlanivimab-etesevimab combotherapy for COVID-19.

Disclosures: The views and opinions expressed in this article are those of the author and do not necessarily reflect the policy or opinions of any previous, current, or potential future employer.

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