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What data/studies have been published to support the use of bamlanivimab and etesevimab?

Comment by InpharmD Researcher

Results from the interim phase II cohort of the BLAZE-1 study suggest the combination of bamlanivimab and etesevimab significantly reduces SARS-CoV-2 viral load after 11 days compared to placebo. Unpublished, ongoing data from the phase III cohort of BLAZE-1 suggest the combination antibody therapy leads to a 87% risk reduction compared to placebo. Bamlanivimab and etesevimab therapy is only recommended for use in outpatients with mild to moderate COVID-19 who are at high risk of clinical progression.
Background

Per COVID-19 guidelines from the National Institutes of Health (NIH), bamlanivimab 700 mg plus etesevimab 1,400 mg is recommended for the treatment of outpatients with mild to moderate COVID-19 who are at high risk of clinical progression as defined by the emergency use authorization criteria. Treatment should be started as soon as possible after the patient has received a positive result on a SARS-CoV-2 antigen or nucleic acid amplification test and within 10 days of symptom onset. The combination of bamlanivimab and etesevimab should NOT be used in patients who are hospitalized due to COVID-19, except in the setting of a clinical trial. Notably, the recommended doses are lower than the doses used in the BLAZE-1 phase III study. Additionally, laboratory data suggests bamlanivimab and etesevimab have activity against the SARS-CoV-2 B.1.1.7 variant (UK variant) but have markedly reduced activity against the B.1.351 variant (South Africa variant). [1]

These recommendations are based on data from the BLAZE-1 trial [Table 1]; however, data from the full phase 3 version of this study have not yet been published. A press release from Lilly, the manufacturer of bamlanivimab and etesevimab, revealed that the combination antibody therapy resulted in four events (0.78%) compared to 15 events in the placebo group (5.8%), representing an 87% risk reduction (P<0.0001). Bamlanivimab and etesevimab together also demonstrated statistically significant improvements on key secondary endpoints of change from baseline to day 7 in SARS-CoV-2 viral load, persistently high SARS-CoV-2 viral load on day 7, time to sustained symptom resolution, and COVID-related hospitalization, ER visit or death from any cause from baseline by day 29. In the new phase III cohort, there were four total deaths due to COVID-19, all of which were in the placebo group. Across the two Phase 3 cohorts of the study that have been analyzed to date, there have been no deaths in patients receiving treatment with bamlanivimab and etesevimab together and 14 deaths in patients receiving placebo. [1-2]

A clinical review of bamlanivimab, etesevimab, and 12 other monoclonal antibodies (mAb) describes each mAb in terms of background, mechanism of action, and clinical trial findings. The authors reviewed bamlanivimab (LY-CoV555) and etesevimab (LY-CoV016) together since Eli Lilly designed etesevimab in hopes of synergizing with bamlanivimab. This review describes bamlanivimab as a recombinant, fully human neutralizing IgG1 mAb which has a high affinity for the receptor-binding domain on the SARS-Cov-2 spike protein. Whereas, etesevimab is a recombinant neutralizing IgG1 mAb that targets a different spike epitope. [3]

References:

[1] National Institutes of Health. COVID-19 Treatment Guidelines Panel. Coronavirus Disease 2019 (COVID-19) Treatment Guidelines. Available at https://www.covid19treatmentguidelines.nih.gov/. Updated March 5, 2021. Accessed March 17, 2021.
[2] Eli Lilly and Company. Lilly's bamlanivimab and etesevimab together reduced hospitalizations and death in Phase 3 trial for early COVID-19. https://investor.lilly.com/news-releases/news-release-details/lillys-bamlanivimab-and-etesevimab-together-reduced. Updated March 10, 2021. Accessed March 17, 2021.
[3] Tuccori M, Ferraro S, Convertino I, et al. Anti-SARS-CoV-2 neutralizing monoclonal antibodies: clinical pipeline. mAbs. 2020;12(1):1854149. doi: 10.1080/19420862.2020.1854149

Relevant Prescribing Information

The U.S. Food and Drug Administration (FDA) has issued an Emergency Use Authorization (EUA) to permit the emergency use of the unapproved products bamlanivimab and etesevimab administered together 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.

Bamlanivimab and etesevimab are not authorized for use in patients: who are hospitalized due to COVID-19; 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.

High risk is defined as patients who meet at least one of the following criteria: 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.

Additional high risk criteria for adolescents 12-17 years include: BMI ≥85th percentile for their age and gender-based on CDC growth charts; sickle cell disease; congenital or acquired heart disease; neurodevelopmental disorders, for example, cerebral palsy; 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. [4-5]

References:

[4] Bamlanivimab [prescribing information]. Indianapolis, IN: Eli Lilly and Company; February 2021.
[5] Etesevimab [prescribing information]. Indianapolis, IN: Eli Lilly and Company; February 2021.

Literature Review

A search of the published medical literature revealed 2 studies investigating the researchable question:

What data/studies have been published to support the use of bamlanivimab and etesevimab?

Please see Tables 1-2 for your response.


 

Effect of Bamlanivimab as Monotherapy or in Combination With Etesevimab on Viral Load in Patients With Mild to Moderate COVID-19: A Randomized Clinical Trial

Design

Ongoing, multipart, phase 2/3, randomized, double-blind, placebo-controlled, single-infusion study

N=592

Objective

To determine the effect of bamlanivimab monotherapy and combination therapy with bamlanivimab and etesevimab on severe acute respiratory syndrome coronavirus 2(SARS-CoV-2) viral load in mild to moderate COVID-19

Study Groups

Part I: 

  • Bamlanivimab (n=317) 
    • 700 mg (n=104)
    • 2,800 mg (n=109)
    • 7,000 mg (n=104)
  • Placebo (n=161)

Part II

  • Bamlanivimab and etesevimab (n=114)
  • Placebo (n=161)

Inclusion Criteria

Age ≥18 years, positive SARS-CoV2- infection, 1 or more mild to moderate symptoms, presented within 3 days of their first positive test result

Exclusion Criteria

SpO2 ≤93% on room air, mechanial ventilation, vasopressor within 24 hours of randomization, serious concomitant systemic diseases, previous use of monoclonal antibody for SARS-CoV2

Methods

Part I of the trial consisted of bamlanivimab monotherapy or placeb followed by Part II with combination therapy of bamlanivimab and etesevimab or placebo. 

Treatment was administered within 3 days of first positive SARS-CoV2 test. Doses for bamlanivam included 700 mg, 2,800 mg, and 7,000 mg. Doses for combination therapy with bamlanivimab and etesevimab were both 2,800 mg. All doses were administered as a single, 1 hour intravenous infusion. 

Duration

Part I: June 17 to August 21, 2020

Part II: August 22 to September 3, 2020

Outcome Measures

Primary endpoint: change in SARS-CoV-2 log viral load at day 11 ± 4 days

Secondary endpoints:

  • viral load (viral clearance at days 7, 11, 15, and 22; viral load area under the curve [AUC] at day 29)
  • symptoms (total symptom score, time to symptom improvement, time to symptom resolution at days 7, 11, 15, and 22)
  • COVID-19–related hospitalization, emergency department visit, or death at day 29

Baseline Characteristics

 

Bamlanivimab

700 mg (n=101)

Bamlanivimab

2,800 mg (n=107)

Bamlanivimab 

7,000 mg (n=101)

Bamlanivimab and etesevimab 

(n=112)

Placebo

(n=156)

Age, years (IQR)

39 (31-58) 45 (31-56) 46 (34-55) 44 (30-60) 46 (35-57)

Female

63 (62.4%) 51 (47.7%) 58 (57.4%) 58 (51.8%) 85 (54.5%)

White

90 (89.1%)    90 (86.5%) 89 (89.0%) 105 (94.6%) 133 (88.1%)

BMI, kg/m2 (IQR)

28.8 (25.1-35.4) 30.4 (25.6-34.0) 27.8 (24.7-32.3) 27.2 (22.9-33.0) 29.2 (25.9-34.2)

Risk factors for severe COVID-19*

74 (73.3%) 78 (72.9%) 63 (62.4% ) 67 (59.8%) 105 (67.3%)

COVID-19 severity

Mild

Moderate

 

83 (82.2%)

18 (17.8%)

 

79 (73.8%)

28 (26.2%)

 

70 (69.3%)

31 (30.7%)

 

92 (82.1%)

20 (17.9%)

 

125 (80.1%)

31 (19.9%)

Duration of symptoms, days (IQR)

5 (3-6)

4 (3-6)

4 (2-7)

4 (3-5)

4 (3-6)

IQR=interquartile range; BMI=body mass index

*Risk factors include: age ≥55 years; BMI of ≥30; a medical history of diabetes, chronic kidney disease, cardiovascular disease, chronic respiratory disease, or immunosuppressive disease; or receiving immunosuppressive treatment

Results

 

Bamlanivimab

700 mg (n=101)

Bamlanivimab

2,800 mg (n=107)

Bamlanivimab 

7,000 mg (n=101)

Bamlanivimab and etesevimab

(n=112)

Placebo

(n=156)

Change in Log Viral Load at day 11 

-3.72  -4.08 -3.49 -4.37* -3.80

Viral load AUC at day 29

70.17 63.74* 71.53 61.69* 74.45

Viral clearance

Day 7

Day 11

Day 15

Day 22

 

10 (9.9%)

13 (12.9%)

25 (24.8%)

41 (40.6%)

 

12 (11.2%)

21 (19.6%)

30 (28.0%)

43 (40.2%)

 

8 (7.9%)

14 (13.9%)

25 (24.8%)

37 (36.6%)

 

14 (12.8%)

30 (27.5%)

36 (33.0%)

40 (36.7%)

 

16 (10.5%)

27 (17.8%)

34 (22.4%)

56 (36.8%)

COVID-19–related hospitalization
or emergency department visit at day 29

1 (1.0%)

2 (1.9%)

2 (2.0%)

1 (0.9%)*

9 (5.8%)

Total symptom score

Day 7

Day 11

Day 15

Day 22

 

1.90 ± 2.49

1.06 ± 1.58*

1.00 ± 2.25

0.46 ± 1.16

 

2.07 ± 2.93

1.59 ± 2.24

1.20 ± 2.03

0.74 ± 1.67

 

2.22 ± 2.97

1.56 ± 2.61

1.00 ± 2.07

0.71 ± 1.54

 

2.14 ± 2.98

1.28 ± 2.48*

1.04 ± 2.43

0.76 ± 2.00

 

2.43 ± 2.67

1.88 ± 2.50

1.24 ± 2.05

0.77 ± 1.67

Symptom improvement

Day 7

Day 11

Day 15

Day 22

 

47 (46.5%)

60 (59.4%)*

63 (62.4%)

70 (69.3%)

 

37 (34.6%)

48 (44.9%)

63 (58.9%)

69 (64.5%)

 

46 (45.5%)

59 (58.4%)*

69 (68.3%)*

71 (70.3%)

 

50 (45.9%)

58 (53.2%)

69 (63.3%)

78 (71.6%)

 

62 (40.8%)

66 (43.4%)

83 (54.6%)

96 (63.2%)

Symptom resolution

Day 7

Day 11

Day 15

Day 22

 

37 (36.6%)

51 (50.5%)*

56 (55.4%)

68 (67.3%)

 

33 (30.8%)

43 (40.2%)

59 (55.1%)

63 (58.9%)

 

34 (33.7%)

44 (43.6%)

60 (59.4%)*

62 (61.4%)

 

38 (34.9%)

50 (45.9%)

63 (57.8%)

75 (68.8%)

 

48 (31.6%)

56 (36.8%)

70 (46.1%)

88 (57.9%)

AUC=area under the curve

*significant difference vs placebo with at least p<0.05

Adverse Events

Common Adverse Events:

Nausea (3 [3%] vs 4 [3.7%] vs 5 [5.0%] vs 4 [3.6%] vs 6 [3.8%]);

Diarrhea (1 [1.0%] vs 2 [1.9%] vs 6 [5.9%] vs 1 [0.9%] vs 7 [4.5%])

Dizziness (3 [3%] vs 3 [2.8%] vs 3 [3.0%] vs 1 [0.9%] vs 3 [1.9%])

Serious Adverse Events:

Urinary tract infection: bamlanivimab and etesevimab combination 1 [0.9%]

Upper abdominal pain: placebo 1 [0.6%]

Study Author Conclusions

Among nonhospitalized patients with mild to moderate COVID-19 illness, treatment with bamlanivimab and etesevimab, compared with placebo, was associated with a statistically significant reduction in SARS-CoV-2 viral load at day 11; no significant difference in viral load reduction was observed for bamlanivimab monotherapy

InpharmD Researcher Critique

Only a single dose of bamlanivimab and etesevimab 2,800 mg was used in the study. It is difficult to assess the efficacy of treatment using the primary endpoint of viral load at day 11 as the body's natural immune response during this stage may have been the predominant factor in reducing viral load. Instead, a more clinical endpoint (e.g., symptom resolution) should have been chosen at an earlier time point (e.g., day 3 or day 7 post-treatment).



References:

Gottlieb RL, Nirula A, Chen P, et al. Effect of Bamlanivimab as Monotherapy or in Combination With Etesevimab on Viral Load in Patients With Mild to Moderate COVID-19: A Randomized Clinical Trial. JAMA. 2021;325(7):632-644. doi:10.1001/jama.2021.0202

 

SARS-CoV-2 Neutralizing Antibody LY-CoV555 in Outpatients with Covid-19

Design

Interim-analysis of a prospective, randomized, phase II, double-blind, placebo-controlled, single-dose study

N=452

Objective

To evaluate the efficacy and safety of LY-CoV555 (bamlanivimab) in patients with recently diagnosed mild or moderate COVID-19 in the outpatient setting

Study Groups

LY-CoV555 (n=309)

  • 700 mg (n=101)
  • 2,800 mg (n=107)
  • 7,000 mg (n=101)

Placebo (n=143)

Inclusion Criteria

≥18 years of age, not hospitalized, had  one or more mild or moderate COVID-19 symptoms (fever, cough, sore throat, malaise, headache, muscle pain, gastrointestinal symptoms, or shortness of breath with exertion), a nasopharyngeal sample for positive SARS-CoV-2 viral infection determination ≤3 days before the start of the infusion, men or non-pregnant women agreeing to use contraception

Exclusion Criteria

SpO2 ≤93%, PaO2/FiO2 <300, respiratory rate ≥30 per minute, heart rate ≥125 bpm, required mechanical ventilation or anticipated impending need for mechanical ventilation, hemodynamic unstable, suspected or proven serious infection of any kind, unstable comorbidities, history of a positive SARS-CoV-2 serology test, history of positive SARS-CoV-2 test, previously received an investigational intervention for SARS-CoV-2, history of convalescent COVID-19 plasma treatment, breastfeeding

Methods

Patients were randomized to receive a single intravenous infusion of neutralizing antibody bamlanivimab in one of three doses (700 mg, 2,800 mg, or 7,000 mg) or placebo. Patients were defined to have moderate symptoms if they presented with shortness of breath OR respiratory rate ≥20 breaths/min plus pulse ≥95 beats/min. All other symptomatic patients were deemed to have mild severity.

The preplanned interim analysis started after the last patient received LY-CoV555 reached day 11. Virologic features and symptoms data were collected up to day 29 of the trial. 

Duration

Interim analysis follow-up: 29 days

Trial protocol follow-up: 85 days; assessment at day 29; follow-up at day 60 and day 85

Outcome Measures

Primary: Change from baseline in the SARS-CoV-2 viral load at day 11 (±4 days) after positive results on testing

Secondary: Safety, symptom severity, hospitalization, and time points for viral clearance

Baseline Characteristics

 

Bamlanivimab (n=309)

Placebo (n=143)

 

Age, years (range)

>65 years

45 (18-86)

33 (10.7%)

46 (18-77)

20 (14.0%)

 

Female

171 (55.3%) 78 (54.5%)   

Race

White

Hispanic/Latino

Black

 

269/305 (88.2%)

135/309 (43.7%)

22/305 (7.2%)

 

120/138 (87.0%)

63/143 (44.1%)

7/138 (5.1%)

 

BMI, kg/m2

≥30 to <40

≥40

29.4

112/304 (36.8%)

24/304 (7.9%) 

29.1

56/139 (40.3%)

9/139 (6.5%) 

 

Risk factors for severe Covid-19

215 (69.6%)

95 (66.4%)

 

Covid-19 status

Mild

Moderate

 

232 (75.1%)

77 (24.9%)

 

113 (79.0%)

30 (21.0%)

 

Median days since onset of symptoms

4

4

 

Mean viral load, Ct value

23.9

23.8

 

Results

 

Bamlanivimab (n=309)

Placebo (n=143)

Difference (95%CI)

Mean change from baseline in viral load at day 11

700 mg (n=101): -3.67

2,800 mg (n=107): -4.00

7,000 mg (n=101): -3.38

-3.47 

-0.20 (-0.66 to 0.25)

-0.53 (-0.98 to -0.08)

+0.09 (-0.37 to 0.55)

Mean change from baseline in viral load at day 7

700 mg (n=101): -2.82

2,800 mg (n=107): -3.01

7,000 mg (n=101): -2.85

-2.56

-0.42 (-0.89 to 0.06)

-0.64 (-1.11 to -0.17)

-0.42 (-0.90 to 0.06)

Mean change from baseline in viral load at day 3

700 mg (n=101): -1.27

2,800 mg (n=107): -1.50

7,000 mg (n=101): -1.27

-0.85 

-0.25 (-0.73 to 0.23)

-0.45 (-0.92 to 0.03)

-0.28 (-0.77 to 0.20)

Hospitalization related to COVID-19 by day 29

5 (1.6%)

700 mg (n=101): 1 (1.0%)

2,800 mg (n=107): 2 (2.0%)

7,000 mg (n=101): 2 (2.0%)

9 (6.3%) ---

Patients with a higher viral load on day 7 had a higher rate of hospitalization than those with a better clearance of viral RNA on day 7, a finding that is consistent with previous studies suggesting that delayed viral clearance is associated with more severe disease.

Adverse Events

Common Adverse Events: Nausea (3.9%), diarrhea (3.2%), dizziness (3.2%), headache (1.6%), pruritus (1.6%), vomiting (1.6%), chills (1.3%), pyrexia (1.3%), chest discomfort (1.0%), fatigue (1.0%), hypertension (1.0%), lipase increased (1.0%), thrombocytosis (1.0%)

Serious Adverse Events: 0%

Percentage that Discontinued due to Adverse Events: 0%

Study Author Conclusions

The safety profile of patients who received bamlanivimab was similar to that of placebo-treated patients. Although the differences in the effects of the three doses of bamlanivimab were not clear, the 2,800 mg dose was the only one to show evidence of accelerated viral clearance. Patients receiving bamlanivimab also had fewer hospitalizations and a lower symptom burden than those who received placebo, with the most pronounced effects observed in high-risk cohorts. 

InpharmD Researcher Critique

Strengths of this study include the placebo-controlled and double-blinded design. Limitations include the fact that this is an interim analysis and the primary outcome is a surrogate endpoint; however, the key secondary endpoint of hospitalization favorably associated with the lower viral load. Additionally, viral samples were nasopharyngeal instead of bronchial; however, it can be argued that nasopharyngeal swabs may be appropriate in these patients.

The study only found a lower viral load with bamlanivimab than placebo at the 2800 mg dose with 11 days. This does not appear to be clinically meaningful, since viral load became substantially reduced from baseline in the majority of patients including placebo by day 11. Earlier treatment time points showed no substantial differences among the 3 doses. However, the study did find the drug to be safe with fewer hospitalizations and lower symptom burden than placebo which could be beneficial for emergency use in high-risk patients with COVID-19.

 

References:

Chen P, Nirula A, Heller B, et al. SARS-CoV-2 Neutralizing Antibody LY-CoV555 in Outpatients with Covid-19. N Engl J Med. 2021;384(3):229-237. doi:10.1056/NEJMoa2029849


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