What data is available regarding bamlanivimab? How effective and what patient population did the studies target?

Comment by InpharmD Researcher

As of November 10, 2020, only a phase II interim analysis has been published on bamlanivimab [Table 1]. The EUA for bamlanivimab states it is only to be used in patients 12 years of age and older weighing at least 40 kg, and who are at high risk for progressing to severe COVID-19 and/or hospitalization. Bamlanivimab is NOT authorized to be used in hospitalized patients or those who require oxygen therapy due to COVID-19. Interim results of a phase II trial included non-hospitalized patients with mild-to-moderate COVID-19 symptoms and had a positive test within 3 days of starting bamlanivimab. Patients included in the ongoing phase III trial include residents or staff in skilled nursing or assisted living facilities with at least one confirmed case of direct SARS-CoV-2 detection within 7 days.
Background

On November 9, 2020, the U.S. Food and Drug Administration (FDA) issued an emergency use authorization (EUA) to Eli Lilly for bamlanivimab (LY-CoV555), an investigational monoclonal antibody therapy, for the treatment of mild to moderate COVID-19 in adult and pediatric patients 12 years or older weighing at least 40 kg and who are at high risk for progressing to severe COVID-19 and/or hospitalization. Monoclonal antibodies could potentially be associated with worsening outcomes when used in hospitalized patients with severe COVID-19, therefore bamlanivimab is not authorized for use in patients that have already been hospitalized or require oxygen therapy due to COVID-19. Bamlanivimab must be administered as a single dose intravenously by trained healthcare providers. [1], [2]

Prior to the FDA issuance of EUA, Eli Lilly company has conducted a randomized, double-blind, placebo-controlled, phase II study, BLAZE-1, to evaluate the efficacy and safety of bamlanivimab alone or in combination with a second antibody for the treatment of outpatient COVID-19. Included patients were not hospitalized, had symptoms of mild or moderate COVID-19, and confirmed positive for SARS-CoV-2 within 3 days. Patients were to be given bamlanivimab 700 mg, 2,800 mg, 7,000 mg, or placebo. The primary outcome of this study is the change from baseline to day 11 in the SARS-CoV-2 viral load. The data from this interim analysis has been published with promising results [Table 1]. A phase III study, BLAZE-2, is also ongoing with the hope of using bamlanivimab as prevention of COVID-19 in long-term care facilities. [3], [4]

A phase III randomized, double-blind, placebo-controlled trial (BLAZE-2) is currently being conducted with 2,400 enrolled participants. This study is looking to evaluate whether bamlanivimab can prevent SARS-CoV-2 infection and COVID-19 in residents and staff in skilled nursing or assisted living facilities. Inclusion criteria includes resident or staff in skilled nursing or assisted living facilities with at least one confirmed case of direct SARS-CoV-2 detection ≤7 days and men or non-pregnant women. Exclusion criteria include a history of confirmed COVID-19 and previously treated with monoclonal antibodies or received an investigational vaccine. Participants are randomized to receive either bamlanivimab IV or placebo. The primary outcome is the percentage of participants with SARS-CoV-2 infection. The primary outcome is estimated to complete by March 8, 2021, with the overall study estimated to be completed by June 29, 2021. [5]

References:

[1] Food and Drug Administration. Bamlanivimab Emergency Use Authorization. https://www.fda.gov/media/143602/download. Published November 10, 2020. Accessed November 10, 2020.
[2] Food and Drug Administration. FACT SHEET FOR HEALTH CARE PROVIDERS EMERGENCY USE AUTHORIZATION (EUA) OF BAMLANIVIMAB https://www.fda.gov/media/143603/download. Published November 10, 2020. Accessed November 10, 2020.
[3] Lilly. Lilly’s neutralizing antibody bamlanivimab (LY-CoV555) receives FDA emergency use authorization for the treatment of recently diagnosed COVID-19. https://investor.lilly.com/news-releases/news-release-details/lillys-neutralizing-antibody-bamlanivimab-ly-cov555-receives-fda. Updated November 9, 2020. Accessed November 10, 2020.
[4] Chen P, Nirula A, Heller B, et al. SARS-CoV-2 Neutralizing Antibody LY-CoV555 in Outpatients with Covid-19 [published online ahead of print, 2020 Oct 28]. N Engl J Med. 2020;10.1056/NEJMoa2029849. doi:10.1056/NEJMoa2029849
[5] Clinicaltrials.gov. A Study of LY3819253 (LY-CoV555) in Preventing SARS-CoV-2 Infection and COVID-19 in Nursing Home Residents and Staff (BLAZE-2). https://www.clinicaltrials.gov/ct2/show/NCT04497987. Updated November 10, 2020. Accessed November 10, 2020.
Literature Review

A search of the published medical literature revealed 1 study investigating the researchable question:

What data is available regarding bamlanivimab? How effective and what patient population did the studies target?

Please see Table 1 for your response.

 

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)

Methods

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

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. 

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

Interim analysis primary outcome: changes from baseline in the viral load at day 11

Interim analysis secondary outcomes: changes from baseline in viral load at day 3 and at day 7; incidence of hospitalization

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

Endpoint

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.



References:

Chen P, Nirula A, Heller B, et al. SARS-CoV-2 Neutralizing Antibody LY-CoV555 in Outpatients with Covid-19 [published online ahead of print, 2020 Oct 28]. N Engl J Med. 2020;10.1056/NEJMoa2029849. doi:10.1056/NEJMoa2029849