MONOCLONAL ANTIBODIES - A REVIEW OF PERTINENT DRUG INFORMATION FOR SARS-COV-2 JESSICA ORTWINE, PHARMD, BCIDP - SOCIETY OF INFECTIOUS DISEASES ...
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Monoclonal Antibodies
A Review of Pertinent Drug Information for SARS-CoV-2
Jessica Ortwine, PharmD, BCIDP
Clinical Pharmacy Specialist, Parkland Health & Hospital System
jessica.ortwine@phhs.org
@jkortwine
Data as of January 13, 2021
Adaptive Immunity
• Active immunity: seroconversion occurs within 1-3 weeks of
COVID-19 symptom onset
• Passive immunity: direct administration of monoclonal antibodies
(mAb) or convalescent plasma
• Benefit of mAb: target specific viral epitopes and domains, mass
produced, administered in a specified quantity, no reliance on donors
Zhao J, et al. Clin Infect Dis. 2020;71:2027-34. https://doi.org/10.1093/cid/ciaa344
Mechanism of Action
• Monoclonal antibodies prevent and possibly treat COVID-19 via
multiple effector functions
• Antibody-mediated neutralization of pathogen
• Antibody-dependent cellular cytotoxicity
• Antibody-dependent cellular phagocytosis
Lu LL, et al. Nat Rev Immunol. 2018;18:46-61. https://doi.org/10.1038/nri.2017.106
Mechanism of Action
• Spike (S) protein essential for:
• Viral attachment to host receptor (S1)
• Virus-cell fusion (S2)
• Monoclonal antibodies (mAbs) bind to
receptor binding domain (RBD) of S
protein
• Block viral entry into host cells
Jiang S, et al. Trends Immunol. 2020;41:355-9. https://doi.org/10.1016/j.it.2020.03.007
Eli Lilly – Bamlanivimab
Alternate Names: LY3819253
LY-CoV555
Bamlanivimab – In vitro Activity
• Greater neutralization potency
than other RBD-binding, ACE2- Neutralization Potency
blocking antibody finalists,
despite similar binding affinities
• Ability to bind to RBD in both
“up” and “down” conformations
may account for increased
neutralization activity
Jones BE, et al. bioRxiv [Preprint]. 2020. https://doi.org/10.1101/2020.09.30.318972
In vivo Animal Data R he s us M acaque
Prophylaxis
Methods Antibody administered intravenously 1 day prior to viral challenge
Viral Inoculum 1.1 x 105 PFU
1 mg/kg (N=4)
2.5 mg/kg (N=4)
Antibody Doses 15 mg/kg (N=3)
50 mg/kg (N=3)
Control (N=4)
Lower respiratory tract (LRT): Nasal swab, throat swab
Sample Types
Upper respiratory tract (URT): BAL, lung tissue
Outcomes Change in viral load (gRNA and sgRNA)
Jones BE, et al. bioRxiv [Preprint]. 2020. https://doi.org/10.1101/2020.09.30.318972
In vivo Animal Data R he s us M acaque
Key Findings
• Reduced viral concentrations and
replication on day 1 in all BAL and most
LRT samples
• Viral replication undetectable in all
locations by day 3 at most doses
Jones BE, et al. bioRxiv [Preprint]. 2020. https://doi.org/10.1101/2020.09.30.318972
Clinical Trials
Trial Name Status
NCT04427501 A randomized, double-blind, placebo-controlled, phase 2 study to evaluate the efficacy and safety of LY3819253 and Recruiting – some
LY3832479 in participants with mild to moderate COVID-19 illness (BLAZE-1) results available
NCT04497987 A phase 3 randomized, double-blind, placebo-controlled trial to evaluate the efficacy and safety of LY3819253 in Recruiting
preventing SARS-CoV-2 infection and COVID-19 in skilled nursing and assisted living facility residents and staff
(BLAZE-2)
NCT04634409 A randomized, double-blind, placebo-controlled, phase 2 study to evaluate the efficacy and safety of mono and Recruiting
combination therapy with monoclonal antibodies in participants with mild to moderate COVID-19 illness (BLAZE-4)
NCT04701658 A prospective cohort study to evaluate the real-world effectiveness of bamlanivimab in participants with mild-to- Not yet recruiting
moderate COVID-19 at high risk for progressing to severe illness, with matched controls (BLAZE-5)
NCT04518410 Adaptive platform treatment trial for outpatients with COVID-19 (ACTIV-2) Recruiting
NCT04501978 A multicenter, adaptive, randomized, blinded controlled trial of the safety and efficacy of investigational therapeutics Halted – results
for hospitalized patients with COVID-19 (ACTIV-3) available
Source: https://clinicaltrials.gov
Ambulatory Treatment BLAZE-1
Study Design Treatment Groups Outcomes
• Phase 2, double-blind RCT • Part A: LY-CoV555 • Primary:
• Non-hospitalized adults monotherapy • Change from baseline viral
load at day 11 (± 4 days)
• 7000 mg IV x 1 from positive results
• ≥ 1 mild/moderate COVID- • 2800 mg IV x 1
19 symptom • Secondary:
• 700 mg IV x 1
• Safety
• 1st positive SARS-CoV-2 • Placebo • Symptom burden
test ≤ 72 hours from start • Part B & C: LY-CoV555 + • Clinical outcomes (eg.
of infusion LY-CoV016 combination COVID-19 related in-patient
hospitalization, ED visit, or
• High risk for complications • 2800 mg/2800 mg IV x 1 death)
(Part C only) • Placebo • Viral clearance
• Antibody pharmacokinetics
Chen P, et al. N Engl J Med. 2020. [Epub ahead of print]. https://doi.org/10.1056/NEJMoa2029849Ambulatory Treatment LY - C o V 5 5 5 M o n o t h e r a p y
Characteristic Ly-CoV555 (N=309) Placebo (N=143)
Ly-CoV555 dosing:
Age (years), median (range) 45 (18-86) 46 (18-77)
≥ 65, n (%) 33 (10.7) 20 (14.0) • 700 mg (N=101)
Body-mass index (kg/m2), median 29.4 29.1 • 2800 mg (N=107)
≥ 30 to < 40, n/total (%) 112/304 (36.8) 56/139 (40.3) • 7000 mg (N=101)
≥ 40, no/total (%) 24/304 (7.9) 9/139 (6.5)
Risk factors for severe COVID-19, n(%) 215 (69.6) 95 (66.4)
Disease status, n(%) Risk factors for severe disease:
Mild 232 (75.1) 113 (79.0)
• Age ≥ 65 years
Moderate 77 (24.9) 30 (21.0)
• BMI ≥ 35 kg/m2
Days since symptom onset, median 4.0 4.0
• Prespecified coexisting illness
Viral load (cycle threshold), mean 23.9 23.8
Chen P, et al. N Engl J Med. 2020. [Epub ahead of print]. https://doi.org/10.1056/NEJMoa2029849Ambulatory Treatment LY - C o V 5 5 5 M o n o t h e r a p y
Primary Outcome: Mean change from baseline in viral load at day 11
Treatment Group Viral Load Change, mean Difference (95% CI)
Placebo -3.47
LY-CoV555, 700 mg -3.67 -0.20 (-0.66 to 0.25)
LY-CoV555, 2800 mg -4.00 -0.53 (-0.98 to -0.08)
LY-CoV555, 7000 mg -3.38 0.09 (-0.37 to 0.55)
Pooled LY-CoV555 doses -3.70 -0.22 (-0.60 to 0.15)
Chen P, et al. N Engl J Med. 2020. [Epub ahead of print]. https://doi.org/10.1056/NEJMoa2029849Ambulatory Treatment LY - C o V 5 5 5 M o n o t h e r a p y
Secondary Outcome: Mean change from baseline in viral load at days 3 and 7
Day 3 Day 5
Treatment Group Viral Load Change, Difference Viral Load Change, Difference
mean (95% CI) mean (95% CI)
Placebo -0.85 -2.56
LY-CoV555, 700 mg -1.27 -0.42 (-0.89 to 0.06) -2.82 -0.25 (-0.73 to 0.23)
LY-CoV555, 2800 mg -1.50 -0.64 (-1.11 to -0.17) -3.01 -0.45 (-0.92 to 0.03)
LY-CoV555, 7000 mg -1.27 -0.42 (-0.90 to 0.06) -2.85 -0.28 (-0.77 to 0.20)
Pooled LY-CoV555 doses -1.35 -0.49 (-0.87 to -0.11) -2.90 -0.33 (-0.72 to 0.06)
Chen P, et al. N Engl J Med. 2020. [Epub ahead of print]. https://doi.org/10.1056/NEJMoa2029849Ambulatory Treatment LY - C o V 5 5 5 M o n o t h e r a p y
Secondary Outcomes: Hospitalizations, ED visits and Death
• No deaths in any treatment group Treatment Group Hospitalization/ED Visits
at Day 29
• No distinction made between ED visits
Placebo 9/143 (6.3)
and hospitalizations
LY-CoV555, 700 mg 1/101 (1.0)
• Post hoc analysis of high-risk patients
• LY-CoV555: 4/96 (4%) hospitalizations LY-CoV555, 2800 mg 2/107 (1.9)
• Placebo: 7/48 (15%) hospitalizations LY-CoV555, 7000 mg 2/101 (2.0)
Pooled LY-CoV555 doses 5/309 (1.6)
Chen P, et al. N Engl J Med. 2020. [Epub ahead of print]. https://doi.org/10.1056/NEJMoa2029849Ambulatory Treatment LY - C o V 5 5 5 M o n o t h e r a p y
Secondary Outcomes: Symptom Score
• Median time to symptom improvement
• Pooled treatment: 6 days
• Placebo: 8 days
Chen P, et al. N Engl J Med. 2020. [Epub ahead of print]. https://doi.org/10.1056/NEJMoa2029849Ambulatory Treatment LY - C o V 5 5 5 M o n o t h e r a p y
Secondary Outcomes: Safety
LY-CoV555
(N=309) Placebo
700 mg 2800 mg 7000 mg Pooled Doses (N=143)
(N=101) (N=107) (N=101) (N=309)
Serious adverse events, n(%) 0 0 0 0 1 (0.7)
Adverse events
Any 24 (23.8) 23 (21.5) 22 (21.8) 69 (22.3) 35 (24.5)
Mild 16 (15.8) 18 (16.8) 10 (9.9) 44 (14.2) 18 (12.6)
Moderate 7 (6.9) 3 (2.8) 8 (7.9) 18 (5.8) 16 (11.2)
Severe 0 2 (1.9) 3 (3.0) 5 (1.6) 1 (0.7)
Infusion-related reactions -- -- -- 7 (2.3) 2 (1.4)
Chen P, et al. N Engl J Med. 2020. [Epub ahead of print]. https://doi.org/10.1056/NEJMoa2029849Ambulatory Treatment LY - C o V 5 5 5 M o n o t h e r a p y
Adverse Event 700 mg (N=101) 2800 mg (N=107) 7000 mg (N=101) Pooled Doses (N=309) Placebo (N=143)
Nausea 3 (3.0) 4 (3.7) 5 (5.0) 12 (3.9) 5 (3.5)
Diarrhea 1 (1.0) 2 (1.9) 7 (6.9) 10 (3.2) 7 (4.9)
Dizziness 4 (4.0) 3 (2.8) 3 (3.0) 10 (3.2) 3 (2.1)
Headache 3 (3.0) 2 (1.9) 0 5 (1.6) 3 (2.1)
Pruritus 2 (2.0) 3 (2.8) 0 5 (1.6) 1 (0.7)
Vomiting 1 (1.0) 3 (2.8) 1 (1.0) 5 (1.6) 4 (2.8)
Chills 0 1 (0.9) 3 (3.0) 4 (1.3) 0
Fatigue 0 1 (0.9) 2 (2.0) 3 (1.0) 0
Hypertension 1 (1.0) 0 2 (2.0) 3 (1.0) 0
Lipase increased 1 (1.0) 0 2 (2.0) 3 (1.0) 0
Blood pressure increased 2 (2.0) 0 0 2 (0.6) 0
Chen P, et al. N Engl J Med. 2020. [Epub ahead of print]. https://doi.org/10.1056/NEJMoa2029849Inpatient Treatment ACTIV-3
Study Design Treatment Groups
• Phase 3, double-blind RCT • LY-CoV555 7000 mg x 1
• Hospitalized adults • Placebo
• + SARS-CoV-2 test ≤ 3 days prior to randomization (or
progressive disease with positive test > 3 days prior) Outcomes
• COVID-19 symptoms ≤ 12 days • Primary: sustained recovery
• None of the following: • Discharge to home
• Stroke • Remain at home for ≥ 14 days
• Meningitis, encephalitis, myelitis • Secondary: all-cause mortality
• MI, myocarditis, pericarditis, CHF NYHA class III/IV • Futility assessment
• Arterial/deep venous thrombosis or pulmonary embolism • “Pulmonary” outcome: oxygen requirements
• End organ failure • “Pulmonary-plus” outcome: extrapulmonary
manifestations
Lundgren JD, et al. N Engl J Med. 2020. [Epub ahead of print]. https://doi.org/10.1056/NEJMoa2033130Inpatient Treatment ACTIV-3
Category Pulmonary Ordinal Outcomes Pulmonary-Plus Ordinal Outcomes
1 • activities
Can independently undertake usual LY-CoV555 7000 mgsymptoms
with minimal/no x1
2 • activities
Symptomatic, currently unable to independently undertake usual Placebo but no need of supplemental O2 (or not above premorbid
requirements)
3 Supplemental O2 14)
6 Invasive ventilation, ECMO, mechanical Invasive ventilation, ECMO, mechanical circulatory support, vasopressor therapy, or
circulatory support, or new receipt of renal new receipt of renal replacement therapy
replacement therapy
7 Death
Lundgren JD, et al. N Engl J Med. 2020. [Epub ahead of print]. https://doi.org/10.1056/NEJMoa2033130Inpatient Treatment LY - C o V 5 5 5 M o n o t h e r a p y
Characteristic Ly-CoV555 (N=163) Placebo (N=151)
Age (years), median (IQR) 63 (50-72) 59 (48-71)
Race or ethnic group, n(%)
Hispanic 41 (25) 33 (22)
Black 33 (20) 34 (23)
Body mass index, n(%)
≥ 30 81 (50) 83 (55)
≥ 40 20 (12) 22 (15)
Days since symptom onset, median (IQR) 7 (5-9) 8 (5-9)
Oxygen requirement, n(%)
None 44 (27) 42 (28)Inpatient Treatment LY - C o V 5 5 5 M o n o t h e r a p y
• Remdesivir
• 40% receiving treatment at the time of randomization
• 95% receiving treatment before or on the day of randomization
• Glucocorticoids
• 49% receiving treatment at the time of randomization
Lundgren JD, et al. N Engl J Med. 2020. [Epub ahead of print]. https://doi.org/10.1056/NEJMoa2033130Inpatient Treatment LY - C o V 5 5 5 M o n o t h e r a p y
Futility Analysis: Pulmonary Ordinal Outcome
Lundgren JD, et al. N Engl J Med. 2020. [Epub ahead of print]. https://doi.org/10.1056/NEJMoa2033130Inpatient Treatment LY - C o V 5 5 5 M o n o t h e r a p y
Pulmonary Ordinal Outcome at Day 5 by Baseline Category
100%
80% Category 7
Category 6
60% Category 5
Category 4
40% Category 3
Category 2
20% Category 1
0%
LY- Placebo LY- Placebo LY- Placebo LY- Placebo
CoV555 CoV555 CoV555 CoV555
2 3 4 5
Baseline Pulmonary Ordinal Outcome Category
Lundgren JD, et al. N Engl J Med. 2020. [Epub ahead of print]. https://doi.org/10.1056/NEJMoa2033130Inpatient Treatment LY - C o V 5 5 5 M o n o t h e r a p y
Additional Efficacy and Safety Outcomes: Assessed through Oct. 26
LY-CoV555 Placebo
(N=163) (N=151)
Sustained recovery*, n(%) 71/87 (82) 64/81 (79)
LY-CoV555 Placebo
Hospital discharge, n(%) 143/163 (88) 136/151 (90) Death, n(%) 1 (0.6) 0
Infusion reaction, n(%) 23 (14) 14 (9) SAE, n(%) 4 (2.5) 2 (1.3)
Grade 3 or 4 event, n(%) 30 (18.4) 21 (13.9)
Composite safety outcome†, n(%) 38 (23) 30 (20)
Death, n(%) 9 (6) 5 (3)
*assessed among patients followed for ≥ 28 days or died within 28 days
†death, serious adverse events (SAE), or clinical grade 3 or 4 adverse events through day 5
Lundgren JD, et al. N Engl J Med. 2020. [Epub ahead of print]. https://doi.org/10.1056/NEJMoa2033130Inpatient Treatment LY - C o V 5 5 5 M o n o t h e r a p y
Time to Sustained Recovery and Hospital Discharge
Lundgren JD, et al. N Engl J Med. 2020. [Epub ahead of print]. https://doi.org/10.1056/NEJMoa2033130Emergency Use Approval
• EUA granted November 9, 2020 for treatment of outpatients ≥ 12 years of
age and ≥ 40 kg with mild/moderate COVID-19 at high risk of progressing
to severe disease and/or hospitalization
High Risk Criteria ≥ 55 Years of Age and 12-17 Years of Age and
• BMI ≥ 35 kg/m2 • Cardiovascular disease • BMI ≥ 85th percentile for age and gender
• CKD • Hypertension • Sickle cell disease
• Diabetes • COPD/other chronic • Congenital or acquired heart disease
• Immunosuppressive disease respiratory disease • Neurodevelopmental disorders
• Receiving immunosuppressive • Medical-related technology dependence
treatment • Asthma, reactive airway or other
• ≥ 65 years of age chronic respiratory disease requiring
daily medication for control
US FDA: Fact Sheet for Health Care Providers Emergency Use Authorization (EUA) of Bamlanivimab.
Available at: https://www.fda.gov/media/143603/downloadEmergency Use Approval
• Dosing
• 700 mg IV x 1
• No dosage adjustments for any specific populations
• Administration
• Administer within 10 days of symptom onset
• Administer over at least 60 minutes
• Observe patients for at least 1 hour after infusion is complete
US FDA: Fact Sheet for Health Care Providers Emergency Use Authorization (EUA) of Bamlanivimab.
Available at: https://www.fda.gov/media/143603/downloadEmergency Use Approval
• Infectious Diseases Society of America (ISDA) Guidelines on the Treatment
and Managements of Patients with COVID-19
• Among ambulatory patients with COVID-19, the IDSA guideline panel suggests
against the routine use of bamlanivimab
• National Institutes of Health (NIH) COVID-19 Treatment Guidelines
• At this time, there are insufficient data to recommend either for or against the use
of bamlanivimab for the treatment of outpatients with mild to moderate COVID-19
Bhimraj A, at al. Treatment and management of patients with COVID-19. Infectious Diseases Society of America.
Available at: http://www.idsociety.org/COVID19guidelines. Accessed [11/22/20]
COVID-19 Treatment Guidelines Panel. Coronavirus Disease 2019 (COVID-19) Treatment Guidelines. National Institutes of Health.
Available at: https://www.covid19treatmentguidelines.nih.gov. Accessed [11/22/20]Eli Lilly – Etesevimab
Alternate Names: JS016
LY3832479
LY-CoV016Etesevimab – In vitro Activity
• Two potential monoclonal
antibodies initially identified from
convalescing patient
• Similar ability to block binding of
SARS-CoV-2 RBD to ACE2 receptor
• Bind to overlapping epitopes
• Lower 50% neutralization dose
against infected cells for CB6
Shi R, et al. Nature. 2020;584:120-4. https://doi.org/10.1038/s41586-020-2381-yIn vivo Animal Data R he s us M acaque
Prophylaxis Treatment
Antibody administered 1 day prior Antibody administered on day 1 and day
Methods
to viral challenge 3 post-viral challenge
Viral Inoculum 1.0 x 105 TCID50
50 mg/kg (N=3/group)
Antibody Dose
Placebo (N=3)
Sample Type Throat swabs
Change in viral load (RNA)
Outcomes
Pathological lung damage
Shi R, et al. Nature. 2020;584:120-4. https://doi.org/10.1038/s41586-020-2381-yIn vivo Animal Data R he s us M acaque
Key Findings
• Low levels of virus detectable among animals
receiving prophylactic doses
• Treatment doses resulted in reduced viral
loads by day 2 compared to placebo
• Reduced infection-related lung damage in
both prophylaxed and treated animals
Shi R, et al. Nature. 2020;584:120-4. https://doi.org/10.1038/s41586-020-2381-yClinical Trials
Trial Name Status
NCT04427501 A randomized, double-blind, placebo-controlled, phase 2 study to evaluate the efficacy and safety of LY3819253 and Recruiting –
LY3832479 in participants with mild to moderate COVID-19 illness (BLAZE-1) preliminary data
available
NCT04497987 A phase 3 randomized, double-blind, placebo-controlled trial to evaluate the efficacy and safety of LY3819253 in Recruiting
preventing SARS-CoV-2 infection and COVID-19 in skilled nursing and assisted living facility residents and staff
(BLAZE-2)
NCT04634409 A randomized, double-blind, placebo-controlled, phase 2 study to evaluate the efficacy and safety of mono and Recruiting
combination therapy with monoclonal antibodies in participants with mild to moderate COVID-19 illness (BLAZE-4)
Source: https://clinicaltrials.govLY - C o V 5 5 5 + LY - C o V 0 1 6
Ambulatory Treatment Combo Therapy(Prelim)
Preliminary Data (N=112)
• Greater change in baseline viral load
compared to monotherapy or placebo
• 1 hospitalization/ED visit
• None in high-risk subgroup
• Similar rates of symptom score change
and adverse events compared to
monotherapy
Eli Lilly. (2020). SARS-CoV-2 neutralizing antibody program update [Press release]. 7 October. Available at:
https://investor.lilly.com/static-files/a6dfdc90-3e16-4511-9a5d-f744b7568276Regeneron: Casirivimab + Imdevimab
Alternate Names: REGN10933 + REGN10987
REGN-CoV2REGN-COV2 – In vitro Activity
• 200 neutralizing mAbs identified 4 finalists selected
Neutralization Potency Antibody Effector Functions
*
*Antibody-dependent cellular phagocytosis
Hansen J, et al. Science. 2020;369:1010-4. https://doi.org/10.1126/science.abd0827REGN-COV2 – In vitro Activity
Baum A, et al. Science. 2020;369:1014-8. https://doi.org/10.1126/science.abd0831In vivo Animal Data R he s us M acaque
Prophylaxis
Treatment
Study 1 Study 2
Antibody administered 1 day
Methods Antibody administered 3 days prior to viral challenge
after viral challenge
Viral Inoculum 1.0 x 105 PFU 1.05 x 106 PFU 1.05 x 106 PFU
0.3 mg/kg (N=4) 25 mg/kg (N=4)
50 mg/kg (N=6)
Antibody Doses 50 mg/kg (N=4) 150 mg/kg (N=4)
Placebo (N=6)
Placebo (N=4) Placebo (N=4)
Nasopharyngeal swab Nasopharyngeal swab Nasopharyngeal swab
Sample Types
BAL Oral swab Oral swab
Outcomes Change in viral load (gRNA and sgRNA)
Baum A, et al. Science. 2020;eabe2402. https://doi.org/10.1126/science.abe2402In vivo Animal Data R he s us M acaque
Key Findings - Prophylaxis Key Findings - Treatment
• Increased rates of gRNA clearance, near complete • Similarly increased viral clearance (gRNA and sgRNA)
ablation of sgRNA among animals receiving 50 mg/kg among animals receiving either 25 mg/kg or 150 mg/kg
• Viral clearance rates similar between NP swab and BAL
fluid samples; more rapid clearance noted on oral swab
samples
Baum A, et al. Science. 2020;eabe2402. https://doi.org/10.1126/science.abe2402In vivo Animal Data Golde n H amste r
Prophylaxis Treatment
Antibody administered 1 day
Methods Antibody administered 2 days prior to viral challenge
after viral challenge
Viral Inoculum 2.3 x 104 PFU
50 mg/kg (N=5)
5 mg/kg (N=5)
Antibody Doses
0.5 mg/kg (N=5)
Placebo (N=5)
Sample Types Lung tissue N/A
Body weight change
Outcomes Change in viral load (gRNA and sgRNA) Body weight change
Area of lung exhibiting pathology typical of pneumonia
Baum A, et al. Science. 2020;eabe2402. https://doi.org/10.1126/science.abe2402In vivo Animal Data Golde n H amste r
Key Findings Weight Loss
• Decreased weight loss among all groups Prophylaxis Treatment
receiving prophylaxis
• Treatment with higher doses prevented
weight loss
• Viral load not significantly impacted by
prophylaxis Viral Load on Day 7 (Prophylaxis) Affected Lung
Genomic RNA Subgenomic RNA
• Significantly less lung affected in animals
receiving prophylactic antibodies
Baum A, et al. Science. 2020;eabe2402. https://doi.org/10.1126/science.abe2402Clinical Trials
Trial Name Status
NCT04425629 Safety, tolerability, and efficacy of anti-spike (S) SARS-CoV-2 monoclonal antibodies for the treatment of ambulatory Recruiting – data
adult patients with COVID-19 available
NCT04426695 Safety, tolerability, and efficacy of anti-spike (S) SARS-CoV-2 monoclonal antibodies for the treatment of hospitalized Recruiting
adult patients with COVID-19
NCT04381936 Randomized Evaluation of COVid-19 thERapY (RECOVERY) Recruiting
NCT04452318 A phase 3, randomized, double-blind, placebo-controlled study assessing the efficacy and safety of anti-spike SARS- Recruiting
CoV-2 monoclonal antibodies in preventing SARS-CoV-2 infection in household contacts of individuals infected with
SARS-CoV-2
NCT04666441 A phase 2 study to assess the virologic efficacy of REGN10933+REGN10987 across different dose regimens in Not yet recruiting
outpatients with SARS-CoV-2 infection
Source: https://clinicaltrials.govAmbulatory Treatment REGN-COV2 Combo Therapy
Patient Population Treatment Groups Outcomes
• Non-hospitalized adults • 2.4 grams IV x 1 • Virologic:
• Symptom onset ≤ 7 days • 8.0 grams IV x 1 • Serum Ab-negative patients
from randomization • Time-weighted average
• Placebo change from baseline in
• SARS-CoV-2 confirmed by viral load through day 7
molecular testing ≤ 72 • Clinical:
hours from randomization
• Serum Ab-negative and
• Not on any putative overall patient populations
COVID-19 therapies • Proportion of patients with
≥ 1 COVID-19-related
medically-attended visit
through day 29
Weinreich DM, et al. N Engl J Med. 2020. [Epub ahead of print]. https://doi.org/10.1056/NEJMoa2035002Ambulatory Treatment REGN-COV2 Combo Therapy
Baseline Demographics
Placebo REGN-COV2 2.4g REGN-COV2 8.0g Total
(N=93) (N=92) (N=90) (N=275)
Age (years), median (IQR) 45 (34-54) 43 (33.5-51) 44 (36-53) 44 (35-52)
Male sex, n (%) 50 (54) 46 (50) 38 (42) 134 (49)
Hispanic or Latino, n (%) 46 (49) 52 (57) 55 (61) 153 (56)
Race, n (%)
White 72 (77) 74 (80) 78 (87) 224 (81)
Black/African American 14 (15) 15 (16) 6 (7) 35 (13)
BMI > 30 kg/m2, n (%) 34 (37) 39 (42) 42 (47) 115 (42)
≥ 1 Risk factor for hospitalization*, n (%) 58 (62) 57 (62) 61 (68) 176 (64)
*Age > 50 years, obesity, cardiovascular disease, chronic lung disease, chronic metabolic disease, chronic kidney disease, chronic liver disease, immunocompromise
Weinreich DM, et al. N Engl J Med. 2020. [Epub ahead of print]. https://doi.org/10.1056/NEJMoa2035002Ambulatory Treatment REGN-COV2 Combo Therapy
Baseline Viral Load
Placebo REGN-COV2 2.4g REGN-COV2 8.0g Total
Baseline serology status: negative N = 31 N = 37 N = 36 N = 104
Viral load, median copies/mL 14 x 106 2.24 x 106 32.05 x 106 15 x 106
Baseline serology status: positive N = 47 N = 36 N = 37 N = 120
Viral load, median copies/mL 4,790 4,460 1,740 3,105
Baseline serology status: unknown N = 13 N = 11 N = 10 N = 34
Viral load, median copies/mL 82,800* 937,000† 2,320,000 145,500
Ranges for all viral loads were 1:71x106 copies/mL with the following exceptions:
*Range 357:25.6x106 copies/mL
†Range 2200:71x106 copies/mL
Weinreich DM, et al. N Engl J Med. 2020. [Epub ahead of print]. https://doi.org/10.1056/NEJMoa2035002Ambulatory Treatment REGN-COV2 Combo Therapy
Results: Key virologic end point
Placebo REGN-COV2 2.4g REGN-COV2 8.0g
MFAS Sero(-) Sero(+) MFAS Sero(-) Sero(+) MFAS Sero(-) Sero(+)
(N=78) (N=28) (N=37) (N=70) (N=34) (N=27) (N=73) (N=35) (N=29)
Time-weighted average change
in viral load through day 7 (log10 -1.34±0.13 -1.37±0.20 -1.24±0.16 -1.60±0.14 -1.89±0.18 -1.24±0.19 -1.90±0.14 -1.96±0.18 -1.63±0.20
copies/mL), mean (SE)
Difference vs. placebo (log10
-0.25±0.18 -0.52±0.26 0.00±0.24 -0.56±0.18 -0.60±0.26 -0.39±0.25
copies/mL)
Weinreich DM, et al. N Engl J Med. 2020. [Epub ahead of print]. https://doi.org/10.1056/NEJMoa2035002Ambulatory Treatment REGN-COV2 Combo Therapy
• Greater viral load reduction among patients with higher baseline viral load
Weinreich DM, et al. N Engl J Med. 2020. [Epub ahead of print]. https://doi.org/10.1056/NEJMoa2035002Ambulatory Treatment REGN-COV2 Combo Therapy
Results: Key clinical end point
Placebo REGN-COV2 2.4g REGN-COV2 8.0g
FAS Sero(-) Sero(+) FAS Sero(-) Sero(+) FAS Sero(-) Sero(+)
(N=93) (N=33) (N=47) (N=92) (N=41) (N=37) (N=90) (N=39) (N=39)
Medically attended visits, n (%) 6 (6) 5 (15) 1 (2) 3 (3) 2 (5) 1 (3) 3 (3) 3 (8) 0
Weinreich DM, et al. N Engl J Med. 2020. [Epub ahead of print]. https://doi.org/10.1056/NEJMoa2035002Ambulatory Treatment REGN-COV2 Combo Therapy
Safety
Placebo REGN-COV2 2.4g REGN-COV2 8.0g
(N=93) (N=88) (N=88)
Serious adverse event 2 (2) 1 (1) 0
Infusion-related reactions Grade ≥ 2 thru Day 4 1 (1) 0 2 (2)
Hypersensitivity reactions Grade ≥ 2 thru Day 29 2 (2) 0 1 (1)
Event leading to death 0 0 0
Event leading to infusion interruption 1 (1) 0 1 (1)
Weinreich DM, et al. N Engl J Med. 2020. [Epub ahead of print]. https://doi.org/10.1056/NEJMoa2035002Ambulatory Treatment E UA D a t a
• Primary Outcome: time-weighted average change in viral load through day 7
Patient Population TWA Change in Viral Load vs.
Placebo (log10 copies/mL)
EUA Interim Data – NEJM
(N=665) (N=275)
Modified full analysis set -0.36 -0.41
High viral load -0.78 --
Seronegative -0.69 -0.56
US FDA: Fact Sheet for Health Care Providers Emergency Use Authorization (EUA) of Casirivimab and Imdevimab.
Available at: https://www.fda.gov/media/143892/downloadAmbulatory Treatment E UA D a t a
• Secondary Outcomes:
Placebo REGN-CoV2 2.4g REGN-CoV2 8.0g Combined
REGN-Cov2
Hospitalization/ER visits within 28 days, n/N (%) 10/231 (4) 4/215 (2) 4/219 (2) 8/434 (2)
High risk patients* 7/78 (9) 2/70 (3) 2/81 (2) 4/151 (3)
Time to symptom improvement, median (days) 6 -- -- 5
*High risk = patients meeting EUA criteria for use
US FDA: Fact Sheet for Health Care Providers Emergency Use Authorization (EUA) of Casirivimab and Imdevimab.
Available at: https://www.fda.gov/media/143892/downloadREGN-COV2 Combo Therapy
Inpatient Treatment (Prelim Data)
Patient Population Available Results (Seronegative Population)
• Hospitalized adults on low-flow O2 • Futility analysis: PASSED
• 217 seronegative • Receipt of REGN-COV2 ↓ risk of death/mechanical
ventilation (HR: 0.78; 80% CI: 0.51-1.2)
• 270 seropositive • Starting 1 week post-treatment, risk of death/mechanical
• 67% received remdesivir ventilation reduced by half
• 74% received corticosteroids • Change in TWA daily viral load:
• Through day 7: -0.54 log10 copies/mL
Treatment Groups • Through day 11: -0.63 log10 copies/mL
• 2.4 grams IV x 1 • On day 5 vs. Placebo: -1.1 log10 copies/mL
• 8.0 grams IV x 1 • Adverse events in overall population:
• 2.4g dose: 20% (Infusion reactions: 0.9%)
• Placebo
• 8.0g dose: 21% (Infusion reactions: 2.7%)
• Placebo: 24% (Infusion reactions: 1.4%)
Regeneron. (2020). REGN-COV2 antibody cocktail program update [Press release]. 29 December. Available at:
https://investor.regeneron.com/news-releases/news-release-details/regeneron-announces-encouraging-initial-data-covid-19-antibodyEmergency Use Approval
• EUA granted November 21, 2020 for treatment of outpatients ≥ 12 years of
age and ≥ 40 kg with mild/moderate COVID-19 at high risk of progressing
to severe disease and/or hospitalization
High Risk Criteria ≥ 55 Years of Age and 12-17 Years of Age and
• BMI ≥ 35 kg/m2 • Cardiovascular disease • BMI ≥ 85th percentile for age and gender
• CKD • Hypertension • Sickle cell disease
• Diabetes • COPD/other chronic • Congenital or acquired heart disease
• Immunosuppressive disease respiratory disease • Neurodevelopmental disorders
• Receiving immunosuppressive • Medical-related technology dependence
treatment • Asthma, reactive airway or other
• ≥ 65 years of age chronic respiratory disease requiring
daily medication for control
US FDA: Fact Sheet for Health Care Providers Emergency Use Authorization (EUA) of Casirivimab and Imdevimab.
Available at: https://www.fda.gov/media/143892/downloadEmergency Use Approval
• Dosing
• 2400 mg (1200mg/1200mg) IV x 1
• No dosage adjustments for any specific populations
• Administration
• Administer within 10 days of symptom onset
• Administer over at least 60 minutes
• Observe patients for at least 1 hour after infusion is complete
US FDA: Fact Sheet for Health Care Providers Emergency Use Authorization (EUA) of Casirivimab and Imdevimab.
Available at: https://www.fda.gov/media/143892/downloadEmergency Use Approval
• Infectious Diseases Society of America (ISDA) Guidelines on the Treatment
and Managements of Patients with COVID-19
• No recommendations available
• National Institutes of Health (NIH) COVID-19 Treatment Guidelines
• At this time, there are insufficient data to recommend either for or against the use
of casirivimab plus imdevimab for the treatment of outpatients with mild to
moderate COVID-19
Bhimraj A, at al. Treatment and management of patients with COVID-19. Infectious Diseases Society of America.
Available at: http://www.idsociety.org/COVID19guidelines. Accessed [1/12/21]
COVID-19 Treatment Guidelines Panel. Coronavirus Disease 2019 (COVID-19) Treatment Guidelines. National Institutes of Health.
Available at: https://www.covid19treatmentguidelines.nih.gov. Accessed [1/12/21]Additional mAb Under Investigation
Name Developer Study Design
Phase 2/3 – outpatient treatment
VIR-7831 Vir biotechnology/GSK
Phase 3 – inpatient treatment
CT-P59 Celltrion Phase 2/3 – outpatient treatment
AZD7442 AstraZeneca/Vanderbilt University Medical
Phase 3 – pre/post-exposure prophylaxis
(AZD8895 + AZD1061) Center/DARPA/BARDA
TY027 Tychan Phase 3 – inpatient treatment
BRII-196/BRII-198 Brii Biosciences/NIAID Phase 3 – inpatient treatment
Yang L, et al. Antibody Therapeutics. 2020;3:205-12. https://doi.org/10.1093/abt/tbaa020Summary
• Monoclonal antibody therapy shown to decrease SARS-CoV-2 viral load and lung damage in animal
models
• LY-CoV555 (Bamlanivimab)
• May decrease rate of hospitalizations or ED visits in some at risk outpatients with mild/moderate COVID-19
• “At risk” population remains poorly defined
• Further studies needed
• Did not improve outcomes in patients hospitalized with COVID-19
• REGN-COV2 (Casirivimab + Imdevimab)
• May decrease rate of medically attended visits in outpatients with mild/moderate COVID-19
• Results driven primarily by patients unable to mount antibody response (seronegative)
• Preliminary data appear positive for inpatient use in patients on low-flow oxygenMonoclonal Antibodies
A Review of Pertinent Drug Information for SARS-CoV-2
Jessica Ortwine, PharmD, BCIDP
Clinical Pharmacy Specialist, Parkland Health & Hospital System
jessica.ortwine@phhs.org
@jkortwine
Data as of January 13, 2021You can also read
