Learning Objectives • Discuss the clinical profiles and trial data for current and emerging anti-SARS-CoV-2 monoclonal antibodies • Assess patients with COVID-19 who are at high risk for clinical progression, hospitalization, and other poor outcomes • Manage patients with COVID-19 who qualify for anti-SARS-CoV-2 monoclonal antibody therapy based on current guidelines from the US Food and Drug Administration • Address barriers to the use of anti-SARS-CoV-2 monoclonal antibody therapies, including patient reluctance and health care disparities COVID-19, coronavirus disease 2019; SARS-CoV-2, severe acute respiratory syndrome coronavirus 2.
Current COVID-19 Statistics in the United States
Fully Vaccinated Population by Age3
Daily Cases
43,100,295 300k
Trends in COVID-19 Cases2
People, %
Total Cases in the United States1
200k
83.2 64.8
66.6
Aged ≥12 years
Aged ≥18 years
55.4
Total
>94
%
100k 0 Jan 23
90 80 70 60 50 40 30 20 10 0
May 4
Aug 14
Nov 24
Mar 6
Jun 16
Sep 22
Aged ≥65 years
of new COVID-19 cases are among unvaccinated people4
1. Google. https://news.google.com/covid19/map?hl=en-US&mid=%2Fm%2F09c7w0&gl=US&ceid=US%3Aen&state=3. Accessed September 27, 2021; 2. Centers for Disease Control and Prevention (CDC). https://www.cdc.gov/coronavirus/2019-ncov/covid-data/covidview/index.html. Accessed September 27, 2021; 3. CDC. https://covid.cdc.gov/covid-datatracker/#vaccinations_vacc-total-admin-rate-total. Accessed September 27, 2021; 4. KFF. https://www.kff.org/policy-watch/covid-19-vaccine-breakthrough-cases-data-from-the-states/. Accessed September 15, 2021.
CURRENT EUA STATUS AND CLINICAL TRIAL DATA OF ANTI-SARS-CoV-2 MONOCLONAL ANTIBODIES Jonathan Li, MD, MMSc Associate Professor of Medicine Brigham and Women’s Hospital Harvard Medical School Boston, Massachusetts
Developing Anti-SARS-CoV-2 mAbs • Spike protein divided into S1 and S21
– S1 attaches to ACE2 receptor in RBD – Creates a conformational change in S2, allowing viral entry
• Current mAbs prevent ACE2 receptor binding1
SARS-CoV-2 Spike Protein2 Receptor-binding domain
SARS-CoV-2 N-terminal domain
Spike protein
Furin cleavage site
ACE2, angiotensin-converting enzyme 2; RBD, receptor binding domain; TMPRSS2, transmembrane serine protease 2. 1. National Institutes of Health (NIH). https://www.covid19treatmentguidelines.nih.gov/therapies/anti-sars-cov-2-antibody-products/anti-sars-cov-2-monoclonal-antibodies/. Accessed August 19, 2021; 2. Wall EC, et al. Lancet. 2021;397(10292):2331-2333.
Characteristics of Anti-SARS-CoV-2 mAbs mAb
Route of Administration
Characteristics
ACE2 receptor interface on spike protein
IV
• Bind to different but overlapping epitopes • No Fc modifications for BAM; amino acid substitutions in Fc region for ETE
EUA for treatment and postexposure prophylaxis
ACE2 receptor interface on spike protein
IV (can be SQ)
EUA for treatment
Highly conserved epitope on spike protein
Emerging
ACE2 receptor interface on spike protein
Status
Binding Site
BAM + ETE1
EUA for treatment and postexposure prophylaxis
CAS + IMD2
SOT3 AZD7442 (tixagevimab + cilgavimab)4
• Bind to nonoverlapping sites • No modifications in Fc region
IV
• Does not compete with ACE2 receptor binding • Amino acid substitutions in Fc region to extend half-life
IM
• Components bind to 2 noncompeting sites • Long-acting mAb (up to 12 months) • Reduced Fc receptor binding
1. US Food and Drug Administration (FDA). https://www.fda.gov/media/145802/download. Accessed September 8, 2021; 2. FDA. https://www.fda.gov/media/145611/download. Accessed September 8, 2021; 3. FDA. https://www.fda.gov/media/149534/download. Accessed September 8, 2021; 4. Precision Vaccinations. https://www.precisionvaccinations.com/vaccines/covid-19-antibody-azd7442. Accessed September 8, 2021.
OUTPATIENT TREATMENT
Efficacy of BAM Monotherapy in Outpatient Treatment of COVID-19 BLAZE-1 Phase 2 Trial
Mean Change From Baseline
Reductions in Viral Load With BAM Monotherapy at Day 11 -3
Placebo
BAM 700 mg
BAM 2800 mg
BAM 7000 mg
-3.2 -3.4 -3.6 -3.8 -4 -4.2
-3.38
-3.47 -3.67 -4a
• 1.6% of patients receiving BAM were hospitalized with COVID-19 vs 6.3% of those receiving placebo • Reduced symptom severity among patients receiving BAM from days 2–6 – Most patients recovered days 7-11
Nearly 70% had >1 risk factor for progression to severe COVID-19. aP=0.02.
N=452 adults from 41 US centers who were recently diagnosed with mild or moderate COVID-19 were randomly assigned within 3 days of diagnosis to 1 IV infusion of BAM 700 mg, BAM 2800 mg, BAM 7000 mg, or placebo. Chen P, et al. N Engl J Med. 2021;384(3):229-237.
SARS-CoV-2 Viral Load With BAM Monotherapy vs BAM + ETE BLAZE-1 Phase 2/3 Trial
700 mg BAM 2800 mg BAM 7000 mg BAM 2800 mg BAM + 2800 mg ETE Placebo
25 30 35 40
12
Treatment
20
Variants, %
Cycle Threshold Value
Mean SARS-CoV-2 Viral Load Cycle Threshold With BAM or BAM + ETE
Treatment-Emergent BAM-Resistant Variants 11.3
9.8
10 8
7.1
6 4 2 0
1
3
7
Trial Day
11
1 BAM 700 mg
BAM 2800 mg
BAM 7000 mg
BAM + ETE
N=577 ambulatory adults at 49 US centers who tested positive for SARS-CoV-2 and had >1 mild to moderate symptom were randomly assigned to a single infusion of BAM 700 mg, BAM 2800 mg, BAM 7000 mg, BAM 2800 mg + ETE 2800 mg, or placebo. Gottlieb RL, et al. JAMA. 2021;325(7):632-644.
BAM + ETE for Treatment of Mild or Moderate COVID-19 BLAZE-1 Phase 3 Trial
Patients, %
BAM + ETE Reduced COVID-19-Related Hospitalization or Death by Day 291 8 7 6 5 4 3 2 1 0
aP<0.001; bP<0.01.
7
70% relative reduction 2.1a
Placebo
• No patients in the BAM + ETE group died • Viral load reduction by day 7 was ~16 times higher in BAM + ETEa • Time to symptom resolution was 1 day shorter in BAM + ETEb • Among those hospitalized, duration was 4 days shorter with BAM + ETE
BAM + ETE
N=1035 ambulatory adolescents and adults who tested positive for SARS-CoV-2 and had >1 risk factor for severe COVID-19 were randomly assigned to 1 dose of placebo or 2800 mg BAM + 2800 mg ETE IV within 3 days of positive test result. Dougan M, et al. N Engl J Med. 2021. [Epub ahead of print].
Treating COVID-19 With CAS + IMD in High-Risk Patients
CAS + IMD Reduces Hospitalization and All-Cause Death 4
Patients, %
3.2 3
70% relative reduction
2 1a
1 0
aP<0.0024; bP<0.0001.
Placebo
CAS + IMD 1200 mg
• When compared with placebo, patients who received CAS + IMD had: – Shorter hospital stays among those who were hospitalized – Lower rate of ICU admission – Faster symptom resolutionb – More rapid viral load reduction
• SAEs occurred in 1.1% of the CAS + IMD group vs 4% of the placebo group – Largely related to COVID-19
In a phase 3 trial, N=4057 (modified full analysis set) adults with ≥1 risk factor for severe COVID-19 and a positive SARS-CoV-2 test ≤72 hours and onset of COVID-19 symptoms ≤7 days before randomization were assigned to CAS + IMD 2400 mg IV, CAS + IMD 1200 mg IV, or placebo. Patients were followed for a median of 45 days with 96.6% of patients having >28 days follow-up. ICU, intensive care unit; SAE, serious adverse event. Weinreich DM, et al. medRxiv. 2021. [Epub ahead of print].
Administering CAS + IMD SQ for Treatment of High-Risk Patients
• “The authorized dosage of CAS 600 mg + IMD 600 mg for SQ administration for treatment is selected based on the totality of the scientific evidence, incorporating clinical data, viral load reduction data (pharmacodynamics) and pharmacokinetic data.”
FDA. https://www.fda.gov/media/145611/download. Accessed September 22, 2021.
Treating COVID-19 With SOT in High-Risk Patients COMET-ICE Phase 3 Trial
Patients, %
Full Analysis: SOT Reduces Hospitalization for >24 Hours or All-Cause Death by Day 291 8 7 6 5 4 3 2 1 0
aPossible
6
79% relative reduction 1b
Placebo
Interim Analysis2,c
Outcome
Placebo, %
SOT, %
ED visit
2
1
Severe or critical progressiond
7
0.7
ICU admission
2
0
SOT a
that 3/6 patients in SOT arm were hospitalized for non-COVID-19 causes; bP<0.001; cInterim analysis was of 291 patient receiving sotrovimab and 292 receiving placebo; safety interim analysis was performed in 868 patients; dDefined as need for supplemental oxygen. N=1057 adults with mild to moderate COVID-19 who were at high risk (aged ≥55 years or adults with ≥1 risk factor) of progression to severe COVID-19 and had a positive SARS-CoV-2 test results and onset of symptoms within the last 5 days were randomly assigned to sotrovimab 500 mg IV or placebo. AE, adverse event; ED, emergency department. 1. GSK. https://www.gsk.com/en-gb/media/press-releases/gsk-and-vir-biotechnology-announce-continuing-progress-of-the-comet-clinical-development-programme-for-sotrovimab/. Accessed September 28, 2021; 2. Gupta A, et al. medRxiv. 2021. [Epub ahead of print].
INPATIENT TREATMENT
Efficacy of CAS + IMD in Reducing Death in Patients Hospitalized With COVID-19 RECOVERY Trial
35
Effect of CAS + IMD on Mortality at Day 28 Among Seronegative vs Seropositive Hospitalized Patients
Rate ratio, 0.94 (0.86−1.03) P=0.17 by log−rank test
30 25 20 15 10
Usual care CAS + IMD
5 0
0
7
14
21
Days Since Randomization
28
Patient Mortality, %
Patient Mortality, %
Effect of CAS + IMD on Mortality at Day 28 Among All Patients Hospitalized With Severe COVID-19
35
Seronegative Rate ratio, 0.80 (0.70−0.91) P=0.0010 by log−rank test
30 25 20 15 10
Seropositive Rate ratio, 1.09 (0.95−1.26)
5 0
0
7
14
21
Days Since Randomization
28
N=9785 patients aged ≥12 years in the UK, Indonesia, and Nepal hospitalized with severe COVID-19 (n=3153 seronegative patients, n=5272 seropositive patients, and n=1360 patients with unknown status) were randomly assigned to usual care alone or usual care plus IV CAS + IMD. Horby PW, et al. medRxiv. 2021. [Epub ahead of print].
Efficacy of BAM Monotherapy in Patients Hospitalized for COVID-19 ACTIV-3
Cumulative Risk of Event
Time to Death, SAE, Organ Failure, or Serious Coinfection in All Participants 40 HR, 1.04 (95% CI: 0.68−1.59) P=0.85
30
Viral RNA by nAba RNA high, nAb – RNA high, nAb +
20 10 0
Sustained Recovery According to nAb Status and Viral Measures
Placebo BAM 0
10
20
30
40
50
60
70
80
Days Since Randomization
90
RNA low, nAb – RNA low, nAb + 0.3
0.5
0.7
Placebo Better
1
1.4
2
BAM Better
N=314 adults hospitalized with COVID-19 who did not require invasive mechanical ventilation and had symptoms for <12 days were randomly assigned to receive 1 infusion of BAM 7000 mg IV or placebo; aP<0.001. HR, hazard ratio; nAb, neutralizing antibody. Lundgren JD, et al. medRxiv. 2021. [Epub ahead of print].
3
PREVENTION
CAS + IMD for Postexposure Prophylaxis Among Patients With Household Exposure to SARS-CoV-2 Symptomatic Infection in Patients Testing Negative Following SARSCoV-2 Exposure
Cumulative Incidence, %
10 8 6
7.8% Placebo
4
CAS + IMD
2 0
aP<0.001.
81.4% relative risk reduction
0 1
8
15
Trial Day
22
1.5%a
Placebo
CAS + IMD
Viral load >104 copies/mL, %a
11.3
1.6
Mean duration of symptomatic infection, week
3.2
1.2
Any symptomatic or asymptomatic infection, %a
14.2
4.8
Outcome
29
N=1505 patients aged ≥12 years with household exposure who had no evidence of prior SARS-CoV-2 infection and had a negative SARS-CoV-2 test were randomly assigned to placebo or CAS + IMD 1200 mg SQ within 96 hours of confirming household contacts’ positive test. N=459 patients at high risk for severe COVID-19. O’Brien MP, et al. N Engl J Med. 2021. [Epub ahead of print].
BAM as Prevention in Nursing and Assisted Living Facilities 25
Efficacy of BAM in Preventing Symptomatic Mild or Worse COVID-19 by Day 57 25
Placebo
20
Staff, %
Residents, %
BLAZE-2 Phase 3 Trial
BAMa
15 10 5 0
aP<0.001.
1
8
15
22
29
36
43
50
57
20
Placebo
15 10
BAM
5 0
1
8
15
22
29
36
43
50
Time Since Infusion, days Time Since Infusion, days Overall, BAM reduced incidence of COVID-19 vs placebo (8.5% vs 15.2%).a
N=1175 unvaccinated adult staff and residents of 74 nursing or assisted living facilities in the US with ≥1 confirmed COVID-19 case were randomly assigned within 7 days of a confirmed case to 1 infusion of 4200 mg BAM IV or placebo. Patients who were SARS-CoV-2 negative at baseline comprised the prevention population; those who were positive comprised the treatment population detailed in another report. Cohen MS, et al. JAMA. 2021;326(1):46-55.
57
Preexposure Prophylaxis With AZD7442 PROVENT Trial
Reduction in First Case of SARSCoV-2 PCR Positive Symptomatic Illness Post Dose1 1.2
Patients, %
1
1
0.8
77% relative reduction
0.6 0.4
– 3 (including 2 deaths) with placebo
• Well tolerated and few AEs
0.2a
0.2 0
• 25 symptomatic cases at the primary analysis • No severe COVID-19 or COVID-19–related deaths with AZD7442
Placebo
AZD7442
N=5197 unvaccinated adults in the US, United Kingdom (UK), Spain, France, and Belgium who where at high risk for inadequate response to vaccination or at high risk for SARS-CoV-2 infection were randomly assigned 2:1 to 1 IM dose of AZD7442 vs placebo given as 2 separate sequential injections. 1. Levin M, et al. IDWeek 2021; virtual conference. Abstract LB-5; 2. AstraZeneca. https://www.astrazeneca.com/media-centre/press-releases/2021/azd7442-prophylaxis-trial-met-primaryendpoint.html#!. Accessed August 30, 2021.
Postexposure Prophylaxis With AZD7442 STORM CHASER Trial
Onset of case post dose
Number of cases, AZD7442
Number of cases, Placebo
Relative risk reduction, %
All participants (primary analysis)
All cases
23/749
17/372
33a
PCR negative (preplanned)
All cases
6/715
11/358
73
≤7 days
5/715
5/358
51
>7 days
1/710
6/353
92
Baseline subgroup
PCR negative (post hoc)
• Overall, cases occurred in 3% of those treated with AZD7442 vs 4.6% in the placebo arm • Among PCR negative patients, cases occurred in 0.8% in the AZD7442 arm vs 3% in the placebo arm • AZD7442 was well tolerated
significant. N=1121 unvaccinated adults in the US and UK with confirmed exposure to a person with laboratory-confirmed COVID-19 within the past 8 days were randomly assigned 2:1 to AZD7442 300 mg IM administered in 2 separate, sequential injections or placebo. PCR, polymerase chain reaction. AstraZeneca. https://www.astrazeneca.com/media-centre/press-releases/2021/update-on-azd7442-storm-chaser-trial.html. Accessed August 13, 2021. aP=not
CURRENT EUA STATUS
History and Current Status of anti-SARS-CoV-2 mAb EUAs
November 21, 2020 FDA issues EUA for outpatient treatment with CAS + IMD combination2
April 16, 2021 FDA revoked EUA for BAM monotherapy2
June 3, 2021
CAS + IMD EUA updated with reduced dosages and possibility for SQ administration3
July 30, 2021
FDA revises CAS + IMD EUA to include postexposure prophylaxis4
November 2020 November 9, 2020 FDA issues EUA for outpatient treatment with BAM monotherapy1
aThis
September 16, 2021 FDA revises BAM + ETE EUA to include postexposure prophylaxis5
September 2021 February 9, 2021 FDA issues EUA for administration of BAM + ETE combination2
May 26, 2021
FDA issues EUA for SOT use in outpatient treatment2
June 25, 2021 Distribution of BAM + ETE paused3
August 27, 2021
BAM + ETE may be used in states in which combined frequency of variants resistant to BAM + ETE is ≤5%5,a
included all 50 states as of September 2, 2021. CMS, Centers for Medicare & Medicaid Services; FDA, US Food and Drug Administration; NIH, National Institutes of Health. 1. CMS. https://www.cms.gov/medicare/covid-19/monoclonal-antibody-covid-19-infusion.. Accessed August 4, 2021; 2. FDA. https://www.fda.gov/news-events/pressannouncements/coronavirus-covid-19-update-fda-revokes-emergency-use-authorization-monoclonal-antibody-bamlanivimab. Accessed August 4, 2021; 3. NIH. https://www.covid19treatmentguidelines.nih.gov/therapies/anti-sars-cov-2-antibody-products/anti-sars-cov-2-monoclonal-antibodies/. Accessed August 4, 2021; 4. FDA. https://www.fda.gov/drugs/drug-safety-and-availability/fda-authorizes-regen-cov-monoclonal-antibody-therapy-post-exposure-prophylaxis-prevention-covid-19. Accessed August 4, 2021; 5. FDA. https://www.fda.gov/media/145801/download. Accessed August 30, 2021.
Current FDA EUA for Treatment Anti-SARS-CoV-2 mAbs
mAb
Indication
700 mg BAM + 1400 mg ETE IV as possible after positive SARS-CoV-2 test and within 10 days of symptom onset
BAM + ETE1
CAS + IMD2
SOT3
Dose and Route of Administration
Treatment of nonhospitalized patients aged ≥12 years with mild to moderate COVID-19 who are at risk for progressing to severe disease
600 mg CAS + 600 mg IMD IV as soon as possible after positive SARS-CoV-2 test and within 10 days of symptom onset • Can be administered SQ in 4 injections if IV infusion would delay treatment or is not feasible
500 mg IV as possible after positive SARS-CoV-2 test and within 10 days of symptom onset
1. FDA. https://www.fda.gov/media/145801/download. Accessed September 8, 2021; 2. FDA. https://www.fda.gov/media/145611/download. Accessed August 5, 2021; 3. FDA. https://www.fda.gov/media/149534/download. Accessed August 5, 2021.
Current FDA EUA for Prevention Anti-SARS-CoV-2 mAbs
mAb CAS +
Indication IMD1
BAM + ETE2
Postexposure prophylaxis for patients aged ≥12 years who have had close contact with a patient infected with SARS-CoV-2, are at high risk for progression to severe COVID-19, and are not fully vaccinated or not expected to mount an adequate immune response to vaccination
Dose and Route of Administration 600 mg CAS + 600 mg IMD SQ or IV as soon as possible after exposure
700 mg BAM + 1400 mg ETE IV as soon as possible after exposure
1. FDA. https://www.fda.gov/media/145611/download. Accessed August 5, 2021; 2. FDA. https://www.fda.gov/media/145801/download. Accessed September 18, 2021.
IDENTIFYING WHICH PATIENTS CAN BE TREATED WITH ANTI-SARS-COV-2 MONOCLONAL ANTIBODIES Jonathan Li, MD, MMSc Associate Professor of Medicine Brigham and Women’s Hospital Harvard Medical School Boston, Massachusetts
NIH Guideline Definitions of the Clinical Spectrum of COVID-19 Mild COVID-19 • Various signs and symptoms of COVID-19 • No shortness of breath, dyspnea, or abnormal chest imaging
Moderate COVID-19 • Evidence of lower respiratory disease during clinical assessment or imaging • SpO2 ≥94% on room air at sea level
Severe COVID-19 • SpO2 <94% on room air at sea level • Ratio of PaO2/FiO2 <300 mm Hg • Respiratory frequency >30 breaths/min, or • Lung infiltrates >50%
Anti-SARS-CoV-2 mAbs are recommended to outpatients aged ≥12 years with mild or moderate COVID-19 who are at high risk for disease progression. PaO2/FiO2, partial pressure of oxygen to fraction of inspired oxygen; SpO2, oxygen saturation. NIH. https://www.covid19treatmentguidelines.nih.gov/therapies/anti-sars-cov-2-antibody-products/anti-sars-cov-2-monoclonal-antibodies/. Accessed August 4, 2021.
Which Patients Meet EUA Criteria for the Use of Anti-SARS-CoV-2 mAbs?
Original EUA Criteria – – – –
Aged ≥65 years Obesity (BMI ≥35 kg/m2) Diabetes CVD (including congenital heart disease) or hypertension – Chronic lung diseases
Expanded EUA Criteria
– An immunocompromising condition or immunosuppressive treatment – Being overweight (BMI >25 kg/m2) as the sole risk factor – CKD – Pregnancy – Sickle cell disease – Neurodevelopmental disorders or other conditions that confer medical complexity – Medical-related technological dependence
• EUA criteria apply to any patient aged ≥12 years. • Anti-SARS-CoV-2 mAb may be used in a patient hospitalized for a reason other than COVID-19 if they meet other EUA criteria. CKD, chronic kidney disease; CVD, cardiovascular disease NIH. https://www.covid19treatmentguidelines.nih.gov/therapies/anti-sars-cov-2-antibody-products/anti-sars-cov-2-monoclonal-antibodies/. Accessed August 4, 2021.
NIH Treatment Algorithm Recommendations for Use of Anti-SARS-CoV-2 mAbs
Not requiring hospitalization or supplemental oxygen
Discharged from hospital inpatient setting in stable condition Discharged from hospital inpatient setting and requires supplemental oxygen Discharged from ED despite new or increasing need for supplemental oxygen
Anti-SARS-CoV-2 mAbs recommended for outpatients with mild or moderate COVID-19 who are at high risk of disease progression as defined by EUA criteriaa • CAS + IMD or • SOT or • BAM + ETE Recommend against dexamethasone or other systemic glucocorticoids
Must be given within 10 days of symptom onset, preferably as soon as possible after onset of symptoms NIH. https://www.covid19treatmentguidelines.nih.gov/management/clinical-management/nonhospitalized-adults--therapeutic-management/. Accessed September 24, 2021.
Prioritizing Anti-SARS-CoV-2 mAb Use With Logistical Constraints NIH Guidelines
• Prioritization applies only when there are logistical constraints or limited supply • Prioritize treatment over prevention • Prioritize over vaccinated who likely have an adequate immune response:
– Unvaccinated or incompletely vaccinated patients at high risk of progressing to severe COVID-19 – Vaccinated patients who are not expected to mount an adequate immune response
NIH. https://www.covid19treatmentguidelines.nih.gov/therapies/statement-on-the-prioritization-of-anti-sars-cov-2-monoclonal-antibodies/. Accessed September 23, 2021.
ANTI-SARS-COV-2 MABS IN SPECIAL POPULATIONS
Considerations for Anti-SARS-CoV-2 Use in Pediatrics and Pregnancy Pediatric1
• Increased risk for severe disease in those with medical complexity, obesity, cardiopulmonary disease, immunocompromised status, as well as minority populations and older teenagers • Though anti-SARS-CoV-2 mAbs are approved for patients aged ≥12 years, approval is based on extrapolation from adult data – No current data for patients <aged 12 years
• Consult pediatric infectious disease specialist
Pregnancy2
• Can be used in pregnancy, particularly for those who have additional risk factors according to EUA criteria • No pregnancy-specific data
– IgG mAbs cross the placenta and have been used safely in pregnant people – Anti-SARS-CoV-2 mAbs expected to cross placenta as well
• Pregnant people should be included in clinical trials
IgG, immunoglobulin G. 1. NIH. https://www.covid19treatmentguidelines.nih.gov/special-populations/children/. Accessed August 19, 2021; 2. NIH. https://www.covid19treatmentguidelines.nih.gov/therapies/antisars-cov-2-antibody-products/anti-sars-cov-2-monoclonal-antibodies/. Accessed August 19, 2021.
Role of Immunosenescence in COVID-19 Risk Chronological Age
Naïve CD4 + T cells
Activated CD4 + T cells
Activated cytotoxic T cells
Naïve CD8 + T cells
Plasma cells
B cells
SARS-COV-2
Pro-inflammatory cytokines
Memory T and B cell terminally differentiated
Cytokine storm
Airway epithelium Microcirculation
IgM
IFN, interferon; IgM, immunoglobulin M; IL, interleukin. Cunha LL, et al. Front Immunol. 2020;11:1748.
Adaptive immune response
IL-6
IFN-γ
IL-2
IL-8
Disruption of epithelium barrier
Naïve T cell amount IgG
Cytokine storm Organ failure
Endothelial cell
Secondary bacterial infection Acute inflammation
• Endothelial Damage • Disseminated intravascular coagulation • Organ failure
Vaccine Efficacy in Aging Patients – 70% of hospitalizations among vaccinated patients – 87% of deaths among vaccinated patients
• Immunosenescence, leading to reduced vaccine efficacy, may necessitate increased anti-SARS-CoV-2 mAb use in aging patients
COVID-19 Statistics Among Vaccinated People by Age, July 20212 18
16
Ages 18-49 Ages 50-64 Aged ≥65
15
14
12
12
People, %
• Breakthrough cases in patients aged ≥65 years account for1
10
10 8
6
6 4
3
5
2 0
4
3 1 Cases
Hospitalizations
Deaths
1. US News. https://www.usnews.com/news/health-news/articles/2021-09-10/vaccinated-have-1-in-13-000-chance-of-breakthrough-case-needing-hospitalization. Accessed September 15, 2021; 2. CDC. https://www.cdc.gov/mmwr/volumes/70/wr/mm7037e1.htm. Accessed September 15, 2021.
TREATING PATIENTS WITH ANTI-SARS-COV-2 MONOCLONAL ANTIBODIES IN REAL-WORLD PRACTICE Lucy Horton, MD, MPH
Associate Professor of Medicine Infectious Disease Specialist University of California San Diego Health San Diego, California
Current Status of Anti-SARS-CoV-2 mAb Use
Some states have reserved mAbs for patients aged >65 years who are unvaccinated or vaccinated but immunocompromised2
mAbs allocated by Department of Health and Human Services based on COVID-19 case burden and demand1
20-FOLD
Increase in orders since mid July1
50
% Of orders in recent weeks are from Alabama, Florida, Texas, Mississippi, Tennessee, Georgia, and Louisiana1
1. CBS. https://www.cbsnews.com/news/monoclonal-antibodies-covid-19-treatment-florida-texas-states/. Accessed September 27, 2021; 2. WebMD. https://www.webmd.com/lung/news/20210922/some-states-limiting-monoclonal-antibody-treatments. Accessed September 27, 2021.
Logistics for Outpatient mAb Treatment Fast turnaround testing needed to identify patients and treat within time window Real-time communication among key stakeholders – Coordinating physicians, infusion center nurses, and pharmacists
Extended-hours including weekend and holiday staffing Continuous supply of product Dedicated space for infusion of COVID-19 patients separated from non-COVID-19 patients – Infusion time up to 1 hour – Postinfusion monitoring for 1 hour
Courtesy of Lucy Horton, MD, MPH.
UC San Diego Health Model COVID-19 Telemedicine Clinic
• Telemedicine clinic established in March 2020 to care for COVID-19 patients isolating at home • Management of mAb treatment – Screening and consenting patients – Coordination with the infusion center – Postinfusion monitoring and follow-up care
• On-site infusion center at hospital dedicated to COVID-19 to prevent patient mixing • Operates 7 days/week, including holidays
Courtesy of Lucy Horton, MD, MPH.
UC San Diego Health Model Infusion Center Staffing
Infectious diseases physician or Advanced Practice Provider: screen patient for eligibility, obtain consent and place orders, provide counseling and education for patient; daily on-call physician
Pharmacists: support with mAb ordering, storage, dosing
Nurses at infusion center to administer mAbs therapy, monitor patients following infusion, and address infusion reactions (experienced phlebotomist often needed)
Support/administrative staff: scheduling telemedicine and infusion visits, coordination of insurance, assist with communications between ID team, pharmacy, infusion center
ID, infectious diseases. Courtesy of Lucy Horton, MD, MPH.
UC San Diego Health Model Process
Ambulatory Results team calls all patients with a new positive test (within 12-24 hours of positive test) to disclose result, triage for monitoring, provide isolation and quarantine instructions • Potential candidates for mAb referred to the ID telemedicine clinic (team notified via secure chat on Epic)
1
2
ID nurse and/or on-call provider prescreens patient IC, infusion center. Courtesy of Lucy Horton, MD, MPH.
3
Same-day telemedicine appointment with ID provider
4
Once patient consented, ID provider places infusion orders; IC staff paged to coordinate patient scheduling
5
Ongoing communication with IC to update appointment times and availability
6
If limited availability, ID provider prioritizes candidates according to risk scores and time since onset of symptoms
UC San Diego Health Model Example of Staff Communication
Ken Adams, MD
Jorge Rios
Patient G.D. consented to mAb treatment. Orders are in
Jorge Rios Thank you Dr Adams. Paging now.
@Dr Adams, Dr Karper I have page for both patients
Grace Cheu Dr Karper, I added 1 more patient for 10:30. I wasn’t able to add him for 10:00 AM because he was expecting a call from his PCP
Page was received. They will be contacting G.D. in a few minutes Hi Dr Adams I’m already paging IC for J.B.
Ken Adams, MD J.B. consented to mAb treatment. Orders in
Kathy Karper, MD M.H. consented and orders are in Courtesy of Lucy Horton, MD, MPH.
Jorge Rios INFUSION SCHEDULE UPDATE Thursday 09/13/21 Update Time Booked/Openings 0830: 1 opening 1030: G.D. 1030: J.B 1130: M.A? Still admitted at this time 1230: R.D. 1330: A.T. 1430: 1 opening 1430: 1 opening
UC San Diego Health Model
COVID-19 Therapeutics Committee Guidelines Scoring System for mAb Therapy Point
Criteria
Point
Criteria
3
Unvaccinated
2
Neurodevelopmental disorder
3
Aged ≥65 years
2
3
BMI ≥35 kg/m2
Medical-related technological dependence
3
Immunocompromised status
2
Diabetes
2
Aged 55-64 years
2
CKD
2
BMI 30-35 kg/m2
2
Pregnancy
2
CVD or HTN
1
Non-White race or ethnicity
2
Chronic lung disease
1
Aged 40-54 years
2
Sickle cell disease
HTN, hypertension. Courtesy of Lucy Horton, MD, MPH.
UC San Diego Health Model Pros & Cons Pros
• Rapid identification and scheduling of eligible patients • Led by group of ID physicians with extensive experience managing high-risk patients in ambulatory setting • “Gatekeeper” approach to ensure equity and prioritize based on risk status Courtesy of Lucy Horton, MD, MPH.
Cons
• Requires on-call physician 365 days per year • Availability of infusion slots per day is limited by staffing – current staffing shortage system-wide • Insurance barriers for some patients
Commonly Asked Questions From Patients About mAb Therapy Will my symptoms resolve quicker if I get mAb therapy? How is it different from a vaccine?
Will I need to postpone my vaccination (or booster dose)?
Are they safe? How much does it cost? Courtesy of Lucy Horton, MD, MPH.
Do I need mAbs if I’m high risk but fully vaccinated?
What are the risks involved, or potential side effects?
Exploring SARS-CoV-2 Variant Differences
Variant Predominance in the US 6/5/21-8/28/211
Differences in Variant Mutations2
100 90
Alpha Beta Gamma Delta Iota Mu Other
80
Cases, %
Alpha
70 60 50 40 30 20
Beta
Delta
9/18/2021
9/11/2021
9/4/2021
8/28/2021
8/21/2021
8/14/2021
8/7/2021
7/31/2021
7/24/2021
7/17/2021
7/10/2021
7/3/2021
6/26/2021
6/19/2021
6/12/2021
0
6/5/2021
10
1. CDC. https://covid.cdc.gov/covid-data-tracker/#variant-proportions. Accessed September 27, 2021; 2. Wall EC, et al. Lancet. 2021;397(10292):2331-2333.
Mutation Sites
Changes in Anti-SARS-CoV-2 mAb Susceptibility by Variant WHO Label
Pango Lineage
Notable Mutations
Alphaa,b
B.1.1.7
Betaa,b
BAM + ETE
CAS + IMD
SOT
In Vitro Susceptibilityd
Activitye
In Vitro Susceptibilityd
Activitye
In Vitro Susceptibilityd
Activitye
N501Y
No change
Active
No change
Active
No change
Active
B.1.351
K417N, E484K, N501Y
Marked change
Unlikely to be active
No changeg
Active
No change
Active
P.1
K417T, E484K, N501Y
Marked change
Unlikely to be active
No changeg
Active
No change
Active
Deltaa,c
B.1.617.2
L452R
No change
Likely to be active
No change
Active
No change
Active
Epsilonb
B.1.429/B. 1.427
L452R
Modest changef
Likely to be active
No change
Active
No change
Active
B.1.526
E484K
Modest change
Likely to be active
No changeg
Active
No change
Active
Gammaa, b
Iotab aWorld
Health Organization variant of concern; bCDC variant being monitored; cCDC variant of concern; dBased on fold reduction in susceptibility reported in FDA EUAs; eAnticipated clinical activity against the variant based on in vitro studies; fETE retains activity; gMarked change for CAS but no change for IMD; combination appears to retain activity. CDC. https://www.cdc.gov/coronavirus/2019-ncov/variants/variant-info.html. Accessed September 28, 2021; WHO. https://www.who.int/en/activities/tracking-SARS-CoV-2-variants/. Accessed September 28, 2021.
ADDRESSING DISPARITIES IN PATIENT USE OF ANTISARS-COV-2 MONOCLONAL ANTIBODIES Monica Gandhi, MD, MPH
Professor of Medicine Associate Division Chief, Division of HIV, Infectious Disease, and Global Medicine University of California, San Francisco Medical Director, HIV Clinic San Francisco General Hospital San Francisco, California
Disparities and Inequity in COVID-19 Prevalence
COVID-19 Statistics by Race/Ethnicity1
Cases
70
Asian Black
Hispanic/ Latino
0.7x
1.1x
1.9x
Hospitalization
1x
2.8x
2.8x
Death
1x
2x
2.3x
60
Population, %
Ratio vs White, nonHispanic people
Racial/Ethnic Breakdown of People Receiving a COVID-19 Vaccine2 Fully Vaccinated
61.3 61.2
Percentage of US Population
50 40 30 20
16.7 17.2 6.4
10 0
Hispanic/ Latino
5.8
Asian
10.1 12.4
Black
4.3 White
2.3
Multiple/ Other
Patients accepting mAbs most likely to be non-Hispanic White patients.3 1. CDC. https://www.cdc.gov/coronavirus/2019-ncov/covid-data/investigations-discovery/hospitalization-death-by-race-ethnicity.html. Accessed September 15, 2021; 2. CDC. https://covid.cdc.gov/covid-data-tracker/#vaccination-demographic. Accessed September 27, 2021; 3. Bierle DM, et al. J Prim Care Community Health. 2021;12:21501327211019282.
Rationale for Disparities in COVID-19 Care and Anti-SARS-CoV-2 mAb Access Access to care
Socioeconomic
Lack of representation in anti-SARS-CoV-2 mAb clinical trials
Disproportionate burden of comorbidities Discrimination
Medical mistrust
COVID-19 Health Disparities
Unemployment ? Biological mechanisms Bierle DM, et al. J Prim Care Community Health. 2021;12:21501327211019282; Haynes N, et al. Circulation. 2020;142(2):105-107.
Poor health literacy
Lack of insurance
Cultural
Increased Risk of COVID-19 Among Racial and Ethnic Minorities
• Racial and ethnic minority groups more likely to
– Live in areas of high COVID-19 incidence
• Higher deprivation areas • Higher social and economic inequities
– Experience crowded living conditions or unstable housing • • • •
Higher unemployment Multigenerational housing High population density Inability to isolate
• Be employed as an essential worker – Higher COVID-19 exposure – Lack of paid sick leave
• Have lower education and income levels
– Lower health literacy – Lower paying jobs with limited job options; increased exposure to COVID-19
• Be less likely to have access to health care
CDC. https://www.cdc.gov/coronavirus/2019-ncov/community/health-equity/racial-ethnic-disparities/increased-risk-exposure.html. Accessed September 15, 2021.
Local Epidemiology of COVID-19 in San Francisco
Chamie G, et al. Clin Infect Dis. 2021;73(suppl 2):S127-S135.
Breakthrough Infections and Outpatient Infections in the Latinx Community in San Francisco
• Crowded living environments • High rates of household transmission • Uninsured patients pose special challenges to administration of mAbs • Language and cultural competency required • Community-based programs throughout pandemic in San Francisco have built up trust
Courtesy of Monica Gandhi, MD, MPH.
Developing Program at San Francisco General Hospital
• Disparities in city exist in administration of anti-SARS-CoV-2 mAb treatment • Provided only in ED at SFGH currently • Outpatient program is developing, involving:
– Social worker to quickly establish insurance eligibility based on our model of RAPID ART delivery program in HIV – LVN for SQ administration of anti-SARS-CoV-2 mAbs in testing plaza on campus – RN for monitoring with physician oversight
LVN, licensed vocational nurse; RN, registered nurse; SFGH, San Francisco General Hospital. Courtesy of Monica Gandhi, MD, MPH.
Addressing Disparities in COVID-19 Care and Anti-SARS-CoV-2 mAb Access Protect workers
Involve FQHCs
Partner with community members Policy initiatives to address disparities (local and federal)
Provide food
Solutions
Safe and viable transportation options Expanded and easily accessible testing
Expand housing
Expand health care coverage Support education
Establish temporary infusion sites
Improve computer and internet access
FQHC, Federally Qualified Health Center. Haynes N, et al. Circulation. 2020;142(2):105-107; National Academies of Sciences, Engineering, and Medicine. Rapid Expert Consultation on Allocating COVID-19 Monoclonal Antibody Therapies and Other Novel Therapeutics. 2021; Washington, DC: The National Academies Press.
Conclusions • Anti-SARS-CoV-2 mAbs can be used for both outpatient treatment of mild or moderate COVID-19 and postexposure prophylaxis • Criteria for high-risk patients and optimal management strategies are expanding and rapidly changing • Established COVID-19 clinic and infusion center protocols can aid in setup of additional clinics • Inequity in anti-SARS-CoV-2 mAbs remain and clinicians should incorporate strategies to expand patient accessibility