Where Is COVID-19 Now? Cases in the United States1
Hot Spots in Areas With Low Vaccination2
Daily Cases
42,465,029 300k 200k
Trends in COVID-19 Cases3
Mar 2, 2020 New cases: 16 7-day avg:16
100k 0
55
%
Fully Vaccinated Americans1 Unvaccinated people are much more likely to be hospitalized with COVID-19 or die from COVID-194
May 16 Aug 6 Oct 27 Jan 17 Apr 9 Jun 30 Sep 20
1. Google. https://news.google.com/covid19/map?hl=en-US&mid=%2Fm%2F09c7w0&gl=US&ceid=US%3Aen&state=3. Accessed September 23, 2021; 2. Washington Post. https://www.washingtonpost.com/health/interactive/2021/vaccinated-counties-delta-hotspots/. Accessed September 17, 2021; 3. CDC. https://www.cdc.gov/coronavirus/2019-ncov/coviddata/covidview/index.html. Accessed September 23, 2021; 4. New York Times. https://www.nytimes.com/interactive/2021/08/10/us/covid-breakthrough-infections-vaccines.html. Accessed August 30, 2021.
What Is the Current Status of Anti-SARS-CoV-2 Monoclonal Antibodies? Onyema Ogbuagu, MBBCh
Associate Professor of Medicine Director, HIV Clinical Trials program, Yale AIDS Program, Infectious Diseases Yale School of Medicine New Haven, Connecticut
Which anti-SARS-CoV-2 mAbs have an EUA and how do you choose which one to use?
Targeting SARS-CoV-2 Spike Protein • Spike protein has S1 and S2 subunits1
– Receptor binding domain (RBD) is where S1 binds to ACE2 on host cell – Conformational change in S2 induced by TMPRSS2 results in viral entry
SARS-CoV-2 Binding to ACE2 Receptor2
Coronavirus spike protein
Nucleocapsid RNA viral genome Membrane protein Spike envelope protein
• ACE2 involved in cardiovascular and respiratory diseases, amino acid absorption in gut and kidney2 • Anti-SARS-CoV-2 mAbs target spike protein RBD and prevent binding to ACE21
TMPRSS2
ACE2 ACE2 receptor
ACE2, angiotensin converting enzyme 2; TMPRSS2, transmembrane serine protease 2. 1. Lan J, et al. Nature. 2020;581(7807):215-220; 2. Wiese O, et al. J Clin Pathol. 2021;74(5):285-290.
Anti-SARS-CoV-2 mAb Binding Sites • Anti-SARS-CoV-2 bind to different places on spike protein RBD – Combination therapies bind to noncompeting regions
RBD Regdanvimab Sotrovimab
Tixagevimab
Bamlanivimab
Imdevimab Cilgavimab
180⁰
BioRxiv. biorxiv.org/content/10.1101/2020.12.23.424199v1.full.pdf. Accessed August 5, 2021.
Etesevimab Casirivimab
Anti-SARS-CoV-2 Monoclonal Antibodies With Current FDA EUA for Treatment mAb
Indication
Dosage and Route of Administration
Casirivimab (CAS) + Imdevimab (IMD)1
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 if IV infusion would delay treatment or is not feasible
Treatment of nonhospitalized patients aged ≥12 years with mild to moderate COVID-19 who are at risk for progressing to severe disease
500 mg IV as possible after positive SARS-CoV-2 test and within 10 days of symptom onset
Treatment of nonhospitalized patients aged ≥12 years with mild to moderate COVID-19 who are at risk for progressing to severe diseasea
700 mg BAM + 1400 mg ETE IV as possible after positive SARS-CoV-2 test and within 10 days of symptom onset
Sotrovimab
(SOT)2
Bamlanivimab (BAM) + Etesevimab (ETE)3 aBAM
+ ETE may be used in states in which combined frequency of variants resistant to BAM + ETE is ≤5%. EUA, emergency use authorization; FDA, US Food and Drug Administration; IV, intravenous; SQ, subcutaneous. 1. FDA. https://www.fda.gov/media/145611/download. Accessed September 23, 2021; 2. FDA. https://www.fda.gov/media/149534/download. Accessed September 23, 2021; 3. FDA. https://www.fda.gov/media/145801/download. Accessed September 23, 2021.
Anti-SARS-CoV-2 Monoclonal Antibodies With Current FDA EUA for Prevention Dosage and Route of Administration
mAb
Indication
CAS + IMD1
Postexposure prophylaxis for patients aged ≥12 years who are at high 600 mg CAS + 600 mg IMD risk of progression to severe COVID-19 and are not fully vaccinated or not expected to mount an adequate immune response to complete SQ vaccination who have had close contact with a patient infected with Can be administered IV SARS-CoV-2 or are at high risk of exposure because of existing infection in the same institutional setting
BAM + ETE2
Postexposure prophylaxis for patients aged ≥12 years who are at high risk of progression to severe COVID-19 and are not fully vaccinated or not expected to mount an adequate immune response to complete 700 mg BAM + 1400 mg ETE IV vaccination who have had close contact with a patient infected with SARS-CoV-2 or are at high risk of exposure because of existing infection in the same institutional setting
1. FDA. https://www.fda.gov/media/145611/download. Accessed September 23, 2021; 2. FDA. https://www.fda.gov/media/145801/download. Accessed September 23, 2021.
History and Current Status of anti-SARS-CoV-2 mAb EUAs
November 2020
FDA issues EUA for outpatient treatment with CAS + IMD combination2
April 2021
FDA revoked EUA for BAM monotherapy2
June 2021
CAS/IMD EUA updated with reduced dosages and possibility for SQ administration3
July 2021
FDA revises CAS + IMD EUA to include postexposure prophylaxis4
November 2020 November 2020
FDA issues EUA for outpatient treatment with BAM monotherapy1
September 2021
FDA revises BAM + ETE EUA to include postexposure prophylaxis5
September 2021 February 2021
FDA issues EUA for administration of BAM + ETE combination2
May 2021
FDA issues EUA for SOT use in outpatient treatment2
June 2021
Distribution of BAM + ETE paused3
August 2021
BAM + ETE may be used in states in which combined frequency of variants resistant to BAM + ETE is ≤5%5,a
CMS, Centers for Medicare & Medicaid Services; NIH, National Institutes of Health. aAs of September 2, 2021, this includes all 50 states. 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.
SARS-CoV-2 Viral Load With BAM Monotherapy vs BAM + ETE BLAZE-1
8 6 4 2 0 -2 -4 -6 -8 -10
700 mg BAM
12
Treatment-Emergent BAM-Resistant Variants 11.3
9.8
10
Variants, %
Change From Baseline for Log Viral Load
Primary Endpoint: Change in SARS-CoV-2 Log Viral Load
8
7.1
6 4 2
Day 3
Day 7 2800 mg BAM
2800 mg BAM and 2800 mg ETE
Day 11 7000 mg BAM Placebo
0
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.
CAS + IMD Outpatient Treatment Reduces Hospitalization and All-Cause Death
Patients, %
Primary Endpoint: Hospitalization and All-Cause Death 5 4.5 4 3.5 3 2.5 2 1.5 1 0.5 0
aP<0.0024; bP<0.0001.
3.2
70% relative reduction
• Patients taking CAS + IMD: – – – – –
Shorter hospitalization Lower rate of ICU admission Symptoms resolved soonerb More rapid viral load reduction Fewer SAEs (SAEs largely due to COVID19)
1a
Placebo
CAS + IMD 1200 mg
Phase 3 portion of the adaptive, randomized, master protocol. 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].
SOT Outpatient Treatment Reduces Hospitalization and All-Cause Death COMET-ICE Trial
Patients, %
Full Analysis Primary Endpoint: Hospitalization or All-Cause Death1 7 6 5 4 3 2 1 0
aPossible
6
79% relative reduction 1b Placebo
SOT a
• Interim analysis showed:c
– No patients in the SOT group were admitted to the ICU2 – Fewer ED visits or hospitalizations for <24 hours were seen in the SOT group vs placebo2 – AE rates were similar between groups, though there were fewer grade 3 or 4 AEs in the SOT group2
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. Ongoing, multicenter, double-blind phase 3 trial. N=1057 adults with mild to moderate COVID-19 who were at high risk (age ≥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].
CAS + IMD for Prevention of COVID-19 Among Patients Testing Negative for SARSCoV-2 Following Household Exposure Cumulative Incidence, %
Primary Endpoint: Incidence of Symptomatic Infection 10 6
7.8% Placebo
4
CAS + IMD
2 0
aP<0.001.
81% relative risk reduction
8
0 1
8
15
22
1.5%
a
• 66% relative risk reduction in overall symptomatic and asymptomatic infection with CAS + IMD • Among symptomatic infected participants, median time to symptom resolution was 2 weeks shorter than placebo • Shorter duration of high viral load with CAS + IMD (0.4 weeks vs 1.3 weeks)
29
Trial Day
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].
Who Should Be Treated With Anti-SARS-CoV-2 Monoclonal Antibodies? Eric S. Daar, MD
Chief, Division of HIV Medicine, Harbor-UCLA Medical Center Investigator, Lundquist Institute for Biomedical Innovation Professor of Medicine, David Geffen School of Medicine, University of California, Los Angeles Los Angeles, California
Clinical Spectrum of COVID-19 NIH Guideline Definitions
Mild Illness Moderate Illness
• Various signs and symptoms of COVID-19 • No shortness of breath, dyspnea, or abnormal chest imaging • Evidence of lower respiratory disease during clinical assessment or imaging • SpO2 ≥94% on room air at sea level • SpO2 <94% on room air at sea level
Severe Illness
• 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 a high risk for disease progression. NIH, National Institutes of Health; 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.
Management of Nonhospitalized Patients Anti-SARS-CoV-2 mAbs in Mild or Moderate COVID-19
• Isolate for 10 days following start of symptoms • Advise when to contact clinician for in-person evaluation • Symptom management
– Analgesics, antitussives, antipyretics – Prone position or breathing exercises among those with dyspnea
• 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 criteria • If patient has access to pulse oximeters at home, patients should inform clinician if SpO2 <95% • Anti-SARS-CoV-2 mAbs should not be used in hospitalized patients or those requiring supplemental oxygen
Must be given as soon as possible following positive viral test and within 10 days of symptom onset NIH. https://www.covid19treatmentguidelines.nih.gov/management/clinical-management/nonhospitalized-adults--therapeutic-management/. Accessed August 18, 2021.
Current EUA Criteria for the Use of Anti-SARS-CoV-2 mAbs
Risk Factors for COVID-19 Progression to Severe Disease Represented in Clinical Trials of Anti-SARS-CoV-2 mAbs
– – – –
Aged ≥65 years Obesity (BMI ≥30 kg/m2) Diabetes CVD (including congenital heart disease) or hypertension – Chronic lung diseases
Limited Representation in Clinical Trials of Anti-SARS-CoV-2 mAbs
– 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
Anti-SARS-CoV-2 mAbs may be used in patients who are hospitalized for a diagnosis other than COVID-19 as long as they meet the 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.
Patient Identification Through Risk Index Atlanta Veterans Affairs System
Criteria History of diabetes Chronic pulmonary disease Renal disease Peripheral vascular disease Congestive HF Dementia Cancer Cerebrovascular accident Liver disease MI Peptic ulcer disease Paralysis AIDS HF, heart failure; MI, myocardial infarction. Paras A, et al. IDWeek 2021. Abstract 544.
Points
1 (without complications) 2 (with complications) 1 2 1 1 1 2 (except skin cancer) 6 (metastatic) 1 1 (mild) 3 (moderate or severe) 1 1 1 6
• Combined laboratory surveillance with active screening – Minimized delay in receiving anti-SARS-CoV-2 mAbs – Study population was primarily non-White (65%) – Results similar to clinical trials
How Do We Use AntiSARS-CoV-2 Monoclonal Antibodies in Real-World Practice? Myron J. Levin, MD
Associate Director, Pediatric HIV Clinic Professor of Pediatrics and Medicine University of Colorado School of Medicine Aurora, Colorado
Linkage Between Testing and Anti-SARS-CoV-2 mAb Infusion
Patient arrives for testing Will have either immediate (rapid) answer or delayed (PCR) answer
If positive, patient referred to infusion site May be where tested or may require referral to a new site
Treatment scheduled for administration as soon as possible following result (EUAs state mAb should be administered <10 days from onset of symptoms)
Patient counseled and consents to treatment, then mAb administered
DHHS, Department of Health and Human Services; PCR, polymerase chain reaction. DHHS. https://www.phe.gov/emergency/events/COVID19/investigation-MCM/Documents/USG-COVID19-Tx-Playbook.pdf. Accessed August 18, 2021.
Patient completes monitoring and leaves the facility, telemedicine follow-up
Establishing Workflow Protocol to Deliver Anti-SARS-CoV-2 mAbs
Positive SARSCoV-2 PCR result
YES
YES
Does patient have a PCP and can they call the patient?
NO Monitor for changes AS, Antimicrobial Stewardship. Patel PC, et al. IDWeek 2021. Abstract 537.
Offer the patient a method of contacting the VA should they change their mind
YES PCP calls patient to verify eligibility and review fact sheet. Does the patient want to proceed?
YES NO YES
VA staff or PCP call patient within 1 week to discuss clinical status Follow-up form with infusion details completed after infusion and postinfusion monitoring
NO
Surveillance software reports results for all patients with positive test Meet mAb EUA criteria?
NO
AS team calls patient to verify eligibility and review fact sheet. Does the patient want to proceed?
Coordinate appointment scheduling with ED/infusion provider, coordinate staffing needs
Patient evaluated, eligibility confirmed, order placed, and infusion coordinated by AS team Day of infusion
Requirements for Anti-SARS-CoV-2 mAb Administration
• Dedicated infusion space
– Existing hospital infusion centers may serve immunocompromised patients – Could use urgent care clinics, community sites, or other health care facilities
• Staffing to manage patient flow, prepare and administer mAb, monitor patients, and address potential infusion reactions • Infusion may take up to 1 hour plus 1 hour postinfusion observation for both IV and SQ administration – Must have access to emergency medical services and medications to treat severe infusion reactions during postinfusion monitoring
DHHS. https://www.phe.gov/emergency/events/COVID19/investigation-MCM/Documents/USG-COVID19-Tx-Playbook.pdf. Accessed August 18, 2021.
Impact of SARS-CoV-2 Variants on Anti-SARS-CoV-2 mAb Susceptibility WHO Label
Pango Lineage
Notable Mutations
Alphaa,b
B.1.1.7
Betaa,b Gammaa,b Deltaa,c Epsilonb Iotab aWorld
BAM + ETE
CAS + IMD
In Vitro Susceptibilityd
Activitye
In Vitro Activitye Susceptibilityd
N501Y
No/minor change
Active
No/minor change
B.1.351
K417N, E484K, N501Y
Marked change
Unlikely to be active
P.1
K417T, E484K, N501Y
Marked change
B.1.617.2
L452R
B.1.429/B.1. 427 B.1.526
SOT In Vitro Susceptibilityd
Activitye
Active
No/minor change
Active
No/minor changeg
Active
No/minor change
Active
Unlikely to be active
No/minor changeg
Active
No/minor change
Active
No/minor change
Likely to be active
No/minor change
Active
No/minor change
Active
L452R
Modest changef
Likely to be active
No/minor change
Active
No/minor change
Active
E484K
Modest change
Likely to be active
No/minor changeg
Active
No/minor change
Active
Health Organization (WHO) variant of concern; bCDC variant being monitored; cCDC variant of concern; dBased on fold reduction in susceptibility reported in FDA EUAs; 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. eAnticipated
40
Common Barriers to the Use of AntiSARS-CoV-2 mAbs
Respondents, %
35 30 25 20 15 10 5 0
Patient reluctance
Lack of Accessibility Lack of clinic Accessibility Lack of Unsure Lack of Lack of familiarity of mAbs protocols of infusion familiarity efficacy and guidance about patient with evolving services with evolving safety data according to selection NIH variant EUA criteria guidelines prevalence
Integritas Communications. Premeeting survey, N=122. August 2021.
What’s New and Where Are We Going With Anti-SARSCoV-2 Monoclonal Antibodies? Myron J. Levin, MD
Associate Director, Pediatric HIV Clinic Professor of Pediatrics and Medicine University of Colorado School of Medicine Aurora, Colorado
PREVENTION
Efficacy of BAM in Preventing COVID-19 in Nursing and Assisted Living Facilities BLAZE-2 Phase 3 Trial
Primary Endpoint: Symptomatic Mild or Worse COVID-19 by Day 57 25
Placebo
20
20
15
BAM
10
Staff,, %
Residents, %
25
a
10
5
5
0
0
1
8
15 22 29 36 43 50
57
Time Since Infusion, days aP<0.001.
Placebo
15
• BAM associated with lower incidence of SARSCoV-2 infection vs placebo (15% vs 31.9% for residents; 19.3% vs 19.8% for staff)
BAM 1
8
15 22 29 36 43 50
57
Time Since Infusion, days
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.
Emerging Long-ActingAnti-SARS-CoV-2 mAb for Prevention AZD7442
• Tixagevimab + cilgavimab (AZD7442) is a long-acting mAb combination1,2 • Binds to distinct sites on the spike protein1,2 – Noncompeting sites; synergistic
• Half-life extension and reduced risk of antibody-dependent enhancement of disease1,2 – Triples durability of its action – May afford up to 12 months of protection from COVID-19
• Preliminary findings indicate efficacy against delta and mu variants3 • Given IM1,2 IM, intramuscularly. 1. Dong J, et al. bioRxiv. 2021 [ePub ahead of print]; 2. Precision Vaccinations. https://www.precisionvaccinations.com/vaccines/covid-19-antibody-azd7442. Accessed September 21, 2021; 3. National Center for Advancing Translational Sciences. https://opendata.ncats.nih.gov/variant/activity. Accessed September 28, 2021.
AZD7442 for Preexposure Prophylaxis PROVENT Trial
Patients, %
Primary Endpoint: First Case of SARS-CoV-2 PCR Positive Symptomatic Illness Post Dose 1.2 1
1
0.8
77% relative reduction
0.6 0.4
0.2 a
0.2 0 aP<0.001.
Placebo
• 25 symptomatic cases at the primary analysis • No cases of severe COVID-19 or COVID-19-related deaths with AZD7442 • Well tolerated and few AEs – Similar between AZD7442 and placebo
AZD7442
N=5197 unvaccinated adults in the US, United Kingdom (UK), Spain, France, and Belgium who where at high risk of inadequate response to vaccination or at high risk of SARS-CoV-2 infection were randomly assigned 2:1 to 1 IM dose of AZD7442 vs placebo given as 2 separate sequential injections. AstraZeneca. https://www.astrazeneca.com/media-centre/press-releases/2021/azd7442-prophylaxis-trial-met-primary-endpoint.html#!. Accessed August 30, 2021.
AZD7442 for Postexposure Prophylaxis STORM CHASER Phase 3 Trial
SARS-CoV-2 Baseline Status PCR ≤8 days
+
PCR
–
Exposure to individual with SARS-CoV-2
Randomized 2:1
Primary Endpoint: Individuals With Symptomatic COVID-19 AZD7442
23/749 (3%)
Placebo
17/372 (4.6%) 33% risk reduction vs placeboa
statistically 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 IM injections or placebo. AstraZeneca. https://www.astrazeneca.com/media-centre/press-releases/2021/update-on-azd7442-storm-chaser-trial.html. Accessed August 13, 2021. aP=not
AZD7442 for Postexposure Prophylaxis STORM CHASER Preplanned Subgroup Analysis
Individuals With Symptomatic COVID-19
SARS-CoV-2 Baseline Status Randomized 2:1 ≤8 days
Exposure to individual with SARS-CoV-2
PCR
–
AZD7442
6/715 (0.8%)
Placebo
11/358 (3%)
Includes individuals who had circulating virus below the threshold of PCR detection and those with missing PCR status at baseline
https://www.astrazeneca.com/media-centre/press-releases/2021/update-on-azd7442-storm-chaser-trial.html
73% risk reduction vs placebo
HOSPITALIZED PATIENTS
Can Anti-SARS-CoV-2 mAbs Be Effective in Hospitalized Patients? ACTIV-3
• BAM monotherapy substudy halted enrollment in October 2020 due to futility1
– 50% of patients receiving BAM and 54% in placebo group were in 1 of the 2 most favorable categories of the pulmonary outcome
• Enrollment closed for BRII-196/BRII-198 and SOT arms2
– BRII-196/BRII-198 arm was suspended due to futility – SOT arm was suspended because patients in the placebo group had more advanced illness vs the SOT arm • Data showed futility after adjustment for imbalance
ACTIV-3 has multiple substudies examining potential COVID-19 treatments vs placebo. Participants must be aged ≥18 years, have a positive test for COVID-19, progressing disease, and symptoms for ≤12 days. Patients could not have previous SARS-CoV-2 IV immunoglobulin, convalescent plasma from a patient who had recovered from COVID-19, or another antiSARS-CoV-2 mAb. All patients receive supportive care as background therapy (including remdesivir, supplemental oxygen, or glucocorticoids where appropriate). Futility analyses are conducted after the first 300 patients are enrolled in each substudy. 1. Lundgren JD, et al. N Engl J Med. 2021;384(10):905-914; 2. NIH. https://www.nih.gov/news-events/news-releases/nih-sponsored-activ-3-clinical-trial-closes-enrollment-into-two-substudies. Accessed August 19, 2021.
CAS + IMD Reduces Risk of Death in Seronegative Hospitalized Patients RECOVERY Trial
Patient Mortality, %
Mortality Reduction at Day 28 Among Severe, Seronegative Hospitalized Patients 35
30 25 20
Usual care CAS + IMD 21
30 20
24a
15 10 5 0
aP=0.001.
All patients
Seronegative
• Among seronegative patients, CAS + IMD resulted in: – Shorter duration of hospital stay (13 days vs 17 days) – Greater proportion discharged alive by day 28 (64% vs 58%) – Reduced risk of progressing to invasive mechanical ventilation or death (30% vs 37%)
• Results not replicated in overall study population
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].
Selected Ongoing Anti-SARS-CoV-2 mAb Trials Treatment Outpatient • 3 phase 2 or phase 3 trials1-4 – Multiple anti-SARS-CoV-2 mAbs, pediatric trial, and new route of administration
Preexposure Prophylaxis
Postexposure Prophylaxis
Phase 2/3 trial in patients at increased risk for COVID-19 due to either risk factors or poor vaccine response7
Phase 2/3 trial in patients at high risk who have been exposed to a patient with confirmed COVID-197
Hospitalized
• 2 phase 3 trials involving multiple anti-SARS-CoV-2 mAbs5,6 1. ClinicalTrials.gov. https://clinicaltrials.gov/ct2/show/NCT04518410. Accessed August 18, 2021; 2. ClinicalTrials.gov. https://clinicaltrials.gov/ct2/show/NCT04723394. Accessed August 18, 2021; 3. ClinicalTrials.gov. https://clinicaltrials.gov/ct2/show/NCT04992273. Accessed August 18, 2021; 4.ClinicalTrials.gov. https://clinicaltrials.gov/ct2/show/NCT04913675. Accessed September 10, 2021; 5. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT04501978. Accessed August 18, 2021; 6. ClinicalTrials.gov. https://clinicaltrials.gov/ct2/show/NCT04315948. Accessed August 18, 2021; 7. ClinicalTrials.gov. https://clinicaltrials.gov/ct2/show/NCT04859517. Accessed August 19, 2021.
How Can We Reduce Disparities in the Use of Anti-SARS-CoV-2 Monoclonal Antibodies? Onyema Ogbuagu, MBBCh
Associate Professor of Medicine Director, HIV Clinical Trials program, Yale AIDS Program, Infectious Diseases Yale School of Medicine New Haven, Connecticut
I know there are many patients who either choose not to use or can’t access anti-SARS-CoV-2 mAbs. How can we help all patients access them?
Examining Disparities in COVID-19 Prevalence and Care
Racial/Ethnic Breakdown of People Receiving a COVID-19 Vaccine1 70
Population, %
60
Fully Vaccinated
Percentage of US Population
– Most likely to be nonHispanic White patients with English as their primary language
50 40 30 20 10 0
• Only 59% of eligible patients at the Mayo Clinic Midwestern practice accepted mAbs2
Hispanic/ Latino
American Indian
Asian
Black
White
Multiple/ Other
– Higher hospitalization rates for non-White, nonEnglish speaking patients, particularly among those who declined mAbs
1. CDC. https://covid.cdc.gov/covid-data-tracker/#vaccination-demographic. Accessed August 30, 2021; 2. Bierle DM, et al. J Prim Care Community Health. 2021;12:21501327211019282.
Reasons for Disparities in COVID-19 Care
• Lack of representation in anti-SARS-CoV-2 mAb clinical trials • Medical mistrust • Cultural differences • Language differences • Concerns about immigration status • Medical misinformation
• Lack of insurance or underinsured • Poor health literacy • Deficits in social determinants of health • Transportation • Inability to take time off work
Education Access and Quality
Health Care and Quality
Neighborhood and Built Environment
Social and Community Context
Economic Stability
Patient education is critical to increasing rate of mAb acceptance. Bierle DM, et al. J Prim Care Community Health. 2021;12:21501327211019282.
Patient Barriers to anti-SARS-CoV-2 mAb Access
Reasons Patients Did Not Receive Anti-SARS-CoV-2 mAbs Hospitalized prior to infusion 3%
Other 15%
Declined 37%
Polk C, et al. IDWeek 2021. Abstract 550.
Out of window 12%
Transportation problem 4%
Asymptomatic/ feeling better 11%
Unable to contact 18%
• Patients could access either BAM or CAS + IMD • Large healthcare system with program to proactively identify and treat patients
Disparities in COVID-19 Prevalence and Trial Enrollment by Race/Ethnicity
• People of color are disproportionately affected by COVID-19, frequently due to social determinants of health, medical mistrust, or reduced access to care1 Race2
Prevalence Ratio
Hospitalization Ratio
Mortality Ratio
White
0.7
0.74
0.82
Black
1.79
1.87
1.68
Hispanic
1.78
1.32
0.94
• Despite being disproportionately affected by COVID-19, people of color are not typically adequately represented in clinical trials of anti-SARS-CoV-2 mAbs BLAZE-12
CAS + IMD Outpatient3
CAS + IMD Prevention4
COMET-ICE5
RECOVERY6
White, %
88
84
86
87
78
Black, %
7
5
9
7
12
Race
1. Mude W, et al. J Glob Health. 2021;11:05015; 2. Chen P, et al. N Engl J Med. 2021;384(3):229-237; 3. Weinreich DM, et al. medRxiv. 2021. [Epub ahead of print]; 4. O’Brien MP, et al. N Engl J Med. 2021. [Epub ahead of print]; 5. Gupta A, et al. medRxiv. 2021. [Epub ahead of print]; 6. Horby PW, et al. medRxiv. 2021. [Epub ahead of print].
Accuracy of Pulse Oximetry Implications for Minority Populations
• Study of patients receiving supplemental oxygen at University of Michigan Hospital and in a multicenter cohort of patients in the ICU • Adjusted for age, sex, and CV score on Sequential Organ Failure Assessment in University of Michigan cohort Race White Black
Arterial Oxygen Saturation <88% U Michigan cohort, U Michigan cohort, % adjusted, % 3.6 3.6 11.7 11.4
Multicenter cohort, % 6.2 17
May result in Black patients not receiving appropriate COVID-19 treatment or recognition of severity N=10,789 pairs of measures of oxygen saturation by pulse oximetry and arterial oxygen saturation in arterial blood gas obtained from 1609 patients in the University of Michigan cohort and N=37,308 pairs obtained from 8392 patients in the multicenter cohort. CV, cardiovascular. Sjoding MW, et al. N Engl J Med. 2020;383(25):2477-2478.
Improving Anti-SARS-CoV-2 mAb Accessibility for Underserved Populations The Right Patient at the Right Time
Identify high-risk patients at testing sites
– Requires prompt turnaround time for test results
Establish temporary infusion sites
– Avoids interaction with immunocompromised patients at a hospital’s infusion center
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Clinicians who stated they have underserved % populations identified those populations as people of color, those with housing instability, and the uninsured or underinsured.
Involve PCPs or a patient’s regular physician – Higher level of trust
FQHCs have ability to reach many patients Consider changes to allocation at state and local levels FQHC, Federally Qualified Health Center; PCP, primary care provider. 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 have EUA for both outpatient treatment of mild or moderate COVID-19 and postexposure prophylaxis • NIH guidelines are frequently updated to reflect expanding EUA patient criteria and recent updates to the EUA • There are protocols for referring patients for treatment with antiSARS-CoV-2 mAbs and establishing infusion services • This is a rapidly advancing field, with new data emerging for outpatient treatment, hospitalized patients, and prevention using anti-SARS-CoV-2 mAbs • Disparities in care remain, and clinicians should adopt practical solutions to ensure patients have access to anti-SARS-CoV-2 mAbs