Staying Vigilant for Immunocompromised Patients

BURDENS OF BEING IMMUNOCOMPROMISED IN THE ERA OF COVID-19 Eric S. Daar, MD

Who Is Immunocompromised in the COVID-19 Pandemic?

• Active treatment for solid tumor and hematologic malignancies • Hematologic malignancies associated with poor responses to COVID-19 vaccines regardless of current treatment status • Receipt of solid-organ transplant or an islet transplant and taking immunosuppressive therapy • Receipt of CAR-T–cell therapy or HCST (within 2 years of transplantation or taking immunosuppressive therapy) • Moderate or severe primary immunodeficiency • Advanced HIV infection or untreated HIV infection • Active treatment with high-dose corticosteroids, alkylating agents, antimetabolites, transplant-related immunosuppressive drugs, cancer chemotherapeutic agents classified as severely immunosuppressive, TNF blockers, and other biologic agents that are immunosuppressive or immunomodulatory (eg, B-cell–depleting agents) CAR, chimeric antigen receptor; HCST, hematopoietic stem cell transplant; TNF, tumor necrosis factor.

Centers for Disease Control and Prevention (CDC). Accessed August 31, 2023. https://www.cdc.gov/vaccines/covid-19/clinical-considerations/interim-considerations-us.html.

COVID-19 Risks in Immunocompromised Patients • Immunocompromised patients are ~3% of the population1 – Autoimmune condition, transplant recipient, taking immunosuppressive medication either long-term or short-term

• They are at increased risk of inadequate response to COVID-19 vaccination2 • Immunocompromised patients with COVID-19 are more likely to – Get severely ill1 – Have prolonged infection and shedding3 – Become hospitalized4 – Have low antibody/neutralization titers to variants5 1. Harpaz R, et al. JAMA. 2016;316(23):2547-2548; 2. Chodick G, et al. Clin Infect Dis. 2022;74(3):472-478; 3. Truong TT, et al. EBioMedicine. 2021;67:103355; 4. Brosh-Nissimov T, et al. Clin Microbiol Infect. 2021;27(11):1652-1657; 5. Strengert M, et al. EBioMedicine. 2021;70:103524.

COVID-19 Outcomes in Immunocompromised Patients OVERALL1,2

2.68 times higher risk of hospitalization LONGER hospital stay More SEVERE ARDS TRANSPLANT1 Up to 89% hospitalization rate

20%-42% ICU admission 29%-52% mechanical ventilation

CANCER1 Up to 74% hospitalization rate Up to 20% ICU admission rate Approximately 10% of patients with cancer require mechanical ventilation

B-CELL–DEPLETING THERAPIES FOR INFLAMMATORY DISEASE3

39% hospitalized 15% required critical care

Longer average length of stay ARDS, acute respiratory distress syndrome; ICU, intensive care unit.

1. Bertini CD Jr, et al. Clin Chest Med. 2023;44(2):395-406; 2. Antinori A, Bausch-Jurken M. J Infect Dis. 2023;228(Suppl 1):S4-S12; 3. Calabrese CM, et al. Arthritis Rheumatol.

2022;74(12):1906-1915.

Mortality in Immunocompromised Patients OVERALL1

CANCER2

Studies have frequently identified a mortality rate 3-4 TIMES HIGHER in immunocompromised patients.

Cancer without COVID-19: death, 4.03%

Mortality Rate, %

TRANSPLANT1 40 30 20

14

10 0 Heart transplant

Kidney transplant

COVID-19 without cancer: death, 5.26%

B-CELL–DEPLETING THERAPIES FOR INFLAMMATORY DISEASE3

32 18.9

Cancer and COVID-19: death, 14.93%

8% mortality rate in patients with immunemediated inflammatory diseases who are taking B-cell-depleting therapies

Lung transplant

1. Bertini CD Jr, et al. Clin Chest Med. 2023;44(2):395-406; 2. Jani CT, et al. Front Oncol. 2023;13:1107384; 3. Calabrese CM, et al. Arthritis Rheumatol. 2022;74(12):1906-1915.

COVID-19 Affects Quality of Life for Immunocompromised Patients • COVID-19 pandemic increased social isolation, anxiety, stress, and depression1 – Already an increased risk for these in immunocompromised patients

• Large increase in fear, often driven by the media2 • More challenging to access health care in general1 • Reduced access to specific treatments3 • Fewer stem cell or organ donors, particularly when travel restrictions were in place3

1. Pullen RL Jr. Nursing. 2022;52(12):27-32; 2. Napiórkowska-Baran K, et al. Int J Immunopathol Pharmacol. 2021;35:20587384211044344; 3. Zomerdijk N, et al. Psychooncology.

2022;31(3):416-424.

Overcoming Medical Misinformation and Medical Mistrust • Medical misinformation is prevalent owing to social media and stories promoted by some news organizations1 • Can create vaccine hesitancy or resistance to treatment and measures such as masking or social distancing1 • Can be overcome by1-3 – Providing patients with educational materials from reputable sources – Involving pharmacists to leverage their high accessibility and widespread community presence – More global strategies such as fact-checking social media posts or community engagement

1. Pullen RL Jr. Nursing. 2022;52(12):27-32; 2. Czerniak K, et al. J Am Med Inform Assoc. 2023;30(4):752-760; 3. Marwitz KK. J Am Pharm Assoc (2003). 2021;61(2):e71-e74.

Patient Education Is Imperative to Improve Long-term Outcomes for Immunocompromised Patients Results From a Clinician Survey

Many immunocompromised patients have COVID-19 fatigue, medical mistrust, lack of understanding of their risk for severe disease, and a desire to minimize any “unnecessary” treatments/therapies.1,2

Patient-clinician communication can help overcome these barriers, yet….

ONLY

51

the risk of severe % Discuss COVID-19 with a minimum of

one-half of their immunocompromised patients2

1/3

1. Pullen RL Jr. Nursing. 2022;52(12):27-32; 2. Integritas Communications. N=41 clinicians surveyed in September 2023.

Do NOT discuss the benefits of COVID-19 vaccination and boosters with all their immunocompromised patients2

WHERE ARE WE NOW WITH COVID-19?

Roger J. Bedimo, MD

Current Status of COVID-19 October 2023

140k 120k 100k 80k 60k 40k 20k 0 1/11/20 8/29/20 4/17/21 12/4/21 7/23/22 3/11/23 9/30/23

There has been a 6% decrease in hospital admissions in the most recent week

Weekly COVID-19 Deaths in the US2 Weekly COVID-19 Deaths

Weekly COVID-19 New Hospital Admissions

COVID-19 New Weekly Hospital Admissions in the US1

25k 20k 15k 10k 5k 0 1/11/20 8/29/20 4/17/21 12/4/21 7/23/22 3/11/23

9/30/23

There has been a 3.8% increase in COVID19 deaths in the most recent week

1. CDC. Accessed October 2, 2023. https://covid.cdc.gov/covid-data-tracker/#trends_weeklydeaths_select_00; 2. CDC. Accessed October 2, 2023. https://covid.cdc.gov/covid-datatracker/#new-hospital-admissions.

Predominant Viral Variants in the US Viral Variants (6/24/23-9/30/23)

Variants by Region (9/17/23-9/30/23)a

75

50

9/30/23

9/16/23

9/2/23

8/19/23

8/5/23

7/28/23

7/8/23

25

0

a

g EG.5 g FL.1.5.1 g XBB.1.16 g XBB.1.16.6 g HV.1 g XBB.2.3 g XBB.1.16.1 g XBB.5.70 g XBB.1.16.11 g XBB g XBB.1.5

6/24/23

Variant Proportion, %

100

Nowcast estimates are available only for Health and Human Services (HHS) regions 2, 3, 4, 5, 6, 7, 8 and 9.

CDC. Accessed October 2, 2023. https://covid.cdc.gov/covid-data-tracker/#variant-proportions.

Pango Lineage of Predominant COVID-19 Variants BA.4 BA.2 BA.5 B.1.1520

FD.2

BA.5.2.6

XBB.1.5.1

BF.7

XBB.1.5.10

BQ.11

XBB.1.5.59

BQ.1

BA.2.75

Origin Strain

XBB BA.1

B.1.617.2

BA.4.6

BQ.1.1

XBB.1.5.68

CH.1.1

XBB.1.5.72

BA.2.75.2

XBB.1.5.70

BN.1

FD.1.1

XBB.1.5

EU.1.1

XBB.1.9.1

FL.1.5.1

EG.5

BA.2.12.1

XBB.1.9.2

EG.6.1

BA.1.1

XBB.1.16

XBB.1.16.1

XBB.2.3 FE.1.1 CDC. Accessed September 19, 2023. https://covid.cdc.gov/covid-data-tracker/#variant-proportions.

GE.1

XBB.1.16.6 XBB.1.16.11

Predicted Efficacy of an Updated Monovalent Vaccine Against Pirola and Eris Subvariants • Updated monovalent booster for fall 2023 that targets XBB.1.51 – Approved by the FDA 9/11/23 and recommended by the CDC

• Monovalent vaccine appears to be effective against BA.2.86 (Pirola), which is growing in prevalence and contains >30 mutations in the spike protein2 • EG.5 (Eris) is dominant in the US and has a few additional mutations over XBB.1.5 and increased transmissibility3,4 – New monovalent vaccine appears to be effective FDA, US Food and Drug Administration.

1. Endpoints News. Accessed September 19, 2023. https://endpts.com/fda-greenlights-updated-covid-shots-making-fall-booster-rollout-imminent/; 2. Chalkias S, et al. medRxiv.

2023:2023.2008.2022.23293434. [Preprint]; 3. Uraki R, et al. bioRxiv. 2023.08.31.555819. [Preprint]; 4. CNBC. Accessed September 6, 2023. https://www.cnbc.com/2023/08/18/covidnew-vaccines-will-likely-protect-against-eris-variant.html.

Range of COVID-19 Vaccine Response in Immunocompromised People 100

Healthy Controls: 95%–100%

Patients With Antibody Response, %

90 80 70 60 50 40 30 20 10

Darker blue color indicates hematologic cancers

0 Cancer

Hemodialysis

Organ Transplant

Napuri NI, et al. Infect Dis Ther. 2022;11(4):1391-1414; Oliver S. CDC Advisory Committee on Immunization Practices; Presented on July 22, 2021.

Immunosuppressive Therapies

Immune Responses to Vaccines SOT Recipients

• In 1 study, approximately 71% of liver or kidney recipients had either antibodies or T cell response after 2 doses of monovalent vaccine1 • Approximately 25% of lung transplant recipients had an antibody response after 2 doses of monovalent vaccine2 • Bivalent booster (after 4 monovalent vaccines/boosters) produced high neutralization titers against both wild type and Omicron subvariants in heart transplant patients3 – Higher titers in patients with previous infection

• Bivalent booster increased the percentage of kidney transplant recipients with above-threshold neutralizing capacity against XBB.1.5 from 52% to 76%4

It is critical that clinicians encourage their SOT recipient patients to have the most up-to-date COVID-19 vaccine.

SOT, solid organ transplant.

1. Schmidt T, et al. Am J Transplant. 2021;21(12):3990-4002; 2. Narasimhan M, et al. Vaccines (Basel). 2021;9(7):708; 3. Peled Y, et al. J Heart Lung Transplant. 2023;42(8):1054-1058; 4. Pedersen RM, et al. Kidney Int Rep. 2023;8)8):1665-1668.

Immune Responses to Vaccines Patients With Current Malignancies

• Cancer patients frequently excluded from COVID-19 vaccine trials1 • Lower overall COVID-19 vaccine response, particularly in patients with hematologic malignancies1,2 – Patients with hematologic malignancy are less likely to have humoral immune response, though they have cellular immune response

• Significantly lower vaccine response in patients receiving CAR-T cell therapy1 • Boosters are at least somewhat effective in patients with cancer, though not to the same degree as the general population1,2 Clinicians must encourage their patients with cancer to receive the most up-to-date COVID-19 vaccine.

1. Jani CT, et al. Front Oncol. 2023;13:1107384; 2. National Institutes of Health (NIH). Accessed September 7, 2023. https://www.covid19treatmentguidelines.nih.gov/specialpopulations/cancer/.

Ending the Federal Public Health Emergency What does that mean for us and for our patients?

The End of the Federal Public Health Emergency • Federal Public Health Emergency (PHE) for COVID-19 declared under Section 319 of the Public Health Service Act in January 2020 – Renewed every 90 days since then – Expired May 11, 2023

• Vaccines, tests, and treatments were free/covered under the PHE and came from the federal supply • Once the federal supply runs out, coverage for costs of services and supplies will vary depending on the type of insurance

Centers for Medicare & Medicaid Services (CMS). Accessed September 7, 2023. https://www.cms.gov/newsroom/fact-sheets/cms-waivers-flexibilities-and-transition-forward-covid19-public-health-emergency.

Implications of the End of the Public Health Emergency COVID-19 Vaccines

COVID-19 Testing

COVID-19 Treatment

After May 11, 2023

Free

Medicare

Indefinitely

Medicaid and CHIP

Until 9/30/2024

Private Insurance

Most companies will cover in-network

Medicare

When ordered by an HCP and performed at a laboratory

Medicaid and CHIP

Until 9/30/2024

Coverage May Vary After 9/30/24

After 9/30/24

Private Insurance

Mandatory coverage ends 5/11/2023

Medicare

No change in existing coverage

Medicaid and CHIP Private Insurance

Until 9/30/2024

After 9/30/24 No change in existing coverage

Access to vaccines, tests, and treatment after the end of the PHE is currently evolving. Tests are again freely available.

CHIP, Children’s Health Insurance Program; HCP, healthcare professional; OTC, over the counter.

CMS. Accessed September 5, 2023. https://www.cms.gov/newsroom/fact-sheets/cms-waivers-flexibilities-and-transition-forward-covid-19-public-health-emergency.

REDUCING COVID-19 RISKS IN IMMUNOCOMPROMISED PATIENTS Brinda Emu, MD

Reducing COVID-19 Risks in Immunocompromised Patients A Checklist

þ Identify immunocompromised patients þ Assess COVID-19 risks in immunocompromised patients þ Patient education (vaccination and other preventive measures) þ Overcoming disparities to care þ Treatment options for immunocompromised patients who become infected with COVID-19

Assessing COVID-19 Risks in Immunocompromised Patients þ Review medical and medication history to identify any immunocompromising or immunosuppressive therapies þ Identify severity or type of immunocompromising condition or medication (ie, hematologic vs solid tumor malignancy) þ Verify COVID-19 vaccination history þ Discuss use of preventive measures, such as mask wearing and social distancing

COVID-19 Vaccine Recommendations for Immunocompromised Patients Aged ≥12 Years Updated 2023-2024 Vaccine

COVID-19 vaccination status prior to updateda vaccine

Unvaccinated 1 dose any mRNA vaccine

Previously received vaccine(s) Number of updated doses indicated

Vaccinated

3 doses updated mRNA vaccine or 2 doses protein vaccine

2 doses any mRNA vaccine

2 doses mRNA of same manufacturer

3 doses any mRNA vaccine

≥1 dose of AAV or protein vaccine, including in combination with an mRNA vaccine dose

1 dose mRNA of same manufacturer

1 dose updated of either mRNA manufacturer or 1 dose protein vaccine

The CDC recommends the updated COVID-19 vaccine for everyone aged ≥6 months.

UPDATE Immunocompromised patients are eligible for ≥1 additional dose.

D aUpdated indicates the monovalent 2023-2024 formula targeting the XBB subfamily.

AAV, adeno-associated viral; mRNA, messenger RNA. CDC. Accessed September 19, 2023. https://www.cdc.gov/vaccines/covid-19/clinical-considerations/interim-considerations-us.html#table-02.

Vaccination Timing Considerations in Immunocompromised Patients • Vaccination should occur 2 weeks before chemotherapy, 3 months after CAR-T therapy, or should be delayed until a neutrophil recovery in a patient undergoing intensive chemotherapy for hematologic malignancy1 • SOT recipients should ideally be vaccinated before transplant2 – Last vaccine >2 weeks prior to transplant or >1 month after transplant

• Vaccination should occur 2 weeks before initiating or resuming immunosuppressive therapies3 1. NIH. Accessed September 5, 2023. https://www.covid19treatmentguidelines.nih.gov/special-populations/cancer/; 2. NIH. Accessed September 5, 2023. https://www.covid19treatmentguidelines.nih.gov/special-populations/transplant/; 3. NIH. Accessed September 7, 2023. https://www.covid19treatmentguidelines.nih.gov/specialpopulations/immunocompromised/.

Addressing Disparities in Care

Multiple Factors Contribute to Disparities in Care Socioeconomic issues

Medical mistrust Lack of representation in treatment clinical trials

Access to care Disproportionate burden of comorbidities

COVID-19 Health Disparities

Poor health literacy

Discrimination

Lack of insurance

Unemployment

Cultural pressures

Bierle DM, et al. J Prim Care Community Health. 2021;12:21501327211019282; Haynes N, et al. Circulation. 2020;142(2):105-107.

Language Barriers as Obstacles to Care • Verbal communication is the most important aspect of care, particularly telemedicine1 • Language barriers were identified as the largest obstacles to providing care for limited English speakers1 • Professional interpreters may be useful, but some patients may have concerns about confidentiality1 • Non-native English speakers have reduced uptake of treatment for COVID-192 • Many clinics or practices provide an interpreter to improve patient/clinician communication

1. Ali PA, Watson R. J Clin Nurs. 2018;27(5-6):e1152-e1160; 2. Bierle DM, et al. J Prim Care Community Health. 2021;12:21501327211019282.

Racial and Ethnic Disparities in Outpatient Treatment of COVID-19

Relative Difference, %

Patients Treated With Nirmatrelvir/r Compared With White or Non-Hispanic Patients

Patients Treated by Medication Type Race

Nirmatrelvir/r, %

mAb, %

Molnupiravir, %

Remdesivir, %

AIAN/ NHOPI

7.9

1.6

0.3

0.4

-10

Asian

11.9

1.7

0.5

0.5

-15

Black

7

2.0

0.9

1.1

White

13.5

3.3

1.2

0.7

Multiple or other

8.5

1.8

0.6

0.8

Hispanic

6.6

1.1

0.4

0.5

AIAN/ NHOPI

Asian

Black

Multiple/ other

Hispanic

0 -5

-20 -25

-19.4 -23.1

-24.9

-30

-29.9

-35 -40

-35.8

Clinicians must work to encourage equitable access to COVID-19 treatment.

AIAN/NHOPI, American Indian or Alaska Native and Native Hawaiian or other Pacific Islander; r, ritonavir.

Boehmer TK, et al. MMWR Morb Mortal Wkly Rep. 2022;71(43):1359-1365.

Active Provider Sites for Oral Antivirals by Zip Code Social Vulnerability Level 40,000 30,000

Oral Antivirals Dispensed by Zip Code Social Vulnerability Level

— Total — High — Medium — Low

20,000 10,000 0

25 1 8 15 22 29 5 12 19 26 5 12 19 26 2 9 16 2330 7 1421

Dec 21 Jan 22

Feb

Mar

Apr

May

Courses of Oral Antivirals Dispensed, Per 100,000 Population

No. of Active Oral Antiviral Provider Sites

Access to Oral Antivirals in Areas of High Social Vulnerability 90 60

— High — Medium — Low

30 0

1 8 15 22 29 5 12 19 26 5 12 19 26 2 9 16 23 30 7 14 21

Jan

Feb

Mar

Apr

Despite the highest prevalence of provider sites, areas of high social vulnerability see the least use of oral antivirals.

Gold JAW, et al. MMWR Morb Mortal Wkly Rep. 2022;71(25):825-829.

May

Strategies to Reach Underserved Populations þ Involve community- and faith-based organizations to educate patients and direct them to vaccination or treatment resources1 – Trusted messengers can help overcome hesitancy about vaccination or treatment

þ Develop literacy level and culturally appropriate educational materials2 þ Increase clinician knowledge of existence of disparities and access to implicit bias training2 þ Address challenges with social determinants of health, such as food, housing, substance use disorder, unemployment, or lack of insurance coverage3 1. Wiltz JL, et al. MMWR Morb Mortal Wkly Rep. 2022;71(3):96-102; 2. Willems SJ, et al. J Allergy Clin Immunol Pract. 2022;10(4):903-908; 3. 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.

Treating COVID-19 in Immunocompromised Patients

Current NIH Treatment Guidelines for Mild or Moderate COVID-19 Therapy

Indication Dosing Regimen • Given within 5 days of symptom onset

Nirmatrelvir/r

Treatment for mild to moderate COVID-19 in patients aged ≥12 years weighing ≥40 kg

Preferred Therapy

• eGFR ≥60 mL/min: Nirmatrelvir 300 mg + ritonavir 100 mg orally twice daily for 5 days • eGFR ≥30 and <60 mL/min: Nirmatrelvir 150 mg + ritonavir 100 mg orally twice daily for 5 days • eGFR <30 mL/min: Not recommended • Child-Pugh Class C: Not recommended • Given within 7 days of symptom onset

Remdesivir

Treatment for mild to moderate COVID-19 in patients aged ≥28 days weighing ≥3 kg

• Patients ≥40 kg: 200 mg IV on day 1, followed by 100 mg IV once daily on days 2 and 3 • Patients ≥3 kg to <40 kg: 5 mg/kg IV on day 1 followed by 2.5 mg/kg on days 2 and 3 • Each infusion should be administered over 30–120 minutes • Patients should be observed for ≥1 hour after infusion as clinically appropriate

Alternative Therapy

Molnupiravir

Treatment for mild to moderate COVID-19 in nonpregnant adults, and only if the above therapies are not available or appropriate

• Given within 5 days of symptom onset • 800 mg orally twice daily for 5 days

eGFR, estimated glomerular filtration rate; IV, intravenous.

NIH. https://www.covid19treatmentguidelines.nih.gov/tables/antiviral-antibody-characteristics/.

DDIs Associated With Nirmatrelvir/r • Ritonavir is a strong CYP3A4 inhibitor, resulting in numerous DDIs • Not appropriate for many immunocompromised patients • May be used with other ritonavir- or cobicistat-boosted regimens • Consider temporarily withholding or adjusting dosage of the concomitant medication or using an alternative • Consider using other COVID-19 treatments • Clinicians must carefully monitor a patient’s concomitant medicine, including over-the-counter and herbal supplements CYP3A4, cytochrome P450 3A4; DDI, drug-drug interaction.

NIH. https://www.covid19treatmentguidelines.nih.gov/therapies/antiviral-therapy/ritonavir-boosted-nirmatrelvir--paxlovid-/.

Algorithm on Potential DDIs With Nirmatrelvir/r Is your patient taking other medications, including over the counter?

Do these medications have potential interactions with nirmatrelvir/r?

In case of significant interactions • Can the concomitant medications be temporarily discontinued?

• Can the dose of the concomitant medications be reduced?

• Can an alternative concomitant medication be used?

• Can increased monitoring for AEs or concomitant medication drug levels be done?

AE, adverse event.

Akinosoglou K, et al. Viruses. 2022;14(11):2540.

If none of these is possible, avoid coadministration with the concomitant medications

Managing DDIs Associated With Nirmatrelvir/r • Withhold or adjust dosage of concomitant medication during treatment with nirmatrelvir/r (5 days) • Continue to withhold or adjust dosage for 2-3 days after last dose of nirmatrelvir/r

Selected Medications With DDIs Prescribe Alternative COVID-19 Therapy Phenobarbital, rifampin, voclosporin, clopidogrel, sildenafil, tacrolimus, St. John’s wort Temporarily Withhold Concomitant Medication Rivaroxaban, ticagrelor, atorvastatin, avanafil, erythromycin, certain chemotherapeutic agents (including docetaxel) Adjust Concomitant Medication Dose Apixaban, rifabutin, digoxin, saxagliptin, tofacitinib, hydrocodone, diazepam, ketoconazole, alprazolam

See full DDI list at Liverpool COVID-19 Drug Interactions (https://www.covid19-druginteractions.org/checker) or NIH Guidelines

(https://www.covid19treatmentguidelines.nih.gov/therapies/antiviral-therapy/ritonavirboosted-nirmatrelvir--paxlovid-/paxlovid-drug-drug-interactions/) NIH. https://www.covid19treatmentguidelines.nih.gov/therapies/antiviral-therapy/ritonavir-boosted-nirmatrelvir--paxlovid-/.

Is COVID-19 Convalescent Plasma Useful in Immunocompromised Patients?

• NIH recommends neither for nor against the use of high-titer CCP in immunocompromised patients due to insufficient evidence1 – FDA issued an EUA for CCP in immunocompromised patients

• Trial data are conflicting and had small enrollment1 • Meta-analysis showed reduced risk of mortality with the use of CCP2 – CCP should be from donors who are recently infected with SARS-CoV-2

CCP, COVID-19 convalescent plasma; EUA, Emergency Use Authorization; FDA, US Food and Drug Administration.

1. NIH. Accessed September 7, 2023. https://www.covid19treatmentguidelines.nih.gov/special-populations/immunocompromised/; 2. Senefeld JW, et al. JAMA Netw Open.

2023;6(1):e2250647.

Risk of Viral Shedding or Prolonged COVID-19 in Immunocompromised Patients • There is evidence that immunocompromised patients are more likely to experience prolonged infection vs immunocompetent patients1 – Some evidence of patients remaining SARS-CoV-2 PCR positive for 150 days, though median times are significantly shorter2

• Vaccination significantly shortened viral shedding1 • COVID-19 treatment does not appear to affect duration of viable virus shedding1 • Persistent shedding has resulted in mutations in the same patient2 PCR, polymerase chain reaction.

1. Kang SW, et al. J Infect. 2023;86(4):412-414; 2. Leung WF, et al. Int J Infect Dis. 2022;114:178-182.

COVID-19 Clearance in Immunocompromised Patients Proportion of Patients With Viral Shedding

Immunocompromised Patients Show Slow Viral Clearance 1.00

• Median of 4 weeks viable virus shedding • Median 5 weeks of subgenomic RNA shedding • Median time for genomic RNA shedding was not reached by end of study period

0.75 0.50 0.25 0

— Genomic RNA PCR — Subgenomic RNA PCR — Virus Culture

0

1

2

3

4

5

6

7

8

9

10

11

12

13

14

Weeks From Diagnosis N=41 immunocompromised patients with hematologic malignancy or SOT were enrolled from February 1, 2022 – April 1, 2022 and submitted weekly saliva samples until 12 weeks after diagnosis or discharge.

Kang SW, et al. J Infect. 2023;86(4):412-414.

Treatment Options for Prolonged, Symptomatic COVID-19 • In the event there is evidence of ongoing SARS-CoV-2 replication, it is possible to use – Longer and/or additional courses of nirmatrelvir/r – Longer and/or additional courses of remdesivir – High-titer CCP from a vaccinated donor who recently recovered from COVID-19 likely caused by a SARS-CoV-2 variant similar to the variant causing the patient’s illness

NIH. Accessed September 7, 2023. https://www.covid19treatmentguidelines.nih.gov/special-populations/immunocompromised/.

UPDATES ON ANTISARS-COV-2 MONOCLONAL ANTIBODIES Roger J. Bedimo, MD

Where we’ve been…

Previously Authorized Anti-SARS-CoV-2 mAbs Binding Site

Route of Administration

CAS + IMD1

ACE2 receptor interface on spike protein

IV, SQ

BAM + ETE

ACE2 receptor interface on spike protein

IV

• No Fc modification for BAM • Fc modification for ETE • Bind to different but overlapping epitopes of RBD

Sotrovimab3

Highly conserved epitope outside RBD

IV

• 2-amino acid Fc modification to increase half-life • Neutralizes other sarbecoviruses

BEB4

ACE2 receptor interface on spike protein

IV

• No Fc modification • Highly conserved contact residues

TIX + CIL5

ACE2 receptor interface on spike protein

IM

• Components bind to 2 noncompeting sites • Long-acting mAb • Reduced Fc receptor binding

mAb

Characteristics • No Fc modification • Bind to nonoverlapping epitopes of RBD

ACE2, angiotensin-converting enzyme 2; BAM, bamlanivimab; BEB, bebtelovimab; CAS, casirivimab; CIL, cilgavimab; ETE, etesevimab; Fc, fragment crystallizable; IM, intramuscular; IMD, imdevimab; RBD, receptor binding domain; SQ, subcutaneous; TIX, tixagevimab.

1. FDA. Accessed September 7, 2023. https://www.fda.gov/media/145611/download; 2. FDA. Accessed September 7, 2023. https://www.fda.gov/media/145802/download; 3. Gupta A, et al. JAMA. 2022;327(13):1236-1246; 4. Westendorf K, et al. Cell Rep. 2022;39(7):110812; 5. Shah M, Woo HG. Front Immunol. 2022;12:830527.

History of Anti-SARS-CoV-2 mAb EUAs for High-Risk Patients November 2020

EUA for treatment with CAS + IMD1

July 2021

FDA revises CAS + IMD EUA to include PEP3

September 2021 FDA revises BAM + ETE EUA to include PEP3

January 2022

BAM + ETE and CAS + IMD no longer authorized due to the Omicron variant3

April 2022

Sotrovimab no longer authorized due to the BA.2 subvariant3

November 2020 February 2021

EUA for treatment with BAM + ETE2

May 2021

EUA for treatment with sotrovimab3

January 2023

TIX + CIL no longer authorized due to the XBB subvariant3

January 2023 August 2021

BAM + ETE may be used where combined frequency of variants resistant to BAM + ETE is ≤5%3

December 2021 TIX + CIL receives EUA for PrEP in immunocompromised patients3

February 2022 EUA for treatment with BEB3

November 2022

BEB no longer authorized due to the BQ subvariants3

Distribution of anti-SARS-CoV-2 mAbs was often paused or restricted by HHS region as variants and subvariants spread at different rates.

PEP, postexposure prophylaxis; PrEP, pre-exposure prophylaxis.

1. FDA. Accessed August 31, 2023. https://www.fda.gov/media/145610/download; 2. FDA. Accessed August 31, 2023. https://www.fda.gov/media/145801/download; 3. Department of Health and Human Services (DHHS). Accessed August 31, 2023. https://aspr.hhs.gov/COVID-19/Therapeutics/updates/Pages/default.aspx.

Anti-SARS-CoV-2 mAbs as PrEP TIX + CIL Significantly Reduces COVID-19 Infection, Hospitalization, and Mortality2 8

7.2

Control

7

Patients, %

• TIX + CIL increased antibody binding in SOT recipients1 • Vaccine strain neutralizing inhibition increased up to 100% in a group of SOT patients after TIX + CIL1 • BA.2 neutralization increased to >70% after TIX + CIL1

TIX + CIL

6 5 4

3.5a

3 2

1.5

1

0.1a

0 Infection

0.6

0.9 0.1b

Severe disease Hospitalization

0c Mortality

aP≤0.001; bP=0.05; cP=0.005.

N=825 immunocompromised patients aged ≥12 years who received TIX + CIL were compared with 4299 immunocompromised patients who did not receive TIX + CIL. Data were collected December 2021 – April 2022.

1. Karaba AH, et al. medRxiv. 2022.05.24.22275467. [Preprint]; 2. Kertes J, et al. Clin Infect Dis. 2023;76(3):e126-e132.

Anti-SARS-CoV-2 mAbs as PEP

81 relative risk reduction %

8 6

7.8% Placebo

4

CAS + IMD

2 0

1.5%c

BAM Prevents Symptomatic COVID-19 by Day 572,b Residents, %

Cumulative Incidence, %

CAS + IMD Significantly Reduces Symptomatic COVID-19 When 1,a Used as PEP 10

25

8

15

Trial Day

22

29

22.5%

20 15

BAM

10

8.8%c

5 0

0 1

Placebo

1

8

15

22

29

36

43

50

Time Since Infusion, days

aN=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 (by

57

January 28, 2021) to placebo or CAS + IMD 1200 mg SQ within 96 hours of confirming household contacts’ positive test and followed until March 11, 2021 (n=459 patients at high risk for severe COVID-19); bN=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 BAM 4200 mg 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. Patients were ineligible if they had recovered from COVID-19, received CCP, inpatient, participating in a vaccine trial, had a previous anti-SARS-CoV-2 mAb, or were pregnant. c P<0.001.

1. O’Brien MP, et al. N Engl J Med. 2021;385(13):1184-1195; 2. Cohen MS, et al. JAMA. 2021;326(1):46-55.

Anti-SARS-CoV-2 mAbs for Treatment BAM + ETE1

CAS + IMD2

• 70% relative risk reduction in hospitalization or allcause death • No deaths among patients receiving BAM + ETE • Faster viral load reduction and composite of reduced hospitalization, ED visit, or all-cause death

• 70% relative reduction in the risk of hospitalization or all-cause death • Shorter hospitalization, lower rate of ICU admission, and more rapid symptom resolution

Sotrovimab3 • 79% relative reduction in risk of hospitalization >24 hours or all-cause death • Reduction in ED visit, hospitalization, death, and their composite

BEB4 • Real-world use showed significant reduction in hospitalization and death composite and death alone • Large risk reductions in immunocompromised patients, older patients, and fully vaccinated patients

ED, emergency department.

1. Dougan M, et al. N Engl J Med. 2021;385(15):1382-1392; 2. Weinreich DM, et al. N Engl J Med. 2021;385(23):e81; 3. Gupta A, et al. JAMA. 2022;327(13):1236-1246; 4. McCreary EK, et al. Open Forum Infect Dis. 2022;9(10):ofac517.

…to Where We’re Going The Future of Anti-SARS-CoV-2 mAbs

Novel Anti-SARS-CoV-2 mAbs for Long COVID AER002

• AER002 is an anti-SARS-CoV-2 mAb in trials to treat adults with long COVID • Phase 2 trial (outSMART-LC) of 30 adults whose long COVID is due to an infection prior to 8/15/22 – AER002 1200 mg administered once by IV vs placebo – Primary outcome: change in PROMIS-29 score from baseline at 3 months postinfusion

ClinicalTrials.gov. Accessed September 7, 2023. https://clinicaltrials.gov/study/NCT05877508.

Novel Anti-SARS-CoV-2 mAbs for PrEP VYD222

• VYD222 is based on adintrevimab, an investigational anti-SARSCoV-2 mAb1 – Likely effective against circulating variants

• Phase 1 trial of single escalating dose to evaluate safety and tolerability in healthy individuals2 – N=30 participants over 3 arms • 8 participants receiving VYD222 and 2 receiving placebo per arm

• Previous discussions with FDA about requirements for filing, including using serum-neutralizing titers as a correlate of protection1

1. Fierce Biotech. Accessed September 7, 2023. https://www.fiercebiotech.com/biotech/invivyd-fda-agree-steps-emergency-approval-covid-monoclonal-antibody; 2. ClinicalTrials.gov. Accessed September 7, 2023. https://clinicaltrials.gov/study/NCT05791318.

Novel Anti-SARS-CoV-2 mAbs for PrEP AZD5156

• AZD5156 is a long-acting mAb1 – Cilgavimab + AZD3152 – Same half-life extension and reduced Fc effector function and complement C1q binding as TIX + CIL

• Broad neutralizing activity across strains1,2 – Retains neutralization against original strain through XBB.1.5 subvariant (most recently tested subvariant)

• Antibody derived from convalescent patients after SARS-CoV-2 infection1 • Builds on safety and efficacy of TIX + CIL1 • Expected to confer protection for 6 months1 1. AstraZeneca. https://www.astrazeneca-us.com/media/statements/2022/first-participant-dosed-in-supernova-phase- I-III-trial-evaluating-azd5156-a-next-generation-long-actingantibody-combination-for-prevention-of-covid-19.html; 2. Francica J, et al. 33rd European Congress of Clinical Microbiology & Infectious Diseases; Copenhagen, Denmark.

April 17, 2023.

AZD3152 Shows Neutralization Activity for Multiple Variants and Subvariants

BA.2.86

EG.5.1

XBB.1.16

XBB.1

XBB.1.5.10/EG.5

PK, pharmacokinetic; sgRNA, single guide RNA. Francica JR, et al. IDWeek. October 11 – 15, 2023; Boston, Massachusetts. Poster 1355.

XBB.1.5/XBB.1.9

SARS-CoV-2 Variants

• AZD3152 significantly reduces viral sgRNA from the lungs in hamsters at both days 3 and 7 • Being developed for both prevention and treatment in high-risk individuals

XBB

BQ.1.1

BQ.1

BF.7

BA.2.75.2

BA.5.9

BA.4.7

BA.4.6

BA.2.75

BA.4/5

BA.2.12.1

BA.2

BA.1.1

BA.1

Gamma

Delta

Beta

Alpha

D614G

AZD3152 SARSCoV-2 Pseudovirus Neutralization, IC50 (ng/mL)

• AZD3152 shows greater pseudovirus neutralization than TIX + CIL (data collection through 8/31/23) • AZD3152 PK data demonstrate similar systemic exposure to CIL in nonhuman primates

AZD3152 loses activity against XBB variants with the F456L mutation, but its escape is variantdependent. AZD3152 has neutralization activity against BA.2.86.

Clinical Trial of Anti-SARS-CoV-2 mAbs in Development for PrEP SUPERNOVA Trial

• Phase 1/3 to assess prevention of symptomatic COVID-19 in immunocompromised patients aged ≥12 years – Includes safety cohort in phase 1 portion – Includes phase 2 substudy to evaluate safety, efficacy, PK, and neutralizing activity of AZD3152 and separately evaluate safety and PK of AZD5156

• Primary endpoint(s), depending on study and substudy – Safety of AZD5156 – Safety, efficacy, and neutralizing activity of AZD3152

• First participant dosed December 2022 ClinicalTrials.gov. Accessed October 10, 2023. https://clinicaltrials.gov/ct2/show/NCT05648110.

Barriers to Use of Anti-SARS-CoV-2 mAbs in Immunocompromised Patients Treater Survey

Rankings of Barriers to Future Use of Anti-SARS-CoV-2 mAbs Respondents, %

30 25 20 15 10 5 0 Logistics of administering at the clinic

Lack of conviction that mAbs will be effective against future variants or subvariants

Integritas Communications. N=41 clinicians surveyed in September 2023.

Managed care restrictions

Patient challenges with Lack of patient interest return visits whenever another dose is needed

Immunocompromised Patient Perspectives on Anti-SARS-CoV-2 mAbs for PrEP Treater Survey

70

%

of surveyed clinicians believe that ≤50% of their immunocompromised patients would be interested in PrEP if one becomes available in the future

• Patients have hesitancy for several reasons – Prior mAbs lost their efficacy – COVID-19 fatigue – Some transplant patients just prefer not to have any medical treatments and/or therapies that are considered optional – Medical mistrust; some people still deny COVID-19 exists – Some are not confident in mAb outcomes and are worried about side effects – Many do not consider themselves at risk

Clinicians will need to educate patients about the benefit:risk ratio of anti-SARS-CoV-2 mAbs for PrEP if or when they become available.

Integritas Communications. N=41 clinicians surveyed in September 2023.

Conclusions • New Omicron subvariants continue to emerge • Immunocompromised patients are at higher risk of severe COVID-19 • Immunocompromised patients often have lower immune response to COVID-19 vaccination, but vaccination is still recommended for everyone • NIH treatment guidelines should be followed for immunocompromised patients with COVID-19, paying close attention to DDIs • Anti-SARS-CoV-2 mAbs were previously effective as both prevention and treatment, and other promising options are in development