AHFS Class:

• Monoclonal Antibodies 8:18.24

Generic Name(s):

• Vilobelimab

Molecular Formula:

• C₆₄₅₆H₉₉₇₆O₂₀₅₄S₄₄

Vilobelimab, an anti-human complement factor C5a (anti-C5a) monoclonal antibody, is used as an antiviral agent.1,2

Coronavirus Disease 2019 (COVID-19)

Vilobelimab is being investigated for and has been used for the treatment of coronavirus disease 2019 (COVID-19)† caused by SARS-CoV-2.1 Vilobelimab is one of several monoclonal antibody medications that have been evaluated for the treatment and prevention of COVID-19.3,4

Although efficacy and safety of vilobelimab have not been definitively established, the drug is available under an FDA emergency use authorization (EUA) to be administered for the treatment of COVID-19 in certain hospitalized adults.1,5

Emergency Use Authorization (EUA)

FDA issued an EUA for vilobelimab to permit use for the treatment of COVID-19 in hospitalized adults when initiated within 48 hours of receiving invasive mechanical ventilation, or extracorporeal membrane oxygenation (ECMO).1,5

FDA issued the EUA for vilobelimab for treatment of COVID-19 after concluding that emergency use of vilobelimab met the criteria for issuance of an EUA for the following reasons: SARS-CoV-2 can cause a serious or life-threatening disease or condition, including severe respiratory illness; based on the totality of scientific evidence available to FDA, it is reasonable to believe that vilobelimab may be effective for the treatment of COVID-19 in certain hospitalized adults receiving invasive mechanical ventilation or ECMO; when used under the conditions described in the EUA, the known and potential benefits of vilobelimab outweigh the known and potential risks of therapy; and there are no adequate, approved, and available alternatives to the emergency use of vilobelimab for the treatment of COVID-19 in such patients.1

The EUA notes that there are FDA-approved alternatives for the treatment of COVID-19 in hospitalized adults when initiated within 48 hours of receiving invasive mechanical ventilation or ECMO including remdesivir, baricitinib, and tocilizumab.1 All of these agents offer a different mechanism of action from vilobelimab.1 Remdesivir is a SARS-CoV-2 nucleotide analog RNA polymerase inhibitor, baricitinib is a Janus kinase (JAK) inhibitor, and tocilizumab is an interleukin-6 (IL-6) receptor antagonist.1 Additionally, vilobelimab is administered via an IV route while baricitinib is only available for oral administration, which can be a concern for patients who are mechanically ventilated or on ECMO.1

To mitigate the risk of this unapproved drug, the EUA for vilobelimab requires that health care providers administering the drug comply with certain mandatory requirements.1 These requirements include providing the patient or caregiver with information consistent with the EUA fact sheet for patients and caregivers and ensuring that all medication errors and serious adverse events potentially attributable to vilobelimab are reported to the FDA as specified in the EUA fact sheet for health care providers.1

For additional information, the vilobelimab EUA letter of authorization ([Web]), EUA fact sheet for health care providers ([Web]), and EUA fact sheet for patients and caregivers ([Web]) should be consulted.1,5,6

Clinical Experience

Treatment of COVID-19 in Hospitalized Patients

The efficacy and safety of vilobelimab for the treatment of COVID-19 in invasively mechanically ventilated adult patients have been evaluated in a randomized, double-blind, placebo-controlled, multicenter, phase 3 trial (PANAMO).1,2 Eligible patients were ≥18 years of age with a confirmed COVID-19 infection in the past 14 days, a PaO2/FiO2 ratio of 60 to 200 mm Hg, and were receiving invasive mechanical ventilation within 48 hours before the initial vilobelimab infusion.2 Enrolled patients were randomized in a 1:1 ratio to receive vilobelimab 800 mg via an IV infusion on days 1, 2, 4, 8, 15, and 22 or matching placebo; both groups additionally received standard COVID-19 care.2 The primary end point was defined as all-cause mortality at day 28 in the full analysis set (i.e., all randomly assigned patients regardless of whether treatment occurred or not).1,2

A total of 368 patients were included in the full analysis set.1,2 Baseline characteristics were well balanced between the groups.2 The median age of enrolled patients was 58 years and 68% were male.1,2 The majority of patients in the overall study population were white (64%); 2.5% were Asian; and 3.5% were Black or African American.2 Common concomitant medical conditions among enrollees included hypertension (46%), obesity (41%), and diabetes (30%).1,2 Results revealed that fewer patients died at day 28 in the vilobelimab group (54 patients) in comparison to placebo (77 patients).1,2

The all-cause mortality rate at 28 days was 32% with vilobelimab versus 42% with placebo.1,2 This decrease in all-cause mortality persisted until day 60 (end of follow-up).1,2

Clinical Perspective

The National Institutes of Health (NIH) COVID-19 treatment guideline recommends that dexamethasone should be administered to all patients with COVID-19 who require mechanical ventilation or ECMO, since the drug has been shown to reduce mortality in critically ill patients with COVID.3 The guideline also recommends that if a patient requiring mechanical ventilation or ECMO has not received a second immunomodulator in addition to dexamethasone, either oral baricitinib or IV tocilizumab should be promptly added to therapy.3

The Infectious Disease Society of America (IDSA) COVID-19 treatment guideline recommends the use of dexamethasone in hospitalized patients with critical disease (e.g., in the intensive care unit requiring mechanical ventilation, ECMO) and states that equivalent total daily doses of alternative glucocorticoids may be administered if dexamethasone is unavailable.4 The IDSA guideline also suggests the use of tocilizumab or sarilumab in this setting.4 However, patients who are steroid responsive and prefer to avoid the adverse effects of tocilizumab or sarilumab given their uncertain mortality benefits, may reasonably decline either treatment.4

Recommendations for the use of vilobelimab in patients who require mechanical ventilation or ECMO are not currently available in either guideline.

Clinicians should consult the most recent NIH ([Web]) and IDSA ([Web]) treatment guidelines for additional information as updates occur frequently.

General

Patient Monitoring

• Monitor for hypersensitivity reactions during administration.1
• Monitor for signs and symptoms of new infections during and after treatment.1

Dispensing and Administration Precautions

• Completion of FDA MedWatch forms to report all medications errors and all serious adverse events potentially related to vilobelimab is mandatory.1 The FDA fact sheet for health care providers should be consulted for requirements and instructions regarding reporting of adverse reactions and medication errors.1

Administration

Vilobelimab is administered by IV infusion.1 Do not administer vilobelimab with other medications in the same IV line.1

Store unopened vials of vilobelimab under refrigeration (2-8°C) in the original carton.1 Protect from light and do not freeze or shake.1

Dilution

The recommended dose of vilobelimab should be diluted in 0.9% sodium chloride as follows:1

• Withdraw 80 mL of 0.9% sodium chloride from a 250 mL 0.9% sodium chloride infusion bag and discard.1
• Withdraw 80 mL of vilobelimab from vials and slowly add to the 0.9% sodium chloride infusion bag to a final concentration of 3.2 mg/mL.1
• Gently invert the infusion bag to avoid foaming and mix the solution.1

Dosage

Treatment of Coronavirus Disease 2019 (COVID-19)

The FDA EUA that permits use of vilobelimab for the treatment of COVID-19† states that the drug may be administered to hospitalized adults receiving invasive mechanical ventilation or ECMO at a dose of 800 mg via IV infusion, for a maximum of 6 doses.1

Treatment with vilobelimab should be initiated within 48 hours of intubation (Day 1) and subsequently administered on Days 2, 4, 8, 15, and 22 if the patient is hospitalized (even if the patient is no longer in an intensive care unit).1

Special Populations

Hepatic Impairment

The manufacturer does not make specific dosage recommendations for patients with hepatic impairment.1

Renal Impairment

The manufacturer does not make specific dosage recommendations for patients with renal impairment.1

Geriatric Patients

The manufacturer does not make specific dosage recommendations for geriatric patients.1

Contraindications

• None.1

Warnings/Precautions

Serious Infections

Serious infections (bacterial, fungal, viral) have been reported in patients with COVID-19 administered vilobelimab.1 Monitor patients for signs and symptoms of new infections during and after treatment with vilobelimab.1 Clinical data are limited regarding the use of vilobelimab in patients with COVID-19 and other active serious infections.1 Consider the risks and benefits of vilobelimab therapy in patients with COVID-19 and other concurrent infections.1

Hypersensitivity Reactions

Hypersensitivity reactions have been reported with vilobelimab.1 Immediately discontinue vilobelimab upon occurrence of signs and/or symptoms of a severe hypersensitivity reaction and initiate appropriate treatment.1

Immunogenicity

There is the potential for immunogenicity development with vilobelimab therapy.1 In the Phase 3 clinical study, 2 patients developed anti-drug antibodies (1 in the vilobelimab group and 1 in the placebo group).1 The clinical significance of this anti-drug antibody development is unclear.1

EUA Requirements for Patient Monitoring and Mandatory FDA MedWatch Reporting

Safety and efficacy of vilobelimab have not been established.1 FDA issued an EUA that permits use of vilobelimab for the treatment of COVID-19† in certain hospitalized adults using the dosages recommended in the EUA.1,5

Only limited data are available to date regarding adverse effects with use of vilobelimab.1 Serious and unexpected adverse events may occur that have not been previously reported with use of vilobelimab.1

Completion of FDA MedWatch forms to report all medication errors and serious adverse events potentially related to vilobelimab is mandatory.1 The FDA fact sheet for health care providers that is provided with the drug and available at the FDA website should be consulted for requirements and instructions regarding reporting of adverse reactions and medication errors.1

Specific Populations

Pregnancy

Data are insufficient to evaluate for a drug-associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes.1 The estimated background risk of major birth defects and miscarriage related to COVID-19 is also unknown.1 Monoclonal antibodies, such as vilobelimab, cross the placenta to a greater degree during the third trimester of pregnancy; therefore, potential fetal effects are more likely to occur during this trimester.1 In a study involving cynomolgus monkeys, vilobelimab placental transport occurred; however, there was no evidence of fetal harm following IV administration throughout pregnancy at doses 2.5 times the maximum recommended human dose.1

The NIH COVID-19 Treatment Guidelines Panel recommends against withholding COVID-19 treatments from pregnant woman specifically because of their pregnancy status.3 Overall, there are limited data on the use of COVID-19 therapeutics, including vilobelimab, in pregnancy; therefore, clinicians should take into consideration several factors (e.g., infection severity, risk of disease progression, medication safety profile) when determining treatment decisions.3

Lactation

It is not known whether vilobelimab is distributed into human or animal milk or has effects on the breast-fed infant or on milk production.1 Maternal immunoglobulin G (IgG) is known to be present in human milk.1

The developmental and health benefits of breast-feeding should be considered along with the mother's clinical need for vilobelimab and any potential adverse effects on the breast-fed child from the drug or from the underlying maternal condition.1

The NIH COVID-19 Treatment Guidelines Panel recommends against withholding COVID-19 treatments specifically because of lactation status.3 Overall, there are limited data on the use of COVID-19 therapeutics, including vilobelimab, in breast-feeding; therefore, clinicians should take into consideration several factors (e.g., infection severity, risk of disease progression, medication safety profile) when determining treatment decisions.3

Pediatric Use

The FDA EUA does not permit the use of vilobelimab for the treatment of COVID-19 in hospitalized pediatric patients when initiated within 48 hours of receiving invasive mechanical ventilation or ECMO.1

Geriatric Use

In clinical studies evaluating the use of vilobelimab for patients receiving invasive mechanical ventilation or ECMO, 53 (30%) were >65 years of age.1 No overall differences in safety or effectiveness were observed between geriatric patients and younger adults.1

Hepatic Impairment

The manufacturer does not make recommendations regarding the use of vilobelimab in patients with hepatic impairment.1

Renal Impairment

The manufacturer does not make recommendations regarding the use of vilobelimab in patients with renal impairment.1

Common Adverse Effects

Adverse effects reported in ≥3% of patients include pneumonia, sepsis, delirium, pulmonary embolism, hypertension, pneumothorax, deep vein thrombosis, herpes simplex, enterococcal infection, bronchopulmonary aspergillosis, increased hepatic enzymes, urinary tract infection, hypoxia, thrombocytopenia, pneumomediastinum, respiratory tract infection, supraventricular tachycardia, constipation, and rash.1

No drug interaction studies have been conducted with vilobelimab to date.1

Description

Vilobelimab is a chimeric monoclonal IgG4-kappa antibody that binds to C5a and thereby blocks interaction of C5a with its receptor.1 When C5a is activated, as part of the innate immune response, an inflammatory cascade is initiated that results in a variety of effects (e.g., increased vascular permeability, coagulation, proinflammatory cytokine release, recruitment and activation of neutrophils and other myeloid cells).1

Vilobelimab administration results in a reduction in C5a plasma concentrations; however, the clinical relevance of this decrease is unclear.1 In the PANAMO study, median C5a plasma concentrations decreased from 118.29 ng/mL at baseline to 14.53 ng/mL at day 8 and remained at approximately this level up to day 30 after vilobelimab initiation.1

Following a single IV infusion of vilobelimab (2 to 4 mg/kg), the maximum serum concentration showed dose proportionality while the AUC showed greater than dose proportionality.1 The elimination half-life after a single 4 mg/kg IV dose was 95 hours in healthy subjects.1

Advice to Patients

The Fact Sheet for Patients and Caregivers: Emergency Use Authorization (EUA) of Vilobelimab for Coronavirus Disease 2019 (COVID-19), available at [Web], must be provided to patients or caregivers prior to administration of vilobelimab.

• Inform patients that FDA authorized the emergency use of vilobelimab, which is an investigational drug that has not received FDA approval, for treatment of COVID-19 in certain hospitalized adult patients.1
• Inform patients that they have the option to accept or refuse vilobelimab.1
• Provide patients with information on available alternative treatments and the risks and benefits of those alternatives.1
• Advise patients of the potential for severe hypersensitivity reactions with vilobelimab administration and to report any reactions that occur during or after administration (e.g., trouble breathing, rash, swelling of the face, eyes, lips, mouth, tongue, or throat).1,6
• Advise patients to monitor for any signs and symptoms of serious infection during and after vilobelimab therapy since the drug can lower the ability of the immune system to fight infections other than COVID-19.1,6
• Advise women to inform their clinician if they are or plan to become pregnant or plan to breast-feed.
• Advise patient to inform their clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs and dietary or herbal supplements, as well as any concomitant illnesses.
• Advise patients of other important precautionary information.

Only references cited for selected revisions after 1984 are available electronically.

1. InflaRx GmbH. Fact sheet for healthcare providers: Emergency use authorization for Gohibic^®. April 2023. From FDA website.[Web]

2. Vlaar APJ, Witzenrath M, van Paassen P et al; PANAMO study group. Anti-C5a antibody (vilobelimab) therapy for critically ill, invasively mechanically ventilated patients with COVID-19 (PANAMO): a multicentre, double-blind, randomised, placebo-controlled, phase 3 trial. Lancet Respir Med. 2022;10(12):1137-1146.

3. National Institutes of Health. Coronavirus disease 2019 (COVID-19) treatment guidelines. Last updated: 2023 April. From NIH website. Accessed 2023 April 26. Updates may be available at NIH website.[Web]

4. Infectious Diseases Society of America. IDSA guideline on the treatment and management of patients with COVID-19. Last updated: 2023 April. From IDSA website. Accessed 2023 April 26. Updates may be available at IDSA website.[Web]

5. US Food and Drug Administration. Letter of authorization: Emergency use authorization for use of Gohibic™ for the treatment of COVID-19 in certain hospitalized adult patients. April 12, 2023. From FDA website.[Web]

6. InflaRx GmbH. Fact sheet for patients and caregivers: Emergency use authorization (EUA) of Gohibic™ for coronavirus disease 2019 (COVID-19). April 2023. From FDA website.[Web]