Label: GOHIBIC- vilobelimab injection

Justification for Emergency Use of Drugs During the COVID-19 Pandemic

There is currently an outbreak of Coronavirus Disease 2019 (COVID-19) caused by SARS-CoV-2, a novel coronavirus. The Secretary of HHS has:

• Determined that there is a public health emergency, or significant potential for a public health emergency, related to COVID-191.
• Declared that circumstances exist justifying the authorization of emergency use of drugs and biological products for the prevention or treatment of COVID-192.

An EUA is a FDA authorization for the emergency use of an unapproved product or unapproved use of an approved product (i.e., drug, biological product, or device) in the United States under certain circumstances, including, but not limited to, when the Secretary of HHS declares that there is a public health emergency, or significant potential for a public health emergency that affects the national security or the health and security of United States citizens living abroad, and that involves biological agent(s) or a disease or condition that may be attributable to such agent(s). Criteria for issuing an EUA include:

• The biological agent(s) can cause a serious or life-threatening disease or condition;
• Based on the totality of the available scientific evidence (including data from adequate and well-controlled clinical trials, if available), it is reasonable to believe that:
  • The product may be effective in diagnosing, treating, or preventing the serious or life-threatening disease or condition; and
  • The known and potential benefits of the product – when used to diagnose, prevent or treat such disease or condition – outweigh the known and potential risks of the product, taking into consideration the material threat posed by the biological agent(s)
• There is no adequate, approved, and available alternative to the product for diagnosing, preventing, or treating the serious or life-threatening disease or condition.

1

See U.S. Department of Health and Human Services, Determination of a Public Health Emergency and Declaration that Circumstances Exist Justifying Authorizations Pursuant to Section 564(b) of the Federal Food, Drug, and Cosmetic Act, 21 U.S.C. § 360bbb-3. February 4, 2020; https://www.federalregister.gov/documents/2020/02/07/2020-02496/determination-of-public-health-emergency. See also U.S. Department of Health and Human Services, Amended Determination of a Public Health Emergency or Significant Potential for a Public Health Emergency Pursuant to Section 564(b) of the Federal Food, Drug, and Cosmetic Act, 21 U.S.C. § 360bbb-3(b). March 15, 2023 ("Amended Determination"); https://www.federalregister.gov/documents/2023/03/20/2023-05609/covid-19-emergency-use-authorization-declaration.

2

See U.S. Department of Health and Human Services, Declaration that Circumstances Exist Justifying Authorizations Pursuant to Section 564(b) of the Federal Food, Drug, and Cosmetic Act, 21 U.S.C. § 360bbb-3, 85 FR 18250 (April 1, 2020); https://www.federalregister.gov/documents/2020/04/01/2020-06905/emergency-use-authorization-declaration. See also Amended Determination ("The declarations issued pursuant to section 564(b)(1) of the FD&C Act that circumstances exist justifying the authorization of emergency use of certain in vitro diagnostics, personal respiratory protective devices, other medical devices and drugs and biological products, as set forth in those declarations, and that are based on the February 4, 2020 determination, remain in effect until those declarations are terminated in accordance with section 564 of the FD&C Act.").

Information Regarding Available Alternatives for the EUA Authorized Use3

Veklury (remdesivir), a SARS-CoV-2 nucleotide analog RNA polymerase inhibitor, is an FDA-approved alternative to GOHIBIC when used for the treatment of COVID-19 in hospitalized adults and when initiated within 48 hours of receiving IMV, or ECMO. Veklury has demonstrated antiviral activity against SARS-CoV-2; whereas GOHIBIC acts by binding to C5a to block its interaction with the C5a receptor, both of which are components of the complement system thought to contribute to inflammation and worsening of COVID-19, offering a different mechanism of action.

Olumiant (baricitinib), a Janus kinase (JAK) inhibitor, is an FDA-approved alternative to GOHIBIC when used for the treatment of COVID-19 in hospitalized adults and when initiated within 48 hours of requiring IMV, or ECMO. As noted, GOHIBIC offers a different mechanism of action. In addition, GOHIBIC has an intravenous route of administration; whereas, Olumiant is available as tablets, offering an alternative route of administration to adult patients who are mechanically ventilated or on ECMO.

Actemra (tocilizumab), an interleukin-6 (IL-6) receptor antagonist, is an FDA-approved alternative to GOHIBIC when used for the treatment of COVID-19 in hospitalized adults and when initiated within 48 hours of receiving IMV, or ECMO. As noted, GOHIBIC offers a different mechanism of action.

Other therapeutics are currently authorized for the same use as GOHIBIC. For additional information on all products authorized for the treatment of COVID-19, please see https://www.fda.gov/emergency-preparedness-and-response/mcm-legal-regulatory-and-policy-framework/emergency-use-authorization.

For information on clinical studies of GOHIBIC and other therapies for the treatment of COVID-19, see www.clinicaltrials.gov.

3

This section only describes the uses for which an FDA-approved drug is considered to be an alternative to GOHIBIC. For additional information, including the full indications for the FDA-approved drugs referenced within this section, please refer to the relevant Prescribing Information at: Drugs@FDA: FDA-Approved Drugs. As stated in the Letter of Authorization, the emergency use of GOHIBIC must be consistent with the terms and conditions of its authorization.

2.1 Recommended Dosage

The recommended dosage of GOHIBIC for the treatment of adults with COVID-19 is 800 mg administered by intravenous infusion after dilution [see Dosage and Administration (2.2)] for a maximum of 6 (six) doses over the treatment period as described below.

Treatment should be started within 48 hours of intubation (Day 1) followed by administration on Days 2, 4, 8, 15 and 22 as long as the patient is hospitalized (even if discharged from ICU).

2.2 Preparation and Administration

5.1 Serious Infections

Serious infections due to bacterial, fungal, and viral pathogens have been reported in patients with COVID-19 receiving GOHIBIC. In patients with COVID-19, monitor for signs and symptoms of new infections during and after treatment with GOHIBIC. There is limited information regarding the use of GOHIBIC in patients with COVID-19 and concomitant active serious infections. The risks and benefits of treatment with GOHIBIC in COVID-19 patients with other concurrent infections should be considered [see Adverse Reactions (6)].

5.2 Hypersensitivity Reactions

Hypersensitivity reactions have been observed with GOHIBIC. If a severe hypersensitivity reaction occurs, administration of GOHIBIC should be discontinued and appropriate therapy initiated.

6.1 Clinical Trial Experience

The following adverse reactions have been observed in the clinical studies of GOHIBIC that supported the EUA. The adverse reaction rates observed in these clinical studies cannot be directly compared to rates in the clinical studies of other products and may not reflect the rates observed in clinical practice.

The safety of GOHIBIC is based on PANAMO, a Phase 3 randomized, placebo-controlled trial in COVID-19 patients requiring IMV or ECMO [see Clinical Studies (14)]. The analysis of adverse reactions included a total of 364 adult patients who received at least one dose of either GOHIBIC (n=175) or placebo (n=189) plus standard of care. Patients received GOHIBIC 800 mg administered by intravenous infusion on Days 1, 2, 4, 8, 15 and 22 or placebo.

During the study, there were 62 deaths in the GOHIBIC arm and 85 deaths in the placebo arm [see Clinical Studies (14)]. Fatal infections occurred in more placebo patients. Nonfatal serious infections occurred in 58 patients (33.1%) in the GOHIBIC arm and in 55 patients (29.1%) in the placebo arm. The most commonly reported nonfatal serious infections with GOHIBIC were pneumonia (18.9% vs 13.8% in placebo), sepsis (14.9% versus 7.4% in placebo), and septic shock (9.1% versus 7.4% in placebo).

Discontinuation of study treatment due to an adverse reaction occurred in 2.9% of the GOHIBIC group and 1.6% of the placebo group. Adverse reactions leading to discontinuation of GOHIBIC included eczema, bronchopulmonary aspergillosis, rash, hemodynamic instability, thrombocytopenia, and multi-organ failure.

The most common adverse reactions occurring in at least 3% of GOHIBIC-treated patients and at least 1% more frequently than observed in the placebo arm are summarized in Table 1.

6.3 Required Reporting for Serious Adverse Events and Medication Errors

The prescribing healthcare provider and/or the provider's designee is/are responsible for mandatory reporting of all serious adverse events (SAEs)4 and medication errors potentially related to GOHIBIC within 7 calendar days from the healthcare provider's awareness of the event, using FDA Form 3500 (for information on how to access this form, see below). The FDA requires that such reports, using FDA Form 3500, include the following:

• Patient demographics and baseline characteristics (e.g., patient identifier, age or date of birth, gender, weight, ethnicity, and race)
• A statement "GOHIBIC use for COVID-19 under Emergency Use Authorization (EUA)" under the "Describe Event, Problem, or Product Use/Medication Error" heading
• Information about the SAE or medication error (e.g., signs and symptoms, test/laboratory data, complications, timing of drug initiation in relation to the occurrence of the event, duration of the event, treatments required to mitigate the event, evidence of event improvement/disappearance after stopping or reducing the dosage, evidence of event reappearance after reintroduction, clinical outcomes).
• Patient's preexisting medical conditions and use of concomitant products
• Information about the product (e.g., dosage, route of administration, NDC #).

Submit AE and medication error reports, using Form 3500, to FDA MedWatch using one of the following methods:

• Complete and submit the report online: www.fda.gov/medwatch/report.htm
• Complete and submit a postage-paid FDA Form 3500 (https://www.fda.gov/media/76299/download) and return by:
  • Mail to MedWatch, 5600 Fishers Lane, Rockville, MD 20852-9787, or
  • Fax to 1-800-FDA-0178, or
• Call 1-800-FDA-1088 to request a reporting form

In addition, please provide a copy of all FDA MedWatch forms to:
InflaRx GmbH
Fax: 1-866-728-2630
E-mail: pvusa@inflarx.de
Or call InflaRx GmbH at 1-888-254-0602 to report AEs.

The prescribing healthcare provider and/or the provider's designee is/are responsible for mandatory responses to requests from FDA for information about AEs and medication errors following receipt of GOHIBIC.

4

SAEs are defined as:

• Death;
• A life-threatening AE;
• Inpatient hospitalization or prolongation of existing hospitalization;
• A persistent or significant incapacity or substantial disruption of the ability to conduct normal life functions;
• A congenital anomaly/birth defect;
• Other important medical event, which may require a medical or surgical intervention to prevent death, a life-threatening event, hospitalization, disability, or congenital anomaly

8.1 Pregnancy

8.2 Lactation

8.3 Pediatric Use

GOHIBIC is not authorized or approved for the emergency use in pediatric patients for the treatment of coronavirus disease 2019 (COVID-19) in hospitalized patients when initiated within 48 hours of receiving invasive mechanical ventilation (IMV), or extracorporeal membrane oxygenation (ECMO).

8.4 Geriatric Use

Of the total number of GOHIBIC-treated patients in clinical studies for COVID-19 receiving invasive mechanical ventilation (IMV), or extracorporeal membrane oxygenation (ECMO), 53 (30%) were >65 years. No overall differences in effectiveness or safety of GOHIBIC have been observed between patients 65 years of age and older and younger adult patients.

12.1 Mechanism of Action

GOHIBIC is a chimeric monoclonal IgG4-kappa antibody that binds to C5a with a dissociation constant of 9.6pM and blocks its interaction with the C5a receptor. C5a is part of the complement system and is activated as part of the innate immune response initiating an inflammatory cascade that includes increased vascular permeability, coagulation, proinflammatory cytokine release, and recruitment and activation of neutrophils and other myeloid cells.

12.2 Pharmacodynamics

The reduction of C5a plasma concentration was evaluated in PANAMO. The median plasma concentrations of C5a at baseline in patients with severe COVID-19 pneumonia requiring IMV or ECMO were elevated and the values were comparable between the GOHIBIC group (118.29 ng/mL) and the placebo group (104.62 ng/mL). In the GOHIBIC group, the median concentrations of C5a decreased to 14.53 ng/mL by Day 8 and remained at approximately this level up to Day 30 after the initiation of treatment. In the placebo group, the median concentrations of C5a remained approximately at the baseline level during the study up to Day 30 after the initiation of the treatment. However, the direct clinical relevance of C5a plasma concentration reduction is unclear.

12.3 Pharmacokinetics

In healthy subjects, following a single intravenous infusion of GOHIBIC ranging from 2 mg/kg to 4 mg/kg, GOHIBIC Cmax showed dose proportionality while the AUC showed greater than dose proportionality. The elimination half-life of GOHIBIC following a 4 mg/kg single intravenous dose in healthy subjects was 95 hours.

Pre-dose plasma samples were collected in patients with severe COVID-19 pneumonia requiring IMV or ECMO. Following intravenous infusion of GOHIBIC 800 mg on Days 1, 2, and 4, the pre-dose geometric mean (geometric CV%) plasma concentration of GOHIBIC on Day 8 was 137.9 µg/mL (51%).

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Animal studies have not been conducted to evaluate the carcinogenic potential of GOHIBIC. The malignancy risk in humans from an antibody that binds C5a, such as GOHIBIC, is currently unknown.

Male and female fertility parameters were evaluated as part of the 13-week and 26-week repeat-dose toxicity studies, respectively. There were no treatment-related changes to sperm morphology, count, or motility in male monkeys administered GOHIBIC for 13-weeks at intravenous doses up to 50.6 mg/kg/week (approximately 2.5 times the MRHD on a mg/kg basis). Following 26-weeks intravenous administration of GOHIBIC, there were no effects on female fertility including menstrual cyclicity identified at doses up to 50 mg/kg/week (approximately 2.5 time the MRHD on a mg/kg basis).

How supplied

GOHIBIC (vilobelimab) 200 mg/20 mL (10 mg/mL) injection is a clear to slightly opalescent, colorless solution in a single-dose vial (NDC 83000-110-04).

Storage and Handling

Store unopened vials refrigerated at 2°C to 8°C (36°F to 46°F) in the original carton to protect from light. Do not freeze. Do not shake.