Ansuvimab-zykl

FDA APPROVED, 12/21/2020, EBANGA

To treat ebola

https://www.fda.gov/drugs/drug-safety-and-availability/fda-approves-treatment-ebola-virus

The U.S. Food and Drug Administration approved Ebanga (Ansuvimab-zykl), a human monoclonal antibody, for the treatment for Zaire ebolavirus (Ebolavirus) infection in adults and children. Ebanga blocks binding of the virus to the cell receptor, preventing its entry into the cell.

Zaire ebolavirus is one of four Ebolavirus species that can cause a potentially fatal human disease. It is transmitted through blood, body fluids, and tissues of infected people or wild animals, and through surfaces and materials, such as bedding and clothing, contaminated with these fluids. Individuals who care for people with the disease, including health care workers who do not use correct infection control precautions, are at the highest risk for infection.

During an Ebola outbreak in the Democratic Republic of the Congo (DRC) in 2018-2019, Ebanga was evaluated in a clinical trial (the PALM trial). The PALM trial was led by the U.S. National Institutes of Health and the DRC’s Institut National de Recherche Biomédicale with contributions from several other international organizations and agencies.

In the PALM trial, the safety and efficacy of Ebanga was evaluated in a multi-center, open-label, randomized controlled trial. 174 participants (120 adults and 54 pediatric patients) with confirmed Ebolavirus infection received Ebanga intravenously as a single 50 mg/kg infusion and 168 participants (135 adults and 33 pediatric patients) received an investigational control. The primary efficacy endpoint was 28-day mortality. The primary analysis population was all patients who were randomized and concurrently eligible to receive either Ebanga or the investigational control during the same time period of the trial. Of the 174 patients who received Ebanga, 35.1% died after 28 days, compared to 49.4% of the 168 patients who received a control.

The most common symptoms experienced while receiving Ebanga include: fever, tachycardia (fast heart rate), diarrhea, vomiting, hypotension (low blood pressure), tachypnea (fast breathing) and chills; however, these are also common symptoms of Ebolavirus infection. Hypersensitivity, including infusion-related events, can occur in patients taking Ebanga, and treatment should be discontinued in the event of a hypersensitivity reaction.

Patients who receive Ebanga should avoid the concurrent administration of a live virus vaccine against Ebolavirus. There is the potential for Ebanga to inhibit replication of a live vaccine virus and possibly reduce the efficacy of this vaccine.

Ebanga was granted an Orphan Drug designation, which provides incentives to assist and encourage drug development for rare diseases. Additionally, the agency granted Ebanga a Breakthrough Therapy designation.

FDA granted the approval to Ridgeback Biotherapeutics, LP.

Ansuvimab, sold under the brand name Ebanga, is a monoclonal antibody medication for the treatment of Zaire ebolavirus (Ebolavirus) infection.^[1][2]

The most common symptoms include fever, tachycardia (fast heart rate), diarrhea, vomiting, hypotension (low blood pressure), tachypnea (fast breathing) and chills; however, these are also common symptoms of Ebolavirus infection.^[1]

Ansuvimab was approved for medical use in the United States in December 2020.^[1][2]

Chemistry

The drug is composed of a single monoclonal antibody (mAb) and was initially isolated from immortalized B-cells that were obtained from a survivor of the 1995 outbreak of Ebola virus disease in Kikwit, Democratic Republic of Congo.^[3] In work supported by the United States National Institutes of Health and the Defense Advanced Projects Agency, the heavy and light chain sequences of ansuvimab mAb was cloned into CHO cell lines and initial production runs were produced by Cook Phamica d.b.a. Catalent under contract of Medimmune.^[4][5]

Mechanism of action

Neutralization

Ansuvimab is a monoclonal antibody therapy that is infused intravenously into patients with Ebola virus disease. Ansuvimab is a neutralizing antibody,^[3] meaning it binds to a protein on the surface of Ebola virus that is required to infect cells. Specifically, ansuvimab neutralizes infection by binding to a region of the Ebola virus envelope glycoprotein that, in the absence of ansuvimab, would interact with virus’s cell receptor protein, Niemann-Pick C1 (NPC1).^[6][7][8] This “competition” by ansuvimab prevents Ebola virus from binding to NPC1 and “neutralizes” the virus’s ability to infect the targeted cell.^[6]

Effector function

Antibodies have antigen-binding fragment (Fab) regions and constant fragment (Fc) regions. The Neutralization of virus infection occurs when the Fab regions of antibodies binds to virus antigen(s) in a manner that blocks infection. Antibodies are also able to “kill” virus particles directly and/or kill infected cells using antibody-mediated “effector functions” such as opsonization, complement-dependent cytotoxicity, antibody-dependent cell-mediated cytotoxicity and antibody-dependent phagocytosis. These effector functions are contained in the Fc region of antibodies, but is also dependent on binding of the Fab region to antigen. Effector functions also require the use of complement proteins in serum or Fc-receptor on cell membranes. Ansuvimab has been found to be capable of killing cells by antibody-dependent cell-mediated cytotoxicity.^[3] Other functional killing tests have not been performed.

History

Ansuvimab is a monoclonal antibody that is being evaluated as a treatment for Ebola virus disease.^[9] Its discovery was led by the laboratory of Nancy Sullivan at the United States National Institute of Health Vaccine Research Center and J. J. Muyembe-Tamfum from the Institut National pour la Recherche Biomedicale (INRB) in the Democratic Republic of Congo, working in collaboration with the Institute of Biomedical Research and the United States Army Medical Research Institute of Infectious Diseases.^[3][10] Ansuvimab was isolated from the blood of a survivor of the 1995 outbreak of Ebola virus disease in Kikwit, Democratic Republic of Congo roughly ten years later.^[3]

In 2018, a Phase 1 clinical trial of ansuvimab was conducted by Martin Gaudinski within the Vaccine Research Center Clinical Trials Program that is led by Julie E. Ledgerwood.^[5][4][11] Ansuvimab is also being evaluated during the 2018 North Kivu Ebola outbreak.^[12]

Ansuvimab has also shown success with lowering the mortality rate from ~70% to about 34%. In August 2019, Congolese health authorities, the World Health Organization, and the U.S. National Institutes of Health promoted the use of ansuvimab, alongside REGN-EB3, a similar Regeneron-produced monoclonal antibody treatment, over other treatments yielding higher mortality rates, after ending clinical trials during the outbreak.^[13][14]

Discovery

A 2016 paper describes the efforts of how ansuvimab was originally developed as part of research efforts lead by Dr. Nancy Sullivan at the United States National Institute of Health Vaccine Research Center and Dr. J. J. Muyembe-Tamfum from the Institut National de Recherche Biomedicale (INRB) in the Democratic Republic of Congo.^[3][10] This collaborative effort also involved researchers from Institute of Biomedical Research and the United States Army Medical Research Institute of Infectious Diseases.^[3][10] A survivor from the 1995 outbreak of Ebola virus disease in Kikwit, Democratic Republic of Congo donated blood to the project that began roughly ten years after they had recovered.^[3] Memory B cells isolated from the survivor’s blood were immortalized, cultured and screened for their ability to produce monoclonal antibodies that reacted with the glycoprotein of Ebola virus. Ansuvimab was identified from one of these cultures and the antibody heavy and light chain gene sequences were sequenced from the cells.^[3] These sequences were then cloned into recombinant DNA plasmids and purified antibody protein for initial studies was produced in cells derived from HEK 293 cells.^[3]

Ansuvimab and mAb100 combination

In an experiment described in the 2016 paper, rhesus macaques were infected with Ebola virus and treated with a combination of ansuvimab and another antibody isolated from the same subject, mAb100. Three doses of the combination were given once a day starting 1 day after the animals were infected. The control animal died and the treated animals all survived.^[3]

Ansuvimab monotherapy

In a second experiment described in the 2016 paper, rhesus macaques were infected with Ebola virus and only treated with ansuvimab. Three doses of ansuvimab were given once a day starting 1 day or 5 days after the animals were infected. The control animals died and the treated animals all survived.^[3] Unpublished data referred to in a publication of the 2018 Phase I clinical trial results of ansuvimab, reported that a single infusion of ansuvimab provided full protection of rhesus macaques and was the basis of the dosing used for human studies.^[5][4]

Development

Ansuvimab was developed by the Vaccine Research Center with support of the United States National Institutes of Health and the Defense Advanced Projects Agency. The heavy and light chain sequences of ansuvimab mAb were cloned into CHO cell lines to enable large-scale production of antibody product for use in humans.^[4][5]

Human safety testing

In early 2018,^[9] a Phase 1 clinical trial of ansuvimab’s safety, tolerability and pharmacokinetics was conducted by Dr. Martin Gaudinski within the Vaccine Research Center Clinical Trials Program that is led by Dr. Julie E. Ledgerwood.^[5][4][11] The study was performed in the United States at the NIH Clinical Center and tested single dose infusions of ansuvimab infused over 30 minutes. The study showed that ansuvimab was safe, had minimal side effects and had a half-life of 24 days.^[5][4]

Ridgeback Biotherapeutics

A license for ansuvimab was obtained by Ridgeback Biotherapeutics in 2018, from the National Institutes of Health–National Institute of Allergy and Infectious Diseases.^[15] Ansuvimab was given orphan drug status in May 2019 and March 2020.^[16][17][18]

Experimental use in the Democratic Republic of Congo

During the 2018 Équateur province Ebola outbreak, ansuvimab was requested by the Democratic Republic of Congo (DRC) Ministry of Public Health. Ansuvimab was approved for compassionate use by the World Health Organization MEURI ethical protocol and at DRC ethics board. Ansuvimab was sent along with other therapeutic agents to the outbreak sites.^[19][20][11] However, the outbreak came to a conclusion before any therapeutic agents were given to patients.^[11]

Approximately one month following the conclusion of the Équateur province outbreak, a distinct outbreak was noted in Kivu in the DRC (2018–20 Kivu Ebola outbreak). Once again, ansuvimab received approval for compassionate use by WHO MEURI and DRC ethic boards and has been given to many patients under these protocols.^[11] In November 2018, the Pamoja Tulinde Maisha (PALM [together save lives]) open-label randomized clinical control trial was begun at multiple treatment units testing ansuvimab, REGN-EB3 and remdesivir to ZMapp. Despite the difficulty of running a clinical trial in a conflict zone, investigators have enrolled 681 patients towards their goal of 725. An interim analysis by the Data Safety and Monitoring Board (DSMB) of the first 499 patient found that ansuvimab and REGN-EB3 were superior to the comparator ZMapp. Overall mortality of patients in the ZMapp and remdesivir groups were 49% and 53% compared to 34% and 29% for ansuvimab and REGN-EB3. When looking at patients who arrived early after disease symptoms appeared, survival was 89% for ansuvimab and 94% for REGN-EB3. While the study was not powered to determine whether there is any difference between REGN-EB3 and ansuvimab, the survival difference between those two therapies and ZMapp was significant. This led to the DSMB halting the study and PALM investigators dropping the remdesivir and ZMapp arms from the clinical trial. All patients in the outbreak who elect to participate in the trial will now be given either ansuvimab or REGN-EB3.^{[21][22][13][12]}

In October 2020, the U.S. Food and Drug Administration (FDA) approved atoltivimab/maftivimab/odesivimab (Inmazeb, formerly REGN-EB3) with an indication for the treatment of infection caused by Zaire ebolavirus.^[23]

FDA approves ansuvimab-zykl for Ebola virus infection

DECEMBER 21, 2020 BY JANICE REICHERT

FDA approves ansuvimab-zykl for Ebola virus infection

Ansuvimab

Monoclonal antibody
Type	Whole antibody
Source	Human
Target	Zaire ebolavirus
Clinical data
Trade names	Ebanga
Other names	Ansuvimab-zykl, mAb114
License data	US DailyMed: Ansuvimab
Routes of administration	Intravenous
Drug class	Monoclonal antibody
ATC code	None
Legal status
Legal status	US: ℞-only [1]
Identifiers
CAS Number	2375952-29-5
DrugBank	DB16385
UNII	TG8IQ19NG2
KEGG	D11875
Chemical and physical data
Formula	C6368H9924N1724O1994S44
Molar mass	143950.15 g·mol−1

//////////Ansuvimab-zykl , EBANGA, FDA 2020, 2020 APPROVALS, MONOCLONAL ANTIBODY, Orphan Drug designation, , Breakthrough Therapy designation , Ridgeback Biotherapeutics,