Atoltivimab/maftivimab/odesivimab

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Atoltivimab/maftivimab/odesivimab
Combination of
Atoltivimab Monoclonal antibody
Maftivimab Monoclonal antibody
Odesivimab Monoclonal antibody
Clinical data
Trade names Inmazeb
Other namesREGN-EB3
AHFS/Drugs.com Monograph
License data
Routes of
administration 		Intravenous
ATC code
  • None
Legal status
Legal status
Identifiers
CAS Number
KEGG

Atoltivimab/maftivimab/odesivimab, sold under the brand name Inmazeb, is a fixed-dose combination of three monoclonal antibodies for the treatment of Zaire ebolavirus (Ebola virus). [2] It contains atoltivimab, maftivimab, and odesivimab-ebgn and was developed by Regeneron Pharmaceuticals. [2]

Contents

The most common side effects include fever, chills, tachycardia (fast heart rate), tachypnea (fast breathing), and vomiting; however, these are also common symptoms of Ebola virus infection. [2] [3]

Atoltivimab/maftivimab/odesivimab is the first FDA-approved treatment for Zaire ebolavirus. [2] Atoltivimab/maftivimab/odesivimab was approved for medical use in the United States in October 2020. [2] [4] [5] [3] [6] The U.S. Food and Drug Administration (FDA) considers it to be a first-in-class medication. [7] It is on the World Health Organization's List of Essential Medicines. [8]

Medical uses

Atoltivimab/maftivimab/odesivimab is indicated for the treatment of infection caused by Zaire ebolavirus. [2]

Contraindications

People who receive atoltivimab/maftivimab/odesivimab should avoid the concurrent administration of a live vaccine due to the treatment's potential to inhibit replication of a live vaccine virus indicated for prevention of Ebola virus infection and possibly reduce the vaccine's efficacy. [2]

Pharmacology

Mechanism of action

Colorized scanning electron micrograph of Ebola virus particles (green) Ebola Virus - Electron Micrograph.tiff
Colorized scanning electron micrograph of Ebola virus particles (green)

Atoltivimab/maftivimab/odesivimab is a combination of Zaire ebolavirus glycoprotein-directed human monoclonal antibodies. [2] The three antibodies target the glycoprotein that is on the surface of the Ebola virus. [2] This glycoprotein normally attaches to the cell via a receptor and fuses the viral and host cell membranes allowing the virus to enter the cell. [2] The antibodies can bind to it simultaneously at three different locations and block attachment and entry of the virus. [2]

This combination drug targets the Zaire species of Ebola virus. The Sudan and Bundibugyo strains have also caused outbreaks, and it is unlikely that it would be effective against these strains. [9]

History

Early development

The 2014 Ebola outbreak killed more than 11,300 people. Regeneron used its VelociGene, VelocImmune and VelociMab antibody discovery and production technologies and coordinated with the U.S. government's Biomedical Advanced Research and Development Authority (BARDA). [10] The therapy was developed in six months and a Phase 1 trial in healthy humans was completed in 2015. [10]

PALM trial

During the 2018 Équateur province Ebola outbreak, a similar monoclonal antibody treatment, mAb114, was requested by the Democratic Republic of Congo (DRC) Ministry of Public Health. mAb114 was approved for compassionate use by the World Health Organization MEURI ethical protocol and at DRC ethics board. mAb114 was sent along with other therapeutic agents to the outbreak sites. [11] [12] [13] However, the outbreak came to a conclusion before any therapeutic agents were given to patients. [13]

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, mAb114 received approval for compassionate use by WHO MEURI and DRC ethic boards and has been given to many patients under these protocols. [13] In November 2018, the Pamoja Tulinde Maisha (PALM [together save lives]) open-label randomized clinical control trial was begun at multiple treatment units testing mAb114, 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.[ citation needed ]

This is the second largest outbreak with (as of January 2020) over 3,400 confirmed or probable cases, including more than 2,200 who have died. [14] [15]

An interim analysis by the Data Safety and Monitoring Board (DSMB) of the first 499 patient found that mAb114 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 mAb114 and REGN-EB3. When looking at patients who arrived early after disease symptoms appeared, survival was 89% for mAB114 and 94% for REGN-EB3. While the study was not powered to determine whether there is any difference between REGN-EB3 and mAb114, 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 mAb114 or REGN-EB3. [16] [17] [18] [19]

In August 2019, Congolese health officials announced it was more effective compared to two other treatments being used at the time. [20] [18] [21]

Among patients treated with it, 34% died; the mortality rate improved if the drug was administered soon after infection, in a timely diagnosis – critical for those infected with diseases like Ebola that can cause sepsis and, eventually, multiple organ dysfunction syndrome, more quickly than other diseases. [22] The survival rate if the drug was administered shortly after the infection was 89%. [14]

Atoltivimab/maftivimab/odesivimab was evaluated in 382 adult and pediatric participants with confirmed Zaire ebolavirus infection in one clinical trial (the PALM trial) and as part of an expanded access program conducted in the Democratic Republic of the Congo (DRC) during an Ebola virus outbreak in 2018/2019. [2] [3] In the PALM trial, the safety and efficacy of atoltivimab/maftivimab/odesivimab was evaluated in a multi-center, open-label, randomized controlled trial, in which 154 participants received atoltivimab/maftivimab/odesivimab (50 mg of each monoclonal antibody) intravenously as a single infusion, and 168 participants received an investigational control. [2] The trial enrolled pediatric and adult participants (including pregnant women) with Zaire ebolavirus infection. [3] All participants received standard, supportive care for the disease. [3] The participants and the health care providers knew which treatment was being given. [3] The primary efficacy endpoint was 28-day mortality. [2] The primary analysis population was all participants who were randomized and concurrently eligible to receive either atoltivimab/maftivimab/odesivimab or the investigational control during the same time period of the trial. [2] Of the 154 participants who received atoltivimab/maftivimab/odesivimab, 33.8% died after 28 days, compared to 51% of the 153 participants who received a control. [2] In the expanded access program, an additional 228 participants received atoltivimab/maftivimab/odesivimab. [2]

Regulatory status

The FDA granted the application of atoltivimab/maftivimab/odesivimab-ebgn orphan drug and breakthrough therapy designations. [2] The FDA granted the approval of Inmazeb to Regeneron Pharmaceuticals with an indication for the treatment of infection caused by Zaire ebolavirus in October 2020. [2] [6]

The drug has also received orphan drug designation from the European Medicines Agency. [23]

Related Research Articles

<i>Ebolavirus</i> Genus of virus

The genus Ebolavirus is a virological taxon included in the family Filoviridae, order Mononegavirales. The members of this genus are called ebolaviruses, and encode their genome in the form of single-stranded negative-sense RNA. The six known virus species are named for the region where each was originally identified: Bundibugyo ebolavirus, Reston ebolavirus, Sudan ebolavirus, Taï Forest ebolavirus, Zaire ebolavirus, and Bombali ebolavirus. The last is the most recent species to be named and was isolated from Angolan free-tailed bats in Sierra Leone. Each species of the genus Ebolavirus has one member virus, and four of these cause Ebola virus disease (EVD) in humans, a type of hemorrhagic fever having a very high case fatality rate. The Reston virus has caused EVD in other primates. Zaire ebolavirus has the highest mortality rate of the ebolaviruses and is responsible for the largest number of outbreaks of the six known species of the genus, including the 1976 Zaire outbreak and the outbreak with the most deaths (2014).

<span class="mw-page-title-main">Regeneron Pharmaceuticals</span> American biotechnology company

Regeneron Pharmaceuticals, Inc. is an American biotechnology company headquartered in Westchester County, New York. The company was founded in 1988. Originally focused on neurotrophic factors and their regenerative capabilities, giving rise to its name, the company then branched out into the study of both cytokine and tyrosine kinase receptors, which gave rise to their first product, which is a VEGF-trap.

<span class="mw-page-title-main">Vaccine Research Center</span>

The Vaccine Research Center (VRC), is an intramural division of the National Institute of Allergy and Infectious Diseases (NIAID), part of the National Institutes of Health (NIH), US Department of Health and Human Services (HHS). The mission of the VRC is to discover and develop both vaccines and antibody-based products that target infectious diseases.

<span class="mw-page-title-main">Dupilumab</span> Drug used to treat allergic diseases

Dupilumab, sold under the brand name Dupixent, is a monoclonal antibody blocking interleukin 4 and interleukin 13, used for allergic diseases such as eczema, asthma and nasal polyps which result in chronic sinusitis. It is also used for the treatment of eosinophilic esophagitis and prurigo nodularis.

<span class="mw-page-title-main">Ebola</span> Viral hemorrhagic fever of humans and other primates caused by ebolaviruses

Ebola, also known as Ebola virus disease (EVD) and Ebola hemorrhagic fever (EHF), is a viral hemorrhagic fever in humans and other primates, caused by ebolaviruses. Symptoms typically start anywhere between two days and three weeks after infection. The first symptoms are usually fever, sore throat, muscle pain, and headaches. These are usually followed by vomiting, diarrhoea, rash and decreased liver and kidney function, at which point some people begin to bleed both internally and externally. It kills between 25% and 90% of those infected – about 50% on average. Death is often due to shock from fluid loss, and typically occurs between six and 16 days after the first symptoms appear. Early treatment of symptoms increases the survival rate considerably compared to late start. An Ebola vaccine was approved by the US FDA in December 2019.

<span class="mw-page-title-main">Brincidofovir</span> Antiviral drug

Brincidofovir, sold under the brand name Tembexa, is an antiviral drug used to treat smallpox. Brincidofovir is a prodrug of cidofovir. Conjugated to a lipid, the compound is designed to release cidofovir intracellularly, allowing for higher intracellular and lower plasma concentrations of cidofovir, effectively increasing its activity against dsDNA viruses, as well as oral bioavailability.

<span class="mw-page-title-main">ZMapp</span> Experimental treatment for Ebola virus disease

ZMapp is an experimental biopharmaceutical drug comprising three chimeric monoclonal antibodies under development as a treatment for Ebola virus disease. Two of the three components were originally developed at the Public Health Agency of Canada's National Microbiology Laboratory (NML), and the third at the U.S. Army Medical Research Institute of Infectious Diseases; the cocktail was optimized by Gary Kobinger, a research scientist at the NML and underwent further development under license by Mapp Biopharmaceutical. ZMapp was first used on humans during the Western African Ebola virus epidemic, having only been previously tested on animals and not yet subjected to a randomized controlled trial. The National Institutes of Health (NIH) ran a clinical trial starting in January 2015 with subjects from Sierra Leone, Guinea, and Liberia aiming to enroll 200 people, but the epidemic waned and the trial closed early, leaving it too statistically underpowered to give a meaningful result about whether ZMapp worked.

TKM-Ebola was an experimental antiviral drug for Ebola disease that was developed by Arbutus Biopharma in Vancouver, Canada. The drug candidate was formerly known as Ebola-SNALP.

rVSV-ZEBOV vaccine Vaccine against Ebola virus disease

Recombinant vesicular stomatitis virus–Zaire Ebola virus (rVSV-ZEBOV), also known as Ebola Zaire vaccine live and sold under the brand name Ervebo, is an Ebola vaccine for adults that prevents Ebola caused by the Zaire ebolavirus. When used in ring vaccination, rVSV-ZEBOV has shown a high level of protection. Around half the people given the vaccine have mild to moderate adverse effects that include headache, fatigue, and muscle pain.

<span class="mw-page-title-main">Ebola vaccine</span> Vaccine against Ebola

Ebola vaccines are vaccines either approved or in development to prevent Ebola. As of 2022, there are only vaccines against the Zaire ebolavirus. The first vaccine to be approved in the United States was rVSV-ZEBOV in December 2019. It had been used extensively in the Kivu Ebola epidemic under a compassionate use protocol. During the early 21st century, several vaccine candidates displayed efficacy to protect nonhuman primates against lethal infection.

<span class="mw-page-title-main">Ebola virus disease treatment research</span>

There is a cure for the Ebola virus disease that is currently approved for market the US government has inventory in the Strategic National Stockpile. For past and current Ebola epidemics, treatment has been primarily supportive in nature.

<span class="mw-page-title-main">2018 Équateur province Ebola outbreak</span> Disease outbreak in the Democratic Republic of the Congo

The 2018 Équateur province Ebola outbreak occurred in the north-west of the Democratic Republic of the Congo (DRC) from May to July 2018. It was contained entirely within Équateur province, and was the first time that vaccination with the rVSV-ZEBOV Ebola vaccine had been attempted in the early stages of an Ebola outbreak, with a total of 3,481 people vaccinated. It was the ninth recorded Ebola outbreak in the DRC.

<span class="mw-page-title-main">Kivu Ebola epidemic</span> Ebola virus outbreak in the eastern DRC from 2018 to 2020

The Kivu Ebola epidemic was an outbreak of Ebola virus disease (EVD) mainly in eastern Democratic Republic of the Congo (DRC), and in other parts of Central Africa, from 2018 to 2020. Between 1 August 2018 and 25 June 2020 it resulted in 3,470 reported cases. The Kivu outbreak also affected Ituri Province, whose first case was confirmed on 13 August 2018. In November 2018, the outbreak became the biggest Ebola outbreak in the DRC's history, and had become the second-largest Ebola outbreak in recorded history worldwide, behind only the 2013–2016 Western Africa epidemic. In June 2019, the virus reached Uganda, having infected a 5-year-old Congolese boy who entered Uganda with his family, but was contained.

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

<span class="mw-page-title-main">Jean-Jacques Muyembe-Tamfum</span> Virologist known for working with Ebola

Jean-Jacques Muyembe is a Congolese microbiologist. He is the general director of the Democratic Republic of the Congo Institut National pour la Recherche Biomedicale (INRB). He was part of team at the Yambuku Catholic Mission Hospital that investigated the first Ebola outbreak, and was part of the effort that discovered Ebola as a new disease, although his exact role is still subject to controversy. In 2016, he led the research that designed, along with other researchers at the INRB and the National Institute of Health Vaccine Research Center in the US, one of the most promising treatment for Ebola, mAb114. The treatment was successfully experimented during recent outbreaks in the DRC, on the express decision of the then DRC Minister of Health, Dr Oly Ilunga, despite a prior negative advice from the World Health Organization.

<span class="mw-page-title-main">Casirivimab/imdevimab</span> Antiviral combination medication

Casirivimab/imdevimab, sold under the brand name REGEN‑COV among others, is a combination medicine used for the treatment and prevention of COVID‑19. It consists of two human monoclonal antibodies, casirivimab and imdevimab that must be mixed together and administered as an infusion or subcutaneous injection. The combination of two antibodies is intended to prevent mutational escape. It is also available as a co-formulated product. It was developed by the American biotechnology company Regeneron Pharmaceuticals.

Atoltivimab is a Zaire ebolavirus glycoprotein-directed human monoclonal antibody that is part of the fixed-dose combination atoltivimab/maftivimab/odesivimab that is used for the treatment of Zaire ebolavirus.

Maftivimab is a Zaire ebolavirus glycoprotein-directed human monoclonal antibody that is part of the fixed-dose combination atoltivimab/maftivimab/odesivimab that is used for the treatment of Zaire ebolavirus.

Odesivimab is a Zaire ebolavirus glycoprotein-directed human monoclonal antibody that is part of the fixed-dose combination atoltivimab/maftivimab/odesivimab that is used for the treatment of Zaire ebolavirus.

Gary P. Kobinger is a Canadian immunologist and virologist who is currently the director at the Galveston National Laboratory at the University of Texas. He has held previous professorships at Université Laval, the University of Manitoba, and the University of Pennsylvania. Additionally, he was the chief of the Special Pathogens Unit at the National Microbiology Laboratory (NML) of the Public Health Agency of Canada (PHAC) in Winnipeg, Manitoba, for eight years. Kobinger is known for his critical role in the development of both an effective Ebola vaccine and treatment. His work focuses on the development and evaluation of new vaccine platforms and immunological treatments against emerging and re-emerging viruses that are dangerous to human health.

References

  1. ↑ "Inmazeb- atoltivimab, maftivimab, and odesivimab-ebgn injection, solution". DailyMed. Retrieved 17 January 2021.
  2. 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 "FDA Approves First Treatment for Ebola Virus". U.S. Food and Drug Administration (FDA) (Press release). 14 October 2020. Retrieved 14 October 2020.PD-icon.svg This article incorporates text from this source, which is in the public domain .
  3. 1 2 3 4 5 6 "Drug Trials Snapshots: Inmazeb". U.S. Food and Drug Administration . 14 October 2020. Retrieved 23 October 2020.PD-icon.svg This article incorporates text from this source, which is in the public domain .
  4. ↑ "Regeneron's Antibody Cocktail REGN-EB3 (Inmazeb) is First FDA-Approved Treatment for Ebola (Zaire Ebolavirus)". Regeneron Pharmaceuticals Inc. (Press release). 14 October 2020. Retrieved 14 October 2020.
  5. ↑ "Inmazeb: FDA-Approved Drugs". U.S. Food and Drug Administration (FDA). Retrieved 15 October 2020.
  6. 1 2 "Drug Approval Package: Inmazeb". U.S. Food and Drug Administration . 12 November 2020. Retrieved 23 December 2020.
  7. ↑ "New Drug Therapy Approvals 2020". U.S. Food and Drug Administration (FDA). 31 December 2020. Retrieved 17 January 2021.
  8. ↑ World Health Organization (2023). The selection and use of essential medicines 2023: web annex A: World Health Organization model list of essential medicines: 23rd list (2023). Geneva: World Health Organization. hdl: 10665/371090 . WHO/MHP/HPS/EML/2023.02.
  9. ↑ "Ebola Treatment Massively Cuts Death Rate, But It's No Cure". Futurity. 16 August 2019. Retrieved 7 November 2019.
  10. 1 2 Stahl N. "Making a Drug You Hope No One Will Ever Need Harnessing the Power of Technology for Good" . Retrieved 6 November 2019.
  11. ↑ Check Hayden E (May 2018). "Experimental drugs poised for use in Ebola outbreak". Nature. 557 (7706): 475–476. Bibcode:2018Natur.557..475C. doi: 10.1038/d41586-018-05205-x . ISSN   0028-0836. PMID   29789732.
  12. ↑ WHO: Consultation on Monitored Emergency Use of Unregistered and Investigational Interventions for Ebola virus Disease. https://www.who.int/emergencies/ebola/MEURI-Ebola.pdf
  13. 1 2 3 "NIH VideoCast - CC Grand Rounds: Response to an Outbreak: Ebola Virus Monoclonal Antibody (mAb114) Rapid Clinical Development". videocast.nih.gov. 13 March 2019. Retrieved 9 August 2019.
  14. 1 2 "Two Ebola drugs show promise amid ongoing outbreak". Nature. Retrieved 6 November 2019.
  15. ↑ "Ebola virus disease – Democratic Republic of the Congo". WHO. 23 January 2020. Archived from the original on 5 March 2020. Retrieved 28 January 2020.
  16. ↑ Mole B (13 August 2019). "Two Ebola drugs boost survival rates, according to early trial data". Ars Technica. Retrieved 17 August 2019.
  17. ↑ "Independent monitoring board recommends early termination of Ebola therapeutics trial in DRC because of favorable results with two of four candidates". National Institutes of Health (NIH). 12 August 2019. Retrieved 17 August 2019.
  18. 1 2 McNeil DG (12 August 2019). "A Cure for Ebola? Two New Treatments Prove Highly Effective in Congo". The New York Times. Retrieved 13 August 2019.
  19. ↑ Kingsley-Hall A. "Congo's experimental mAb114 Ebola treatment appears successful: authorities | Central Africa". www.theafricareport.com. Retrieved 15 October 2018.
  20. ↑ Dwyer C (27 November 2018). "Ebola Treatment Trials Launched In Democratic Republic Of The Congo Amid Outbreak". NPR.org. Retrieved 28 May 2019.
  21. ↑ Molteni M (12 August 2019). "Ebola is Now Curable. Here's How The New Treatments Work". Wired. Retrieved 13 August 2019.
  22. ↑ "'Ebola is Now a Disease We Can Treat.' How a Cure Emerged from a War Zone". MSN .
  23. ↑ "Palm Ebola Clinical Trial Stopped Early As Regeneron's REGN-EB3 Therapy Shows Superiority to ZMAPP in Preventing Ebola Deaths". Regeneron. Retrieved 6 November 2019.

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