Atoltivimab/maftivimab/odesivimab

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Atoltivimab/maftivimab/odesivimab
Combination of
AtoltivimabMonoclonal antibody
MaftivimabMonoclonal antibody
OdesivimabMonoclonal antibody
Names
Trade namesInmazeb
Other namesREGN-EB3
Clinical data
Routes of
use
Intravenous
External links
AHFS/Drugs.comMonograph
US NLMAtoltivimab/maftivimab/odesivimab
Legal
License data
Legal status

Atoltivimab/maftivimab/odesivimab, developed as REGN-EB3 and 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]

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]

The combination 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]

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

File:Ebola Virus - Electron Micrograph.tiff 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.[8]

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).[9] The therapy was developed in six months and a Phase 1 trial in healthy humans was completed in 2015.[9]

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.[10][11][12] However, the outbreak came to a conclusion before any therapeutic agents were given to patients.[12]

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.[12] 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.

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.[13][14]

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.[15][16][17][18]

In August 2019, Congolese health officials announced it was more effective compared to two other treatments being used at the time.[19][17][20]

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.[21] The survival rate if the drug was administered shortly after the infection was 89%.[13]

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.[22]

References

  1. "Inmazeb- atoltivimab, maftivimab, and odesivimab-ebgn injection, solution". DailyMed. Retrieved 17 January 2021.
  2. 2.00 2.01 2.02 2.03 2.04 2.05 2.06 2.07 2.08 2.09 2.10 2.11 2.12 2.13 2.14 2.15 2.16 2.17 2.18 "FDA Approves First Treatment for Ebola Virus". U.S. Food and Drug Administration (FDA) (Press release). 14 October 2020. Retrieved 14 October 2020. Public Domain This article incorporates text from this source, which is in the public domain.
  3. 3.0 3.1 3.2 3.3 3.4 3.5 "Drug Trials Snapshots: Inmazeb". U.S. Food and Drug Administration. 14 October 2020. Retrieved 23 October 2020. Public Domain 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. 6.0 6.1 "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. "Ebola Treatment Massively Cuts Death Rate, But It's No Cure". Futurity. 16 August 2019. Retrieved 7 November 2019.
  9. 9.0 9.1 Stahl, Niel. "Making a Drug You Hope No One Will Ever Need Harnessing the Power of Technology for Good". Retrieved 6 November 2019.
  10. Check Hayden, Erika (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.
  11. WHO: Consultation on Monitored Emergency Use of Unregistered and Investigational Interventions for Ebola virus Disease. https://www.who.int/emergencies/ebola/MEURI-Ebola.pdf
  12. 12.0 12.1 12.2 "NIH VideoCast - CC Grand Rounds: Response to an Outbreak: Ebola Virus Monoclonal Antibody (mAb114) Rapid Clinical Development". videocast.nih.gov. Retrieved 9 August 2019.
  13. 13.0 13.1 "Two Ebola drugs show promise amid ongoing outbreak". Nature. Retrieved 6 November 2019.
  14. "Ebola virus disease – Democratic Republic of the Congo". WHO. 23 January 2020. Retrieved 28 January 2020.
  15. Mole, Beth (13 August 2019). "Two Ebola drugs boost survival rates, according to early trial data". Ars Technica. Retrieved 17 August 2019.
  16. "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.
  17. 17.0 17.1 McNeil, Jr., Donald G. (12 August 2019). "A Cure for Ebola? Two New Treatments Prove Highly Effective in Congo". The New York Times. Retrieved 13 August 2019.
  18. Kingsley-Hall A. "Congo's experimental mAb114 Ebola treatment appears successful: authorities | Central Africa". www.theafricareport.com. Retrieved 15 October 2018.
  19. "Ebola Treatment Trials Launched In Democratic Republic Of The Congo Amid Outbreak". NPR.org. Retrieved 28 May 2019.
  20. Molteni, Megan (12 August 2019). "Ebola is Now Curable. Here's How The New Treatments Work". Wired. Retrieved 13 August 2019.
  21. "'Ebola is Now a Disease We Can Treat.' How a Cure Emerged from a War Zone".
  22. "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.

Further reading

External links

Identifiers: