Partnering to Rapidly Advance ZMapp® for Ebola Treatment | SRI International

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Partnering to Rapidly Advance ZMapp® for Ebola Treatment

SRI worked with partners to develop treatment for patients in life-saving time.

Ebola virus (EBOV) can cause severe, fatal illness in humans, sometimes characterized by hemorrhage, multi-organ failure and a shock-like syndrome. There are no approved vaccines or treatments for EBOV infection, but ZMapp, a cocktail of monoclonal antibodies, proved effective against EBOV in preclinical models. When the 2014 EBOV outbreak led to several U.S. patients contracting the disease, SRI worked with its partners to bring ZMapp from the lab to patients in life-saving time.

ZMapp, manufactured by Mapp Biopharmaceutical, Inc., is a cocktail of three monoclonal antibodies (c13C6+c2G4+c4G7) that had shown protection against EBOV in preclinical models. Efficacy had been clearly demonstrated, but little was known about ZMapp’s safety and pharmacokinetics, and this information would be required before initiating human clinical trials.

Partnering to respond to life-or-death need

SRI holds the contract for preclinical development of anti-infective agents from the National Institute of Allergy and Infectious Diseases (NIAID), part of the National Institutes of Health (NIH). Mapp and SRI collaborated to conduct safety studies of ZMapp, and to develop appropriate methods for measuring the three antibodies in the blood following treatment.

SRI designed a rodent toxicity study conducted under FDA’s Good Laboratory Practice (GLP) regulations to determine the safety of ZMapp prior to human clinical trials. The study was intended to be the first of several safety studies performed, but during the study, several people in the U.S. contracted EBOV.

The FDA approved treating humans with ZMapp under expanded access provisions (also known as “compassionate use”) prior to formal approval for human clinical testing.

Because of the critical need to use ZMapp and the cocktail’s use in human cases was imminent, SRI, in consultation with NIAID, Mapp and the FDA, redesigned the ongoing toxicity study to

include additional dose administrations and to extend the post-treatment recovery period for extended evaluation of responses. SRI also developed a detection method in serum, and researchers developed assays to determine the presence of anti-drug antibodies that could potentially inactivate the ZMapp antibodies.

Concentrated efforts slash time to IND application

Due to the urgency of the outbreak, including the possibility that EBOV infections could spread throughout the United States, SRI proceeded in record time. SRI modified the design of the ongoing toxicity study and completed the final report within eight weeks of completing the experimental phase of the study.

The study demonstrated that while ZMapp had minor effects on the liver, these resolved quickly after cessation of treatment, and the three-mAb cocktail was well tolerated. SRI also developed methods for measuring the three antibodies in blood, and demonstrated that anti-drug antibodies were not formed against the cocktail components.

Mapp filed an Investigational New Drug (IND) application for ZMapp in February 2015, just seven months after initiation of the clinical safety program. By comparison, the industry average for this development period is about three years.

SRI continues work with ZMapp, developing additional methods for measuring antibodies in multiple species including human, and conducting studies to identify potential cross-reactivity of the cocktail in human and animal tissues.

Research and development activities described were supported by:

NIAID/NIH under Contract Number HHSN272201100022I. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.