NOTE: Information included in this monograph is based upon preclinical information. No human data are available.

Transcription

1 ZMapp: Monoclonal antibody consisting of three mouse/human chimeric IgG1 monoclonal antibodies (c2g4, c4g7, and c13c6) LeafBio/MAPP Biopharmaceuticals Information as of October, NOTE: Information included in this monograph is based upon preclinical information. No human data are available. Summary 1 Indications ZMapp is an investigational immunotherapy agent that that may be used for the experimental treatment of Ebola virus-infected patients. ZMapp has not yet been studied in humans for safety or effectiveness. Monitoring Parameters 2 Improvement of infection and decrease in viral loads following administration of ZMapp. Dose 2 ZMapp dosing, safety, and efficacy in human patients has not been established. An experimental study administered three doses of ZMapp 50 mg/kg spaced 3 days apart to rhesus macaques. Higher doses may be necessary if the viral load is high. Pediatrics ZMapp dosing, safety, and efficacy in pediatric patients has not been established. Geriatrics ZMapp dosing, safety, and efficacy in geriatric patients has not been established. Renal Insufficiency & Hepatic impairment ZMapp dosing, safety, and efficacy in patients with renal and hepatic impairment have not been established. Pregnancy Category and Breastfeeding ZMapp dosing, safety, and efficacy has not been established in pregnant or breastfeeding patients. How supplied and storage Unknown. Introduction 2 ZMapp is a monoclonal antibody consisting of three IgG1 monoclonal antibodies (c2g4, c4g7, and c13c6) designed for use in the treatment of patients infected with Ebola virus. No clinical trials exist to date, but current studies in non-human primates demonstrate promise with 100% recovery when treated with ZMapp. Without any licensed therapies for Ebola virus infection, few options are available outside of supportive care. The only treatments thus far that have demonstrated any benefit when administered after 24 hours of exposure to Ebola virus have been the antibody-based candidates; both of which are not overwhelmingly efficacious. ZMapp appears to be more efficacious than the alternative. ZMapp demonstrated excellent response rates in a non-human primate study and has been given as compassionate and experimental treatment to 3 human beings of which two have recovered. C2G4, c4g7, c13c6 mab (ZMAPP ) October

2 Pharmacology 3 ZMapp is composed of one chimeric monoclonal antibody (c13c6) and two humanized monoclonal antibodies from ZMab (c2g4 and c4g7) providing passive immunity to the individual by selectively binding to the protein virus, activating the immune system, and arresting viral replication. 3 Pharmacokinetics 2 Rhesus macaques have about 55-80ml of blood per kg of body weight. It is estimated that a dose of 50 mg/kg of ZMapp will lead to a serum level of about mcg/ml. The low median effective concentration values for EBOV-G are mcg/ml as demonstrated on the table taken directly from the paper published by Qiu, X. et al. below: X Qiu et al. Nature 000, 1-7 (2014) doi: /nature13777 Clinical Trials To date, there are no human clinical trials have been undertaken. C2G4, c4g7, c13c6 mab (ZMAPP ) October

3 Experimental Study 2 : An experimental study assigned 18 rhesus macaques into three treatment groups of six animals and one control group (Group G) of three animals. Treatment consisted of ZMapp 50mg/kg administered at 3, 6, and 9 days post infection (dpi) (Group D); 4, 7 and 10 dpi (Group E); or 5, 8, and 11 dpi (Group F). Control groups received mab 4E10 as an IgG isotype control or PBS. All animals in the treatment group survived the infection despite detection of fever, leukocytosis, thrombocytopenia, and viremia in the majority of all the animals; whereas, all animals in the control group died at 4, 8, and 8 dpi (p = 3.58 x 10-5, log-rank test, χ 2 = 23.25, d.f. = 3). Group E animals were sicker than the others and neared clinical limit for euthanasia at 5 and 8 dpi, but still survived with reversal of disease symptoms and physiological abnormalities, including significant liver damage, after 12 dpi, 2 days after ZMapp was last administered. ZMapp also lowered the viral loads to undetectable levels in two of the animals in the F group. The figures from the clinical study demonstrating the clinical scores and viremia load for each ZMapptreated group are included (Figure 1 and 2, respectively). Figure 1: Clinical scores for each ZMapp-treated group 2 Arrows indicate treatment days. Dashed line represents humane endpoint threshold. Faded symbols/lines are the other two treatment groups, for comparison. Control group (Group G) is shown in black on all three panels. a, Clinical score of Group D (blue); b, clinical score of Group E (orange); c, clinical score of Group F (green). C2G4, c4g7, c13c6 mab (ZMAPP ) October

4 From: Reversion of advanced Ebola virus disease in nonhuman primates with ZMapp Xiangguo Qiu,1, Gary Wong,1, 2, Jonathan Audet,1, 2, Alexander Bello,1, 2, Lisa Fernando,1, Judie B. Alimonti,1, Hugues Fausther-Bovendo,1, 2, Haiyan Wei,1, 3, Jenna Aviles,1, Ernie Hiatt,4, Ashley Johnson,4, Josh Morton,4, Kelsi Swope,4, Ognian Bohorov,5, Natasha Bohorova,5, Charles Goodman,5, Do Kim,5, Michael H. Pauly,5, Jesus Velasco,5, James Pettitt,6, 10, Gene G. Olinger,6, 10, Kevin Whaley,5, Bianli Xu,3, James E. Strong,1, 2, 7, Larry Zeitlin5, & Gary P. Kobinger Nature (2014) DOI: /nature13777 Figure 2: Viraemia for each ZMapp-treated group 2 Arrows indicate treatment days. Faded symbols/lines are the other two treatment groups, for comparison. Control group (Group G) is shown in black on all three panels. a, TCID 50 of Group D (blue); b, TCID 50 of Group E (orange); c, TCID 50 of Group F (green). d, Viraemia by RT qpcr of Group D (blue); e, Viraemia by RT qpcr of Group E (orange); f, Viraemia by RT qpcr of Group F (green). From: Reversion of advanced Ebola virus disease in nonhuman primates with ZMapp Xiangguo Qiu,1, Gary Wong,1, 2, Jonathan Audet,1, 2, Alexander Bello,1, 2, Lisa Fernando,1, Judie B. Alimonti,1, Hugues Fausther-Bovendo,1, 2, Haiyan Wei,1, 3, Jenna Aviles,1, Ernie Hiatt,4, Ashley Johnson,4, Josh Morton,4, Kelsi Swope,4, Ognian Bohorov,5, Natasha Bohorova,5, Charles Goodman,5, C2G4, c4g7, c13c6 mab (ZMAPP ) October

5 Do Kim,5, Michael H. Pauly,5, Jesus Velasco,5, James Pettitt,6, 10, Gene G. Olinger,6, 10, Kevin Whaley,5, Bianli Xu,3, James E. Strong,1, 2, 7, Larry Zeitlin5, & Gary P. Kobinger Nature (2014) DOI: /nature13777 Drug Interactions No drug-drug interaction studies have been conducted with ZMapp.. Adverse Effects No clinical trials have been conducting assessing the safety of ZMapp. To date any adverse effects experienced by the three patients who have received ZMapp have not be disclosed to the public. Recommendation In the event of an identified patient with confirmed Ebola Virus Disease, contact Dr. Miles Brennan via at and please cc and These individuals are available to provide information regarding the availability and use of its product. The UWHC Pharmaceutical Research Center must be informed via pager (2717) of any contacts made to secure any investigational therapies. References 1. Experimental Serum ZMapp May Have Been Key to Recovery of Two Ebola Patients: Reports. Published August 4, Accessed October 17, Qiu X, Wong G, Audet J, et al. Reversion of advanced Ebola virus disease in nonhuman primates with ZMapp. Nature. 2014;514(7520): Nine questions about this new Ebola drug. CNN Health Cable News Network Website. Published August 5, Accessed October 17, Author: Jaimie Goecks, DPH-4 Reviewed and approved by: UWHC Ebola Task Force Date: 10/30/14 C2G4, c4g7, c13c6 mab (ZMAPP ) October