The filoviruses (family Filoviridae), comprising five ebolaviruses, a cuevavirus, and two Marburg viruses, are negative-strand RNA viruses that cause severe hemorrhagic fever with up to 90% human case fatality rate. The 2014?2016 epidemic in Western Africa, caused by the Zaire ebolavirus (EBOV) species demonstrated the potential for these viruses to cause dire health emergencies of global scope, and highlighted the need for development of therapeutics and vaccines. Sudan virus (SUDV), Bundibugyo virus (BDBV), and Marburg virus (MARV) have all caused large human outbreaks with high case fatality rates, and thus have similar epidemic potential. In particular, while SUDV, the subject of this proposal caused the 2nd largest filovirus outbreak to date, no therapy or vaccine is currently available. Our product, CM-SV1, is a humanized first-in-class, single dose, monoclonal antibody (mAb) against SUDV for use as both a prophylactic and a therapeutic agent, thus serving the needs of frontline medical staff and infected persons. mAbs represent an attractive therapeutic modality for filoviruses because mAb cocktails or convalescent IgG has been demonstrated to provide post-exposure protection of non-human primates. Furthermore, mAbs are generally well-tolerated and have favorable pharmacokinetic and safety profiles. Given the sporadic and unpredictable nature of outbreaks, it would be highly advantageous to have mAb therapies against each of the filoviruses ready for rapid deployment as emergency therapeutics. To date, we have produced CM-SV1 in both HEK293 and N. bethathasmia (tobacco) and have demonstrated efficacy in lethal challenge models in murine and guinea pig models of SUDV infection. The purpose of this proposal is to first determine developability of CM-SV1 and then to develop CM-SV1 to a technology readiness level (TRL) 5 in preparation for investigational new drug (IND) filing. In Phase I, we will engineer the Fc portion CM-SV1 to have improved prophylactic capabilities, produce CM-SV1 in an industry standard for manufacturing (Chinese Hamster ovary cells), determine developability, demonstrate non-inferior efficacy compared to HEK produced CM-SV1 in a murine challenge model, and determine success in engineering enhanced half-life. In Phase II, we will determine non-inferior efficacy compared to HEK produced CM-SV1 in a guinea pig challenge model, determine toxicity, prepare and file a pre-IND application and conduct a Type B meeting with FDA, and finally demonstrate efficacy of CM-SV1 in a non-human primate SUDV lethal challenge model. At the culmination of this program CM-SV1 will be optimized for cGMP manufacture and IND preparation.

Public Health Relevance

Filoviruses, including ebolaviruses and Marburg virus, cause a rapidly progressing and fatal hemorrhagic fever and as demonstrated in the 2013-2016 West Africa epidemic, have the potential to cause widespread disease. Currently, there are no therapeutic strategies on market to mitigate Sudan virus (SUDV), one of the five types of ebolavirus that poses a highly lethal risk to communities, aid workers and civilian populations in the event of a pandemic. We are developing CM-SV1, a first-in-class single dose monoclonal antibody that can be used both as a therapeutic and a prophylactic treatment in the unfortunate event of a SUDV outbreak.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Small Business Innovation Research Grants (SBIR) - Phase II (R44)
Project #
5R44AI136273-02
Application #
9649173
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Repik, Patricia M
Project Start
2018-02-16
Project End
2020-01-31
Budget Start
2019-02-01
Budget End
2020-01-31
Support Year
2
Fiscal Year
2019
Total Cost
Indirect Cost
Name
Celdara Medical, LLC
Department
Type
DUNS #
828763263
City
Lebanon
State
NH
Country
United States
Zip Code
03766