Pyronaridine as an Oral Treatment for Ebola

Eight rhesus macaques (4M/4F, origin TBD depending on availability; target age and weight: 3-6 years, 3.5-6 kg) will be procured by Collaborations Pharma from a UTMB-approved vendor. Macaques will be screened by the vendor to confirm that they are seronegative for Simian Immunodeficiency Virus (SIV), Simian T-Lymphotrophic Virus-I (STLV-1), and Macacine herpesvirus 1 (Herpes B virus), negative for Simian Retrovirus (SRVl & SRV2) by PCR, negative for Trypanosoma. UTMB ARC veterinarians will implant DST-micro-T implantable temperature loggers (Star-Oddi, Gardabaer, Iceland) into each animal prior to placement on study. Following the required recovery period, animals will be acclimated for up to 7 days in the ABSL4. In-life hands-on NHP manipulations at UTMB will be conducted while animals are under sedation. The study will be randomized (by gender and weight) and run in a blinded manner. Unblinding will occur upon completion of in-life activities and all sample analyses. Following transfer to the BSL-4 vivarium, clinical observations will be performed per UTMB ARC SOPs. Animals will be observed, at minimum, twice daily (6-8 hours apart during the light cycle). Observations will increase in number as the clinical score warrants. Any animal exhibiting signs consistent with significant distress/moribundity shall be evaluated for euthanasia per the approved IACUC protocol. As possible, blood will be collected just prior to euthanasia for terminal processing. Terminal blood will be collected via intracardiac puncture. On Study Day 0, NHPs will be challenged with a target dose of 1,000 PFU EBOV (e.g. Ebolavirus H. sapiens-tc/COD/1995/Kikwit-9510621, with > 90% 7U content at the GP editing position) via i.m. injection. On the day of challenge, the EBOV stock will be thawed and diluted to the appropriate concentration required for the target challenge dose. Preparation and retention of the EBOV challenge material will be performed according to SOP. Following preparation of the challenge suspension, aliquots will be removed before the first animal is dosed and after the last animal is dosed for titration purposes. At minimum, two aliquots will be prepared for each removal: one for plaque assay analysis (i.e., challenge dose confirmation to be performed the day of the challenge) and the other for frozen (= -65°C) storage in the event repeat plaque assay titration is needed. Should repeat plaque assay titration be needed, sample freeze-thaw will be documented. The viral dose administered will be verified via plaque assay on Vero E6 cell monolayers per SOP. Challenge doses will be expressed as PFU administered. NHPs will be treated with Vehicle (Group 1; n=2 [1M/1F]) or pyronaridine (Group 2; n=6 [3M/3F]) via oral gavage just after challenge. In vivo staff will be blinded to treatment groups and the treatment syringes will be prepared by staff not working in the ABSL4 vivarium.