Open Access134. KRP-A218, an Orally Active and Selective PI4KB Inhibitor with Broad-Spectrum Anti-Rhinovirus Activity, Has Potent Therapeutic Antiviral Activity In vivo
Author(s) -
Toshiyuki Matsui,
Motomichi Fujita,
Yuji Ishibashi,
Tyzoon Nomanbhoy,
Jonathan S. Rosenblum,
Michiaki Nagasawa
Publication year - 2021
Publication title -
open forum infectious diseases
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.546
H-Index - 35
ISSN - 2328-8957
DOI - 10.1093/ofid/ofab466.134
Subject(s) - rhinovirus , antiviral drug , virology , in vivo , viral load , viral replication , medicine , virus , immunology , pharmacology , biology , microbiology and biotechnology
Background Rhinovirus (RV) is a major respiratory virus that poses a threat to immunocompromised people and those with underlying disease. However, there are no approved therapies. Moreover, RV infection cannot be prevented by a vaccine because there are over 100 serotypes. Here we report the pharmacological profile of a novel small-molecule host-targeted antiviral (HTA), KRP-A218 (A218). A highly potent and selective inhibitor of phosphatidylinositol 4 kinase beta (PI4KB), a key host factor of RV replication, A218 is undergoing clinical study. Methods in vitro antiviral activities of A218 and Vapendavir (Vap), a virus-targeted antiviral, were examined by inhibition of CPE, viral load, or replication. in vivo antiviral activity and pathological analysis of A218 were examined in coxsackievirus B3 (CVB3; belong to the genus enterovirus as with RV)-infected mice as a surrogate model of RV infection as CVB3, unlike RV, replicates very well in both mouse and human tissue. Daily oral dosing of A218 (1-10 mg/kg) was started 2 days post intraperitoneal infection with CVB3. Tissue viral load, pancreas pathological change at 4 days post infection, and survival rate up to 14 days were evaluated. PI4KB heterozygous kinase-dead mice (PI4KB KD) were established by a CRISPR-Cas9 system. Viral load and survival rate following viral infection were evaluated in these mice. Results A218 showed broad antiviral activity for RV and enteroviruses (Table) and has a higher barrier to drug resistance than Vap. These results are consistent with expectations for HTAs. Repeated dosing of A218 starting 2 days post infection decreased viral load and improved acute pancreatitis, accompanied by decrease of inflammatory and pancreatitis markers in plasma. Moreover, therapeutic dosing of A218 improved survival rate in a CVB3-infected lethal mouse model (Figure). These results show the first evidence that a PI4KB inhibitor has potent therapeutic efficacy in a severe viral infection model. Similar effects were observed in PI4KB KD, supporting the on-target effect of A218. Table. Antiviral activity of A218 and Vap against RV/EV infectionFigure. Therapeutic effect of A218 on survival rate in CVB3-infected mice Conclusion A218 is a promising therapeutic agent for improving the exacerbation of pathological conditions caused by RV infection. Nonclinical package including GLP-Tox also supports the ongoing first-in-human study of A218. Disclosures Toshiyuki Matsui, MPharm , Kyorin pharmaceutical Co., LTD (Employee) Motomichi Fujita, PhD , Kyorin Pharmaceutical Co., Ltd. (Employee) Yuji Ishibashi, PhD , Kyorin Pharmaceutical co., ltd. (Employee) Tyzoon Nomanbhoy, PhD , ActivX Biosciences (Other Financial or Material Support, Full time employee of ActivX, a wholly owned subsidiary of Kyorin Pharmaceuticals) Jonathan S. Rosenblum, PhD , ActivX Biosciences (Employee) Michiaki Nagasawa, PhD , Kyorin Pharmaceutical Co., Ltd (Employee)