Abstract Title
Oral Direct-Acting Antiviral CDI-988 for norovirus infection prevention and treatment: Mechanism of Action and Phase 1 Study Results
Presenter
Sam Lee, Cocrystal Pharma Inc.
Co-Author(s)
Sam Lee PhD1, Lyn Frumkin MD/PhD2, Curtis Scribner MD3, Georgina Kilfoil MS4, Marie Crouch PhD1, Irina Jacobson PhD1, Juan Pizarro PhD1, Biing Lin MS1, Hong Xiao MS1, Janet Adolphson MS1, Claire Hafer1, Bill Kramer PhD5
1; Cocrystal Pharma Inc; 19805 North Creek Parkway, Bothell, WA 98011
2; Independent consultant, Seattle, WA
3; Independent consultant, Oakland, CA
4; Ashcroft consulting, Sydney, Australia
5; Kramer consulting, North Potomac, MD
Abstract Category
Prevention & Control (antivirals)
Abstract
Introduction: Human norovirus is a leading cause of acute gastroenteritis, responsible for approximately 21 million cases in the United States and 685 million globally every year. No approved treatment or vaccine is available for the treatment of norovirus infection. CDI-988 is a first-in-class structure-based pan-viral protease inhibitor and clinical drug candidate currently under development as an oral treatment for noroviruses as well as coronaviruses.
Materials and Methods:
Proteases from seventeen clinically important strains of norovirus including several from genogroups GII.4 and GII.17 were purified for cocrystal structure determination and in vitro potency assays. A randomized, double-blind, placebo-controlled CDI-988 Phase 1 study was conducted for safety, tolerability, PK, and food effects.
Results:
High resolution X-ray crystal structures of the norovirus proteases complexed with CDI-988 revealed that it binds to a highly conserved region of the active site, consistent with in vitro broad-spectrum activity against the norovirus proteases from multiple norovirus genogroups including GII.4 and GII.17. In the single-ascending dose (SAD) and multiple-ascending dose (MAD) cohorts, all doses were well tolerated with few adverse events (AEs). There were no deaths, serious AEs, or discontinuations due to study drug. In addition, there were no clinically relevant ECG changes, laboratory values, or physical exam findings.
Conclusions:
Our study demonstrates that CDI-988, a novel broad-spectrum oral protease inhibitor being developed for the prevention and treatment of noroviruses and coronaviruses, was safe and well tolerated in a Phase 1 SAD/MAD study in healthy volunteers.
Materials and Methods:
Proteases from seventeen clinically important strains of norovirus including several from genogroups GII.4 and GII.17 were purified for cocrystal structure determination and in vitro potency assays. A randomized, double-blind, placebo-controlled CDI-988 Phase 1 study was conducted for safety, tolerability, PK, and food effects.
Results:
High resolution X-ray crystal structures of the norovirus proteases complexed with CDI-988 revealed that it binds to a highly conserved region of the active site, consistent with in vitro broad-spectrum activity against the norovirus proteases from multiple norovirus genogroups including GII.4 and GII.17. In the single-ascending dose (SAD) and multiple-ascending dose (MAD) cohorts, all doses were well tolerated with few adverse events (AEs). There were no deaths, serious AEs, or discontinuations due to study drug. In addition, there were no clinically relevant ECG changes, laboratory values, or physical exam findings.
Conclusions:
Our study demonstrates that CDI-988, a novel broad-spectrum oral protease inhibitor being developed for the prevention and treatment of noroviruses and coronaviruses, was safe and well tolerated in a Phase 1 SAD/MAD study in healthy volunteers.