Cocrystal Pharma's CC-42344 Shows Activity Against H5N1 Avian Influenza in Preclinical Studies
Key Insights
Cocrystal Pharma's broad-spectrum antiviral CC-42344 demonstrated inhibitory activity against the highly pathogenic avian influenza A (search) (H5N1) PB2 protein (search) in recently completed in vitro studies.
The company is currently conducting a Phase 2a clinical trial with orally administered CC-42344 for influenza A (search) treatment, with topline results expected in the second half of 2024.
Crystal structure analysis confirmed that CC-42344 binds to the highly conserved PB2 region of the avian H5N1 strain, similar to its activity against pandemic and seasonal influenza A (search) viruses.
Cocrystal Pharma's investigational broad-spectrum antiviral CC-42344 has demonstrated inhibitory activity against the highly pathogenic avian influenza A (search) (H5N1) PB2 protein (search) recently identified in infected dairy cattle, according to newly completed in vitro studies announced by the Bothell, Washington-based biotechnology company.
The findings come as the CDC (search) has reported increasing concern over avian flu outbreaks in the United States, including the first documented cases of humans exposed to infected dairy cows. According to James Martin, CFO and co-CEO of Cocrystal, "The CDC reported three additional cases of avian influenza infection from exposure to dairy cows in early June and avian flu is now confirmed in more than 100 dairy herds in 12 U.S. states."
Mechanism of Action and Structural Analysis
CC-42344 represents a new class of antiviral drugs designed to block essential steps in the replication and transcription of the influenza A (search) virus. Using its proprietary structure-based platform, Cocrystal created a high-resolution crystal structure of the avian PB2 protein (search) and confirmed that CC-42344 binds to its highly conserved PB2 region.
The crystal structure analysis of the avian influenza A (search) (H5N1) PB2 protein (search) revealed new mutations located outside the PB2 active site. However, subsequent studies demonstrated that CC-42344 binds to the active site of the avian influenza A (H5N1) PB2 protein as previously shown with pandemic and seasonal influenza A PB2. Preliminary in vitro assays confirmed that CC-42344 exhibits high potency against the avian influenza A (H5N1) PB2 protein.
Clinical Development Progress
Cocrystal is currently conducting a Phase 2a clinical study with orally administered CC-42344 and expects to report topline results in the second half of 2024. This study is evaluating the safety, tolerability, antiviral and clinical benefits in influenza A (search) infected subjects. The Phase 2a human challenge study is being conducted in the United Kingdom to evaluate safety, viral and clinical measures of oral CC-42344 in healthy volunteers who are challenged with influenza A.
CC-42344 was advanced into Phase 2a testing following favorable safety and tolerability results reported in a Phase 1 study in healthy volunteers conducted in Australia in late 2022. In vitro testing showed CC-42344's excellent antiviral activity against influenza A (search) strains, including pandemic and seasonal strains, as well as against strains resistant to Tamiflu® and Xofluza®, while also demonstrating favorable pharmacokinetic and safety profiles.
Public Health Context
The therapeutic potential of CC-42344 against H5N1 addresses a significant unmet medical need. According to the World Health Organization, avian influenza A H5N1 (search) was reported in 889 cases and caused 463 deaths in 23 countries between 2003 and April 2024. On April 1, 2024, the CDC (search) reported a case of highly pathogenic avian influenza A H5N1 in a farmworker in Texas during a multistate outbreak of avian influenza in dairy cows, with two additional cases subsequently reported in farmworkers in Michigan.
CDC (search) analysis of sera collected from people across all 10 Health & Human Services regions during the 2022-2023 and 2021-2022 flu seasons revealed extremely low to no population immunity to clade 2.3.4.4b A (H5N1) viruses in the U.S. Antibody levels remained low regardless of whether participants received seasonal flu vaccination, indicating that seasonal flu vaccination did not produce antibodies to H5N1 viruses.
Broad-Spectrum Approach
"The findings validate our broad-spectrum approach to the treatment and prevention of pandemic flu. This is important as there are no specific FDA-approved vaccines to prevent infections by this virus in humans," said Sam Lee, PhD, President and co-CEO of Cocrystal. "These findings support our previously reported preclinical data showing that CC-42344 is highly active against seasonal and pandemic influenza A (search) strains, including emerging mutations. CC-42344 is an inhibitor compound providing a unique mechanism of action with a high barrier to resistance."
CC-42344 inhibits the first step in influenza A (search)'s viral replication by binding to a highly conserved PB2 site of the influenza polymerase complex (search) that is essential to replication. The compound was discovered using Cocrystal's proprietary structure-based drug discovery platform technology, which employs unique structure-based technologies and Nobel Prize-winning expertise to create first- and best-in-class antiviral drugs.