Coronaviruses, which are named for the crown-like spikes on their surfaces, primarily cause infections in birds and mammals.1 There are seven types of coronaviruses that are known to infect humans.2 These can lead to a range of disease in humans from upper respiratory tract infections, similar to the common cold, to lower respiratory tract infections such as bronchitis and pneumonia. However, in the last few decades, the outbreaks of severe acute respiratory syndrome (SARS) in 2003, Middle East respiratory syndrome (MERS) in 2012, and now severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), have demonstrated the deadliness of several coronaviruses when they cross the species barrier and infect humans.3
The current COVID-19 pandemic is caused by a novel human coronavirus, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The two previous outbreaks with the highly pathogenic SARS-CoV and MERS-CoV were quickly suppressed through rigorous infection control. COVID-19, however, has resulted in a global pandemic, overwhelming health care systems worldwide and resulting in millions of deaths around the world as well as lasting health problems of unknown duration in many who have survived the illness.
Enanta’s Approach to Treating SARS-CoV-2
Although the ingenuity of science and rapid clinical development have delivered life-saving vaccines, there is an urgent need for direct-acting antiviral treatments that specifically target the SARS-CoV-2 virus. We believe that a convenient, oral antiviral treatment that can be easily prescribed could be an important option for clinicians and COVID-19 patients. Our goal is to develop a safe, effective, once-daily, convenient antiviral with a short treatment duration for patients diagnosed with COVID-19.
When the pandemic began, Enanta took a two-pronged approach to discovering such an antiviral by evaluating compounds in its chemical library while simultaneously starting a more targeted, rational-drug-design program specifically for this virus. The advantage with a classical discovery approach is that our scientists can make potent, purpose-built inhibitors against multiple different targets within the virus. Although these selective drug candidates take time to discover, optimize, and move into the clinic, they have the benefit of being specifically designed to work against the SARS-CoV-2 virus.
Read More »
Enanta has focused significant resources and dedicated its long-standing expertise in virology, and viral protease inhibitors specifically, to discover and develop oral treatments for COVID-19. Discovery programs were initiated for protease and polymerase inhibitors, classes of drugs long used to treat HIV and hepatitis C. These drugs block viral replication by inhibiting critical enzymes that are required for a virus to replicate.
Enanta’s protease inhibitor program quickly produced leads specifically designed to disrupt SARS-CoV-2 replication by binding to the active site of the enzyme, which is a region of the viral RNA that is conserved across currently circulating SARS-CoV-2 variants. Importantly, as these drug candidates do not target the spike protein, they are likely to be effective against currently emerging variants with spike protein variations that can elude monoclonal antibodies or vaccine immunity. Finally, these leads have been selected to demonstrate pan-coronavirus activity, to enable the ability to possible treated other human coronaviruses in addition to SARS-CoV-2.
In August 2021, Enanta nominated EDP-235 from these early leads as its first oral protease inhibitor clinical candidate for COVID-19. Enanta presented data on EDP-235 at the International Society for Influenza and Other Respiratory Virus Diseases (ISIRV) – World Health Organization (WHO) Virtual Conference.
In human liver microsomes, EDP-235 showed good human Caco-2 cell permeability and a low plasma clearance. Consistent with this in vitro data, EDP-235 had robust plasma exposure with an oral bioavailability of 95% in rats. Moreover, EDP-235 had favorable in vivo penetration into multiple target tissues, including lung, kidney, liver and heart. Based on allometric scaling, EDP-235 is projected to have a long half-life of 16 hours with an efficacious dose of 100 to 500 mg once-daily in humans. Taken together, these data indicate that EDP-235 has the potential for once-daily oral dosing with a low pill burden and without the need for ritonavir boosting.
Enanta initiated a Phase 1 single and multiple ascending dose study to evaluate the safety, tolerability, and pharmacokinetics of EDP-235 in healthy volunteers in February 2022. In March 2022, the U.S. Food and Drug Administration granted Fast Track designation for EDP-235.
- Centers for Disease Control and Prevention: Human Coronavirus Types
- Andersen, K.G., Rambaut, A., Lipkin, W.I. et al. The Proximal Origin of SARS-CoV-2. Nature Medicine 26, 450–452 (2020). https://doi.org/10.1038/s41591-020-0820-9
- Chowell, G., Abdirizak, F., Lee, S. et al. Transmission Characteristics of MERS and SARS in the Healthcare Setting: a Comparative Study. BMC Medicine 13, 210 (2015). https://doi.org/10.1186/s12916-015-0450-0