About SARS-CoV-2

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, we took a two-pronged approach to discovering such an antiviral by evaluating compounds in our 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.

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We focused significant resources and dedicated our long-standing expertise in virology, and viral protease inhibitors specifically, to discover and develop oral treatments for COVID-19.  We initiated discovery programs 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.

Our 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, we nominated EDP-235 from these early leads as our 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. EDP-235 has since received Fast Track designation from the U.S. Food and Drug Administration.

In a biochemical assay, EDP-235 inhibited the SARS-CoV-2 3CL protease with an IC50 of 5.8 nM. In Vero cells, EDP-235 potently blocked the replication of SARS-CoV-2 with an EC90 of 11 nM. Importantly, this activity was retained against proteases from SARS-CoV-2 variants, including Omicron where an EC90 of 5.1nM was observed. Additionally, EDP-235 was shown to have potent antiviral activity across other human coronaviruses. 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. Specifically, the drug levels in the lung were four times greater than in the plasma.  Excellent penetration into monocytes and macrophages was also observed, which may help in mitigating the macrophage-mediated cytokine storm observed in high-risk COVID-19 patients. Taken together, these data indicate that EDP-235 has the potential to be a best-in-class, potent, once-daily oral treatment for COVID-19.

In February 2022, we initiated a randomized, double-blind, placebo-controlled Phase 1 study to evaluate the safety, tolerability, and pharmacokinetics of oral EDP-235 in healthy volunteers in single ascending doses and multiple ascending doses for seven days, and the effect of food.

Data from the Phase 1 study demonstrated EDP-235 was generally safe and well-tolerated up to 400 mg for seven days with infrequent adverse events, the majority of which were mild. Results demonstrated strong exposure multiples over the EC90, which is a measure of potency, specifically the concentration of drug that results in 90% inhibition of viral replication in vitro.

EDP-235 200 mg taken once daily with food resulted in mean trough plasma levels at steady state that were 3-fold and 7-fold over the plasma-protein-adjusted EC90 for the Alpha variant and Omicron variant, respectively, while 400 mg resulted in levels that were 6-fold and 13-fold over the plasma-protein-adjusted EC90for the respective variants. These target exposure multiples were achieved without the need for ritonavir boosting and its associated drug-drug interactions. EDP-235 is projected to have four times higher drug levels in lung tissue compared to plasma, which would be expected to drive the 400 mg multiples to 28-fold and 52-fold for the respective variants. 

In October, we announced the initiation of a Phase 2 study, SPRINT, (SARS-Cov-2 PRotease INhibitor Treatment) in non-hospitalized, symptomatic adults with mild or moderate COVID-19. The study is designed to evaluate the safety, tolerability, and antiviral activity of 200mg and 400mg once-daily doses of EDP-235 compared to placebo. We are targeting to report data from SPRINT in the first half of 2023.  

In January 2023, we announced a new research program focused on the discovery and development of inhibitors of the SARS-CoV-2 papain-like protease (PLpro) for the oral treatment of COVID-19. PLpro is an essential enzyme, which, along with 3CL protease (3CLpro, or Mpro), plays an important role in viral replication and acts to suppress innate immune response. As this mechanism is distinct from 3CL protease inhibition, it has the potential to be used alone or in combination with 3CL protease inhibitors such as EDP-235 or other compounds to provide a range of treatment regimens for different patient populations suffering from COVID-19.

  1. Centers for Disease Control and Prevention: Human Coronavirus Types
  2. 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
  3. 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