About Respiratory Syncytial Virus (RSV)
Respiratory syncytial virus (RSV) causes severe lung infections, including bronchiolitis and pneumonia. High risk populations include premature babies, young infants, and children. However, the virus is not limited to affecting only babies and children. Adults aged 65 and older and people with weakened immune systems (e.g. organ transplant, chemotherapy) are also at high risk.
In terms of prevalence, globally there are an estimated 33 million cases of RSV annually in children younger than 5 years of age, with about 3 million hospitalized and more than 100,000 dying each year from complications associated with the infection.1 In the U.S. alone, there are 2.1 million hospitalizations and outpatient visits in children under 5 years of age. However, of that 2.1 million, 78% of the children are older than 1 year of age.1,2 For adults 65 years and older, RSV results in more than 177,000 hospitalizations and 14,000 deaths annually in the U.S.3
A monoclonal antibody (palivizumab) is available in some high-resource countries to prevent infant RSV infections, but it is only partially effective, and is only given to the less than 2% of U.S. infants who have severe forms of heart disease, chronic lung disease, or severe prematurity.4 Currently, no safe and effective treatments exist for RSV infection.
In the U.S. alone, there are 2.1 million hospitalizations and outpatient visits in children under 5 years of age.
= 100,000 children
Globally there are an estimated 33 million cases of RSV annually in children younger than 5 years of age.
Enanta’s Approach to Treating RSV
Enanta’s most advanced candidate for RSV is EDP-938, a potent N-protein inhibitor of both RSV-A and RSV-B activity which has Fast Track designation from the U.S. Food and Drug Administration (FDA) and is currently in multiple Phase 2 studies. It is highly active against all RSV-A and B laboratory strains and clinical isolates tested in vitro in various cell lines and assays.
We chose to develop an N-protein inhibitor because it can disrupt the virus’ ability to replicate after it has already infected a cell, as compared to a fusion inhibitor which works by preventing a cell from becoming infected. Targeting the N protein allows for an expanded treatment window in vitro as compared to fusion inhibitors. Our N-inhibitor strategy aims to improve efficacy and potentially expand the treatment window for patients experiencing RSV infections over what an entry inhibitor might offer.
Another advantage of targeting the N-protein is that it is the most conserved gene in the viral genome, indicating it is not as malleable to change as the F-protein. This results in a much higher barrier to resistance for EDP-938 as compared to fusion inhibitors. EDP-938 has demonstrated a very high barrier to resistance in vitro.5 In contrast, the fusion protein can mutate quickly and easily to escape the effects of fusion inhibitors. This has been observed both in vitro and in vivo.6,7
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EDP-938 has been evaluated in a Phase 2a randomized, double-blind, placebo-controlled, human challenge study in healthy adult subjects inoculated with RSV. A total of 115 subjects were enrolled, inoculated with RSV, and subsequently treated with either EDP-938 (at two different doses) or placebo. Results of this challenge study showed that EDP-938 resulted in a highly statistically significant (p<0.001) reduction in viral load and resolution of clinical symptoms compared to placebo. The key secondary efficacy endpoint, area under the curve for total symptom score, was met with a highly statistically significant reduction observed in the intent-to-treat population for each of the EDP-938 dosing groups, compared to the placebo arm (p<0.001 for each of the EDP-938 groups compared to placebo).
Overall, EDP-938 was generally safe, well-tolerated and demonstrated a favorable safety profile over five days of dosing and through Day 28 of follow-up, comparable to placebo for both dosing groups. There were no serious adverse events and no discontinuations of study drug. EDP-938 demonstrated good pharmacokinetics, with mean trough levels maintained at approximately 20-40x above the in vitro EC90 for RSV-infected human cells. To read more about the RSV Phase 2 Challenge study, the results of which were recently published in The New England Journal of Medicine, click here.
EDP-938 was also evaluated in RSVP, a Phase 2b study in otherwise healthy adults with community-acquired RSV. In this low-risk patient population which had mild, self-resolving infection, EDP-938 did not meet its primary endpoint of reduction in total symptom score compared to placebo, or the secondary antiviral endpoints. However, a statistically significant difference in the number of subjects achieving undetectable RSV RNA at the end of treatment at Day 5 was observed with EDP-938 compared to placebo (p=0.033). Further, EDP-938 demonstrated a favorable safety profile, consistent with that observed in approximately 500 subjects exposed to date.
Antiviral treatment for RSV, including EDP-938, has the greatest potential to show optimal efficacy in high-risk populations, as these patients have reduced RSV immunity which manifests in a longer duration of viral shedding and greater disease severity, allowing a bigger window to realize the full potential of EDP-938. Moving forward, our broad clinical development plan will focus on evaluating EDP-938’s potential in populations with the greatest unmet need, namely those who are at high-risk for severe disease, including pediatric patients and high-risk adults.
We currently have two ongoing studies evaluating EDP-938. Recruitment is ongoing for RSVPEDs, a Phase 2 randomized, double-blind, placebo-controlled study in hospitalized and non-hospitalized pediatric RSV patients and RSVHR, a Phase 2b study in a high-risk adult population, including the elderly and/or those with asthma, chronic obstructive pulmonary disease, or congestive heart failure.
For more information on our clinical trials, click here.
In January 2022, we nominated EDP-323, a novel, oral direct-acting antiviral selectively targeting the RSV L-protein, which is essential for RSV replication. In April 2023, EDP-323 received Fast Track designation from the FDA. The candidate has shown sub-nanomolar potency against RSV-A and RSV-B in vitro and is not expected to have cross resistance to other classes of inhibitors. EDP-323 could be used alone or in combination with other agents, such as EDP-938, to potentially broaden the treatment window or addressable patient populations. In June 2023, we announced positive topline data from a Phase 1 study assessing the safety, tolerability, and pharmacokinetics (PK) of orally administered single ascending doses (SAD) and multiple ascending doses (MAD) of EDP-323 in healthy adult subjects. Data from the Phase 1 study demonstrated favorable safety, tolerability, and PK supportive of once-daily dosing, with good exposure multiples, thereby supporting further clinical advancement of EDP-323. A human challenge study evaluating EDP-323 is planned for the fourth quarter of 2023.
- Li, You et al. Global, regional, and national disease burden estimates of acute lower respiratory infections due to respiratory syncytial virus in children younger than 5 years in 2019: a systematic analysis.” Lancet (London, England) vol. 399,10340 (2022): 2047-2064. doi:10.1016/S0140-6736(22)00478-0
- Hall, Caroline Breese et al. “The Burden of Respiratory Syncytial Virus Infection in Young Children.” The New England Journal of Medicine vol. 360,6 (2009): 588-98. doi:10.1056/NEJMoa0804877
- Centers for Disease Control and Prevention: RSV in Older Adults and Adults with Chronic Medical Conditions
- Red Book: 2021 Report of the Committee on Infectious Diseases, 32nd Edition. Editor: David W. Kimberlin
- Rhodin, Michael H J et al. “EDP-938, a Novel Nucleoprotein Inhibitor of Respiratory Syncytial Virus, Demonstrates Potent Antiviral Activities in Vitro and in a Non-Human Primate Model.”PLoS Pathogens vol. 17,3 e1009428. 15 Mar. 2021, doi:10.1371/journal.ppat.1009428
- Stray, Kirsten et al. “Drug Resistance Assessment Following Administration of Respiratory Syncytial Virus (RSV) Fusion Inhibitor Presatovir to Participants Experimentally Infected With RSV.” The Journal of Infectious Diseases vol. 222,9 (2020): 1468-1477. doi:10.1093/infdis/jiaa028
- Yan, Dan et al. “Cross-resistance Mechanism of Respiratory Syncytial Virus Against Structurally Diverse Entry Inhibitors.” Proceedings of the National Academy of Sciences of the United States of America vol. 111,33 (2014): E3441-9. doi:10.1073/pnas.1405198111