Simon Portsmouth Shares Insights from P-III Trial of Ensitrelvir for the Prevention of Symptomatic SARS-CoV-2 Infection

Shots:

Simon spoke about the enrollment of the first participant in Japan in the P-III (SCORPIO-PEP) study to evaluate the safety and efficacy of Ensitrelvir for the prevention of symptomatic SARS-CoV-2 infection
He mentioned how this study will supplement data from the pivotal SCORPIO-SR trial's P-III segment which showed ensitrelvir's effectiveness in treating mild-to-moderate COVID-19 patients
The interview gives an understanding of how Shionogi is working on the research and development of its therapeutics to protect people worldwide from the threat of infectious diseases

Smriti: To start with, please tell our PharmaShots readers about the study design of the trial (SCORPIO-PEP) to evaluate the safety and efficacy of the novel COVID-19 oral antiviral ensitrelvir.

Simon Portsmouth: There remains a need to develop therapeutics that can prevent SARS-CoV-2 infection after exposure. Part of managing COVID-19 in the longer term is identifying strategies to minimize the spread of the virus by significantly decreasing the events of symptomatic COVID-19 infection in household members in contact with a SARS-CoV-2 infected person. As such, this study will evaluate the safety and efficacy of the investigational COVID-19 oral antiviral, ensitrelvir, compared to placebo for the prevention of symptomatic SARS-CoV-2 infection in study participants exposed to household contacts who are symptomatic and tested positive for SARS-CoV-2.

This is a randomized, double-blind, placebo-controlled global Phase 3 study that will recruit approximately 2,200 participants. The study includes participants who have a negative screening test for SARS-CoV-2 infection, have no COVID-19 related symptoms, and who have had exposure to a household person with symptomatic SARS-CoV-2 infection.

Smriti: Tell us more about Shionogi’s drug ensitrelvir (MOA, ROA, and formulation).

Simon Portsmouth: Ensitrelvir, an oral antiviral drug for COVID-19 currently approved under the emergency regulatory approval system in Japan, is a 3CL protease inhibitor created through joint research between Hokkaido University and Shionogi. Known as Xocova® in Japan, ensitrelvir received emergency regulatory approval from the Ministry of Health, Labour and Welfare (MHLW) for the treatment of SARS-CoV-2 infection in November 2022. It remains an investigational drug outside Japan.

SARS-CoV-2 has an enzyme called 3CL protease, which is essential for the replication of the virus. Ensitrelvir suppresses the replication of SARS-CoV-2 by selectively inhibiting the 3CL protease. Ensitrelvir is the first antiviral agent to show both clinical symptomatic efficacy for five typical Omicron-related symptoms (primary endpoint) and antiviral efficacy (key secondary endpoint) in a predominantly vaccinated population of patients with mild to moderate SARS-CoV-2 infection, regardless of risk factors, from the results of the Phase 3 part of the pivotal SCORPIO-SR trial (Phase 2/3 study) conducted in Japan, South Korea, and Vietnam during the Omicron-dominant phase of the epidemic.

With regard to safety, most adverse events were mild in severity and no deaths were seen in the study. Among the most common treatment-related adverse events were temporary decreases in high-density lipoprotein and increased blood triglycerides, as observed in previous studies. Initial exploratory analyses from the Phase 2/3 study also indicated a reduced risk of development of long COVID and further evaluations in this regard are still ongoing.

Smriti: Shionogi mentions the enrollment of participants in the US. Is the company planning to expand it in other countries for the prevention of symptomatic SARS-CoV-2 infection?

Simon Portsmouth: This is a global study. Participating sites are located in the United States, Germany, Spain, Bulgaria, South Africa, Chile, Argentina, Japan, Philippines, Thailand and Vietnam.

Smriti: Can you please share with us, the results of the study that assessed ensitrelvir based on which the company received fast-track designation by the US FDA in Apr 2023?

Simon Portsmouth: In April 2023, the U.S. Food and Drug Administration (FDA) granted Fast Track designation to ensitrelvir for COVID-19. FDA Fast Track designation is designed to facilitate the development and expedite the review of potential new therapies that treat serious conditions and fulfill an unmet medical need.

The designation as granted to ensitrelvir based on an investigational new drug application (IND) submitted to the FDA. It was not based on one study in particular. Shionogi has a comprehensive, global clinical development program underway for ensitrelvir that includes four Phase 3 trials. We look forward to sharing the results of these studies when available.

Smriti: Brief our readers about two trials that the company mentioned (SCORPIO-HR and SCORPIO-SR).

Simon Portsmouth: Both studies are evaluating ensitrelvir, an investigational oral antiviral. SCORPIO-HR is a global Phase 3 trial for patients with symptomatic, mild-to-moderate COVID-19, who are not hospitalized and who have tested positive for SARS-CoV-2. Patients, regardless of risk factors or vaccination status are included in the study. SCORPIO-HR is also evaluating the potential effect of ensitrelvir on the symptoms of long COVID.

Shionogi conducted SCORPIO-SR in patients in Japan, South Korea, and Vietnam with mild-to-moderate COVID-19, regardless of risk factors for COVID-19 progression and vaccination status.

Smriti: Does Shionogi’s pipeline consist of other drugs for other infectious diseases incl. COVID?

Simon Portsmouth: Shionogi has a long history of small molecule drug discovery. Our current pipeline includes projects across several therapeutic areas including infectious disease.

Smriti: Please tell us about the investigator-initiated research study that is ongoing in hospitalized patients for the management of COVID-19 as part of the new Strategies and Treatments for Respiratory Infections & Viral Emergencies (STRIVE) platform protocol.

Simon Portsmouth: Earlier this year, the first patient was enrolled in a global multi-site clinical trial evaluating ensitrelvir, an investigational oral antiviral, in patients who are hospitalized for the management of COVID-19 as part of the new Strategies and Treatments for Respiratory Infections & Viral Emergencies (STRIVE) platform protocol. STRIVE was developed under the auspices of NIH’s Accelerating COVID-19 Therapeutic Interventions and Vaccines (ACTIV) public-private partnership.

Ensitrelvir is the first drug to be evaluated in the STRIVE program, a new agile research approach set up to rapidly assess interventions during epidemics adversely affecting public health. It will evaluate the safety and efficacy of a five-day course of ensitrelvir, given in addition to standard of care, for hospitalized patients with COVID-19, when compared to placebo. The study will recruit 1,500 patients across sites worldwide and is expected to be complete in early 2024.

Image source: Canva

About the Author:

Simon Portsmouth is SVP and Head of Clinical Development at Shionogi. He joined Shionogi in Florham Park NJ in 2015. His area of interest is in the development of medicines for infectious diseases. Recent development activities include the successful New Drug application for cefiderocol (Fetroja) and baloxavir marboxil (Zofluza), and the clinical development of Ensitrelvir, a 3CL protease inhibitor for SARS-Co-V2. Simon did MBChB (Medicine) and M.D. from the Sheffield University Medical School.