Shionogi Protease Inhibitor for COVID-19

No longer recruiting at 204 trial locations

Overseen By Cavan Reilly, PhD

Age: 18+

Sex: Any

Trial Phase: Phase 3

Sponsor: University of Minnesota

Must not be taking: Strong CYP3A inducers

Disqualifiers: Severe hepatic impairment, Renal failure, Pregnancy, others

Pivotal Trial (Near Approval) This treatment is in the last trial phase before FDA approval

Prior Safety Data This treatment has passed at least one previous human trial

Approved in 1 Jurisdiction This treatment is already approved in other countries

Compensation: Varies

Number of Visits: 60

Duration: 5 days

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests a new treatment called ensitrelvir, a protease inhibitor designed to help people hospitalized with COVID-19. The goal is to determine if this medication can improve patient outcomes by stopping the virus from replicating. Participants will receive either ensitrelvir with the usual COVID-19 care or a placebo plus usual care. The trial seeks individuals currently hospitalized with COVID-19 symptoms, confirmed by a test, who developed symptoms within the last 14 days. As a Phase 3 trial, this study represents the final step before FDA approval, offering participants a chance to contribute to a potentially groundbreaking treatment.

Do I have to stop taking my current medications for the trial?

The trial protocol does not specify if you must stop taking your current medications. However, you cannot use a strong CYP3A inducer within 14 days prior to enrollment, and you cannot take medications that have a drug-drug interaction with S-217622.

Is there any evidence suggesting that this treatment is likely to be safe for humans?

Research has shown that ensitrelvir, a medication from Shionogi, is generally safe for treating COVID-19. A study involving over 3,000 patients in Japan found no new safety concerns with this drug. This finding is reassuring, indicating that the treatment is well-tolerated. Although the study did not find a significant difference in the speed of symptom improvement, the absence of new safety issues is encouraging. Prospective trial participants can feel more confident about the treatment's safety based on these findings. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising?

Researchers are excited about the Shionogi Protease Inhibitor (S-217622) for COVID-19 because it offers a new mechanism of action by targeting the virus's protease enzyme, which is crucial for the virus to replicate. Unlike other COVID-19 treatments like antivirals remdesivir and molnupiravir, which also inhibit viral replication but through different mechanisms, this treatment specifically blocks the protease, potentially halting the virus more effectively. Additionally, S-217622 is administered orally in just a five-day course, making it easy and convenient for patients. This combination of a novel mechanism and straightforward administration could make it a powerful tool in the fight against COVID-19.

What evidence suggests that this treatment might be an effective treatment for COVID-19?

Research has shown that ensitrelvir, which participants in this trial may receive, may help reduce severe outcomes in high-risk COVID-19 patients. Studies have found that it can quickly remove the virus from the body. Early data suggested that patients taking ensitrelvir recovered faster than those taking a placebo. The treatment also proved effective against different strains of the virus in lab studies. These findings suggest that ensitrelvir could be a good option for improving outcomes in patients hospitalized with COVID-19. ^{1 4 5 6 7}

Who Is on the Research Team?

Cavan Reilly, PhD

Principal Investigator

University of Minnesota

Jason Baker, MD

Principal Investigator

University of Minnesota

Are You a Good Fit for This Trial?

Adults hospitalized for COVID-19 with symptoms of a lower respiratory tract infection can join this trial. They must have tested positive for SARS-CoV2 within the last 14 days and shown symptoms in the past two weeks. Excluded are those with severe health conditions, certain drug interactions, or women who could get pregnant but won't use contraception.

Inclusion Criteria

You have tested positive for SARS-CoV2 within the past 14 days using a specific type of test.

Informed consent for trial participation

I am hospitalized for COVID-19 with symptoms affecting my lungs.

Exclusion Criteria

I have had a cardiac arrest during this hospital stay and my doctors think I have less than 48 hours to live.

I am unable or unwilling to follow the study's procedures.

You are currently pregnant.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

1-2 weeks

Treatment

Participants receive ensitrelvir or placebo in addition to standard of care for 5 days

5 days

Daily visits during hospitalization

Follow-up

Participants are monitored for safety and effectiveness after treatment

60 days

Periodic assessments up to 60 days post-treatment

What Are the Treatments Tested in This Trial?

Interventions

• Shionogi Protease Inhibitor (S-217622)

Trial Overview The STRIVE trial is testing Shionogi's Protease Inhibitor (S-217622) against a placebo to see if it helps hospitalized COVID-19 patients when added to standard treatments like remdesivir. It's randomized and controlled, meaning some people will get the real drug and others a dummy pill without knowing which one they're taking.

How Is the Trial Designed?

Group I: S-217622 (ensitrelvir) plus standard of care (SOC) Experimental Treatment 1 Intervention

Study investigational agent (ensitrelvir) will be administered as oral tablets with dosing of 375mg (3 tabs) once on Day 0 and 125mg (1 tab) once daily on Days 1-4. All participants will receive the full 5-day course, including those who are discharged from hospitalization prior to Day 4.

Group II: placebo plus standard of care (SOC) Placebo Group 1 Intervention

Study investigational placebo will be administered as oral tablets with dosing of 375mg (3 tabs) once on Day 0 and 125mg (1 tab) once daily on Days 1-4. All participants will receive the full 5-day course, including those who are discharged from hospitalization prior to Day 4.

Who Is Running the Clinical Trial?

University of Minnesota

Lead Sponsor

Trials

1,459

Recruited

1,623,000+

National Institute of Allergy and Infectious Diseases (NIAID)

Collaborator

Trials

3,361

Recruited

5,516,000+

Published Research Related to This Trial

Shikonin, derived from the herb Lithospermum erythrorhizo, effectively inhibits inflammation in mouse models, showing comparable efficacy to dexamethasone, a common anti-inflammatory drug.

The study reveals that shikonin targets the proteasome in macrophages, leading to reduced TNFα release and blocking the activation of NF-κB, which suggests its potential as a novel anti-inflammatory agent.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Shikonin extracted from medicinal Chinese herbs exerts anti-inflammatory effect via proteasome inhibition. Lu, L., Qin, A., Huang, H., et al.[2021]

Ensitrelvir is a protease inhibitor that effectively reduces viral load and symptoms in COVID-19 patients, showing a good tolerability profile in clinical trials with considerations for potential drug interactions.

Despite its benefits, ensitrelvir may face limited clinical use due to concerns about drug interactions, the emergence of resistant variants, and the availability of alternative treatments.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Lessons learnt from the preclinical discovery and development of ensitrelvir as a COVID-19 therapeutic option. Ferraro, S., Convertino, I., Cappello, E., et al.[2023]

(2-methyl-n-butyl) shikonin (MBS) effectively reduces the viability of human gastric cancer cells (SGC-7901) in a dose- and time-dependent manner, with an IC50 of 10.113 micromol/L at 24 hours and 4.196 micromol/L at 48 hours.

MBS induces apoptosis in SGC-7901 cells by down-regulating the anti-apoptotic protein Bcl-2 and up-regulating pro-apoptotic markers, with the involvement of the ERK1/2 and JNK signaling pathways, as evidenced by changes in protein expression and mitochondrial membrane potential.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Mechanisms of (2-methyl-n-butyl) shikonin induced apoptosis of gastric cancer SGC-7901 cells]. Wang, HB., Ma, XQ.[2012]

A phase 3 study is being conducted to evaluate the efficacy and safety of ensitrelvir, a novel oral protease inhibitor, in treating mild-to-moderate COVID-19 in patients regardless of their vaccination status or risk factors.

Preliminary results from a phase 2b study indicated that ensitrelvir reduced the time to resolution of COVID-19 symptoms compared to placebo, suggesting it may be an effective treatment option for patients with mild-to-moderate disease.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A phase 2/3 study of S-217622 in participants with SARS-CoV-2 infection (Phase 3 part). Yotsuyanagi, H., Ohmagari, N., Doi, Y., et al.[2023]

The combination of shikonin and gefitinib showed a synergistic antitumor effect in both in vitro and in vivo models of EGFR wild-type non-small cell lung cancer, suggesting a potential new treatment strategy.

The mechanism behind this enhanced efficacy appears to involve the inhibition of the PKM2/STAT3/cyclinD1 pathway, which is crucial for tumor growth and survival.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Shikonin enhances sensitization of gefitinib against wild-type EGFR non-small cell lung cancer via inhibition PKM2/stat3/cyclinD1 signal pathway. Tang, JC., Ren, YG., Zhao, J., et al.[2023]

Two new steroidal alkaloids, wallichimine A and wallichimine B, were isolated from the plant Sarcococca wallichii, along with five known alkaloids, using advanced techniques like mass spectrometry and NMR spectroscopy.

Wallichimine B (compound 2) demonstrated the strongest immunosuppressive effects, significantly inhibiting the production of nitric oxide and the proinflammatory cytokine TNF-α, suggesting that steroidal alkaloids could be promising candidates for developing anti-inflammatory drugs.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Antiinflammatory Steroidal Alkaloids from Sarcococca wallichii of Nepalese Origin. Adhikaria, A., Vohra, MI., Jabeen, A., et al.[2015]

PMM-034, a derivative of shikonin, demonstrated significant antiviral activity against enterovirus 71 (EV71) in rhabdomyosarcoma (RD) cells, with a 50% inhibitory concentration of 2.31 μg/mL, while showing only weak cytotoxicity.

Treatment with PMM-034 led to a marked reduction in EV71 replication, as indicated by decreased levels of VP1 mRNA and protein, and also suppressed pro-inflammatory cytokines, suggesting its potential as an effective EV71 inhibitor.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Antiviral activity of shikonin ester derivative PMM-034 against enterovirus 71 in vitro. Zhang, Y., Han, H., Sun, L., et al.[2018]

In a phase 2a study involving 69 Japanese patients with mild-to-moderate COVID-19, ensitrelvir significantly reduced SARS-CoV-2 viral titer compared to placebo, with a notable decrease in viral RNA by -1.4 to -1.5 log10 copies/mL.

The treatment with ensitrelvir also led to a median reduction of approximately 50 hours in the time to infectious viral clearance, and all reported adverse events were mild to moderate, indicating a favorable safety profile.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A Randomized Phase 2/3 Study of Ensitrelvir, a Novel Oral SARS-CoV-2 3C-Like Protease Inhibitor, in Japanese Patients with Mild-to-Moderate COVID-19 or Asymptomatic SARS-CoV-2 Infection: Results of the Phase 2a Part. Mukae, H., Yotsuyanagi, H., Ohmagari, N., et al.[2022]

S-217622 (Ensitrelvir) is an approved treatment for SARS-CoV-2 that works by inhibiting a key enzyme (3CLpro) necessary for the virus's replication, and its analog YY-278 shows similar antiviral activity against this enzyme and the virus itself.

YY-278 not only retains favorable pharmacokinetic properties, such as good bioavailability, but also demonstrates broad anti-coronaviral activity against multiple coronaviruses, suggesting its potential for treating COVID-19 and other related diseases.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Synthesis of deuterated S-217622 (Ensitrelvir) with antiviral activity against coronaviruses including SARS-CoV-2. Yang, Y., Cao, L., Yan, M., et al.[2023]

Ensitrelvir, a small-molecule antiviral targeting the 3C-like protease of SARS-CoV-2, showed comparable antiviral activity to nirmatrelvir in vitro across multiple cell lines and effectively reduced virus levels in animal models.

In vivo, ensitrelvir demonstrated equal to or greater efficacy than nirmatrelvir at similar or slightly lower unbound-drug plasma concentrations, suggesting it could be a valuable treatment option for SARS-CoV-2 infections.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Efficacy comparison of 3CL protease inhibitors ensitrelvir and nirmatrelvir against SARS-CoV-2 in vitro and in vivo. Kuroda, T., Nobori, H., Fukao, K., et al.[2023]

Shikonin effectively reduces the symptoms of collagen-induced arthritis (CIA) in mice, showing a dose-dependent suppression of arthritis severity, including reduced swelling and cartilage destruction.

The mechanism of shikonin involves inhibiting Th17 cytokines while promoting Treg responses, achieved by downregulating the TLR4/MyD88 signaling pathway, which is crucial for inflammatory responses.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Toll-Like Receptor 4-Myeloid Differentiation Primary Response Gene 88 Pathway Is Involved in the Shikonin Treatment of CIA by Regulating Treg/Th17 Expression. Dai, Q., Li, J., Yun, Y., et al.[2022]

Shikonin, derived from the plant Lithospermum erythrorhizon, effectively inhibits the growth of human cervical cancer cells (HeLa) with a 50% growth inhibition observed at a concentration of 18.9 µmol L-1, and induces apoptosis characterized by distinct morphological changes and DNA fragmentation.

The mechanism of shikonin-induced cell death involves the activation of caspase-3 and the subsequent reduction of ICAD, leading to the activation of CAD, which is crucial for the apoptotic process.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Shikonin regulates HeLa cell death via caspase-3 activation and blockage of DNA synthesis. Wu, Z., Wu, LJ., Li, LH., et al.[2015]

Shikonin significantly inhibits the viability, adhesion, migration, and invasion of gastric cancer cells (MGC-803) at a concentration of 1 μM, with a 50% inhibitory concentration of 1.854 μM.

The mechanism of action involves the suppression of key proteins and pathways, specifically through the Toll-like receptor 2 (TLR2) and nuclear factor-kappa B (NF-κB), indicating its potential as a therapeutic agent for gastric cancer.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Shikonin inhibits the cell viability, adhesion, invasion and migration of the human gastric cancer cell line MGC-803 via the Toll-like receptor 2/nuclear factor-kappa B pathway. Liu, JP., Liu, D., Gu, JF., et al.[2015]

Citations

1. shionogi.com shionogi.com/global/en/news/2024/06/20240628_0.html

Shionogi Presented New Clinical Data on the COVID-19 ... This study provides strong evidence suggesting the efficacy of ensitrelvir in reducing severe outcomes among high-risk COVID-19 patients based on real-world ...

2. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC8982737/

Discovery of S-217622, a Noncovalent Oral SARS-CoV-2 ... S-217622 displayed antiviral activity in vitro toward a range of SARS-CoV-2 variants and coronavirus families, favorable drug metabolism and pharmacokinetic ( ...

3. shionogi.com shionogi.com/us/en/news/2022/04/new-data-for-shionogis-covid-19-once-daily-oral-antiviral-s-217622-show-rapid-virus-clearance.html

New Data for Shionogi's COVID-19 Once-Daily Oral ... “These results demonstrate that S-217622 rapidly eliminates SARS-CoV-2 in patients versus placebo, marking its potential, if approved, as an ...

4. jamanetwork.com jamanetwork.com/journals/jamanetworkopen/fullarticle/2814871

Efficacy and Safety of 5-Day Oral Ensitrelvir for Patients ... Resolution of 5, 12, and 14 COVID-19 symptoms was achieved when all the symptoms disappeared, improved, or were maintained after first ...

5. sciencedirect.com sciencedirect.com/science/article/pii/S1341321X24003210

Ensitrelvir for the treatment of COVID-19: Final analysis of a ... In the effectiveness analysis set (n = 1584), the median time to resolution was 60.0, 144.0, 48.0, and 156.0 h for general symptoms, respiratory symptoms, ...

6. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/39960062/

Results from the SCORPIO-HR, Phase 3 ... - PubMed Despite the evidence of antiviral activity with ensitrelvir, this trial did not demonstrate a significant difference in time to sustained symptom resolution.

7. shionogi.com shionogi.com/global/en/news/2022/04/20220424.html

New Data for Shionogi's COVID-19 Once-Daily Oral ... Its main purpose was to confirm the antiviral effect and clinical symptom improvement of S-217622 when orally administered once daily for five ...