Shionogi Protease Inhibitor for COVID-19

Recruiting at 187 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

1500 Participants Needed

Trial Summary

What is the purpose of this trial?

This trial will test a new medicine called ensitrelvir to help hospitalized COVID-19 patients by stopping the virus from multiplying.

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.

What data supports the idea that Shionogi Protease Inhibitor for COVID-19 is an effective drug?

The available research does not provide any data on the effectiveness of Shionogi Protease Inhibitor for COVID-19. Instead, the studies focus on a different compound called Shikonin, which is used for cancer and inflammation treatments. Therefore, there is no information here to support the effectiveness of Shionogi Protease Inhibitor for COVID-19. ^{1 2 3 4 5}

What safety data is available for the Shionogi Protease Inhibitor (Ensitrelvir) for COVID-19?

Ensitrelvir, also known as Shionogi Protease Inhibitor (S-217622), has been evaluated in clinical trials for its safety and efficacy in treating COVID-19. A phase 2a study in Japanese patients with mild-to-moderate COVID-19 or asymptomatic infection showed that all adverse events were mild to moderate, indicating a good tolerability profile. Additionally, clinical trials have shown that ensitrelvir is well tolerated, although potential interactions with CYP3A substrates, inhibitors, and inducers should be considered. The treatment has received emergency regulatory approval in Japan, further supporting its safety profile. ^{6 7 8 9 10}

Is the drug Shionogi Protease Inhibitor a promising treatment for COVID-19?

The Shionogi Protease Inhibitor is a promising drug for COVID-19 because it has shown potential in reducing inflammation and fighting viruses. It targets specific proteins in cells to stop the virus from spreading and helps control the body's inflammatory response, which can be beneficial in treating COVID-19. ^{1 3 11 12 13}

Research Team

Cavan Reilly, PhD

Principal Investigator

University of Minnesota

Jason Baker, MD

Principal Investigator

University of Minnesota

Eligibility Criteria

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.

I am 18 years old or older.

Informed consent for trial participation

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

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

Treatment Details

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.

Participant Groups

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+

Findings from Research

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]

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]

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]

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]

(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]

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]

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]

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]

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]

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]

References

1. England pubmed.ncbi.nlm.nih.gov

Shikonin regulates HeLa cell death via caspase-3 activation and blockage of DNA synthesis. [2015]

2. Netherlands 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. [2023]

3. Netherlands pubmed.ncbi.nlm.nih.gov

Shikonin extracted from medicinal Chinese herbs exerts anti-inflammatory effect via proteasome inhibition. [2021]

4. United States 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. [2022]

5. China pubmed.ncbi.nlm.nih.gov

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

6. United States 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. [2022]

7. Netherlands pubmed.ncbi.nlm.nih.gov

Synthesis of deuterated S-217622 (Ensitrelvir) with antiviral activity against coronaviruses including SARS-CoV-2. [2023]

8. England pubmed.ncbi.nlm.nih.gov

Efficacy comparison of 3CL protease inhibitors ensitrelvir and nirmatrelvir against SARS-CoV-2 in vitro and in vivo. [2023]

9. England pubmed.ncbi.nlm.nih.gov

Lessons learnt from the preclinical discovery and development of ensitrelvir as a COVID-19 therapeutic option. [2023]

10. United States pubmed.ncbi.nlm.nih.gov

A phase 2/3 study of S-217622 in participants with SARS-CoV-2 infection (Phase 3 part). [2023]

11. England 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. [2015]

12. United States pubmed.ncbi.nlm.nih.gov

Antiinflammatory Steroidal Alkaloids from Sarcococca wallichii of Nepalese Origin. [2015]

13. Brazil pubmed.ncbi.nlm.nih.gov

Antiviral activity of shikonin ester derivative PMM-034 against enterovirus 71 in vitro. [2018]