GSK3915393 for Pulmonary Fibrosis

Recruiting at 60 trial locations

Overseen By EU GSK Clinical Trials Call Center

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: GlaxoSmithKline

Must be taking: Antifibrotics

Must not be taking: Immunomodulatory, Corticosteroids, CYP3A4 inducers

Disqualifiers: Interstitial lung disease, Autoimmune diseases, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

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

Compensation: Varies

Number of Visits: Unknown

Duration: 12 weeks

150 Participants Needed

Trial Summary

What is the purpose of this trial?

Idiopathic Pulmonary Fibrosis is a chronic lung disease which causes scarring of the lungs and difficulty in breathing. GSK3915393 is a new medicine, which is being tested in participants with IPF for the first time. The study will assess the safety and effectiveness of GSK3915393 in IPF participants.

Will I have to stop taking my current medications?

The trial requires that if you are taking antifibrotic medications like nintedanib or pirfenidone, you must be on a stable dose for at least 12 weeks before screening. If you are not taking these, you must have stopped them at least 4 weeks before screening. Some other medications, like certain immunomodulatory therapies and specific enzyme inhibitors, must be stopped at least 14 days before joining the trial.

What data supports the effectiveness of the drug GSK3915393 for pulmonary fibrosis?

Research suggests that targeting the interaction between TRIB3 and GSK-3β, which is involved in promoting lung fibrosis, could be an effective treatment strategy for pulmonary fibrosis. This indicates that GSK3915393, if it disrupts this interaction, might help treat the condition. ^{1 2 3 4 5}

How does the drug GSK3915393 differ from other treatments for pulmonary fibrosis?

GSK3915393 is unique because it targets the glycogen synthase kinase-3β (GSK-3β) pathway, which is involved in the progression of pulmonary fibrosis. By inhibiting GSK-3β, this drug may help reduce the formation of myofibroblasts, which are cells that contribute to lung scarring, potentially offering a novel approach compared to existing treatments. ^{2 5 6 7 8}

Research Team

GSK Clinical Trials

Principal Investigator

GlaxoSmithKline

Eligibility Criteria

This trial is for adults with Idiopathic Pulmonary Fibrosis (IPF), diagnosed within the last 5 years, who have a certain level of lung function and are either on stable antifibrotic treatment or not taking it. They must be able to consent and meet specific weight and body mass index criteria.

Inclusion Criteria

My latest chest scan shows signs of a specific lung condition.

My lung function is at least 45% of what is expected for someone healthy.

I have been on a stable dose of nintedanib or pirfenidone for at least 12 weeks.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive either GSK3915393 or placebo to evaluate efficacy and safety in IPF

12 weeks

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

Treatment Details

Interventions

• GSK3915393

Trial Overview The study tests GSK3915393's safety and effectiveness against IPF compared to a placebo. Participants will randomly receive either the new medicine or an inactive substance to see if there's an improvement in their lung condition.

Participant Groups

Group I: Placebo Experimental Treatment 1 Intervention

Participants will receive placebo.

Group II: GSK3915393 Experimental Treatment 1 Intervention

Participants will receive GSK3915393

Who Is Running the Clinical Trial?

GlaxoSmithKline

Lead Sponsor

Trials

4,834

Recruited

8,389,000+

Headquarters

London, UK

Known For

Vaccines & Medicines

Top Products

**Advair (salmeterol, fluticasone propionate)**, **Shingrix (shingles vaccine)**, **Augmentin (amoxicillin/clavulanate potassium)**, **Ventolin (salbutamol sulfate)

Dame Emma Walmsley

GlaxoSmithKline

Chief Executive Officer since 2017

MA in Classics and Modern Languages from Oxford University

Dr. Hal Barron

GlaxoSmithKline

Chief Medical Officer since 2018

MD from Harvard Medical School

Findings from Research

In a study of 210 idiopathic pulmonary fibrosis (IPF) patients, those with the DSP rs2076295*G allele showed significantly lower mortality and better outcomes with nintedanib treatment, indicating a potential genetic marker for treatment efficacy.

Patients with the TT genotype of DSP rs2076295 benefited more from pirfenidone, suggesting that genetic profiling could help tailor antifibrotic therapy in IPF, although the MUC5B rs35705950*T allele did not influence treatment outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

DSP rs2076295 variants influence nintedanib and pirfenidone outcomes in idiopathic pulmonary fibrosis: a pilot study. Doubkova, M., Kriegova, E., Littnerova, S., et al.[2022]

The study identifies a critical pathway involving the proteins TRIB3, GSK-3β, A20, and C/EBPβ that promotes the development of pulmonary fibrosis (PF) in alveolar macrophages, highlighting a potential target for therapeutic intervention.

Knocking down TRIB3 or disrupting its interaction with GSK-3β effectively treated PF, suggesting that targeting this pathway could lead to new treatment strategies for this chronic lung disease.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

TRIB3‒GSK-3β interaction promotes lung fibrosis and serves as a potential therapeutic target. Liu, S., Lv, X., Wei, X., et al.[2021]

In a study of 92 patients with idiopathic pulmonary fibrosis (IPF) receiving pirfenidone, the drug showed an acceptable safety profile, with skin-related (25%) and gastrointestinal (17.5%) adverse events being the most common, leading to discontinuation in 22.5% of cases.

Despite some patients experiencing significant improvements in lung function, the overall decline in lung function (%FVC and %DLCO) was noted over 36 months, highlighting the need for further research through prospective observational registries to better understand pirfenidone's long-term efficacy in real-world settings.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Longitudinal "Real-World" Outcomes of Pirfenidone in Idiopathic Pulmonary Fibrosis in Greece. Tzouvelekis, A., Karampitsakos, T., Ntolios, P., et al.[2022]

Pirfenidone effectively reduces lung fibrosis in patients with systemic sclerosis-associated interstitial lung disease (SSc-ILD) by inhibiting the hedgehog (Hh) signaling pathway, as demonstrated in a study involving 25 patients and 10 healthy controls.

The treatment also upregulates the protein Sufu in lung fibroblasts and inhibits the phosphorylation of GSK-3β, suggesting a dual mechanism of action that could be beneficial for other lung diseases driven by Hh signaling, such as idiopathic pulmonary fibrosis.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Anti-fibrotic effects of pirfenidone by interference with the hedgehog signalling pathway in patients with systemic sclerosis-associated interstitial lung disease. Xiao, H., Zhang, GF., Liao, XP., et al.[2020]

GSK3008348, an inhaled drug targeting the αvβ6 integrin, was found to be safe and well tolerated in a phase 1 trial with 29 healthy participants, with no serious adverse events reported.

The pharmacokinetic profile showed that maximum plasma concentrations were reached within 30 minutes, and the drug's exposure was dose proportional at doses up to 3000 mcg, supporting its potential as a treatment for idiopathic pulmonary fibrosis.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Safety, tolerability and pharmacokinetics of GSK3008348, a novel integrin αvβ6 inhibitor, in healthy participants. Maden, CH., Fairman, D., Chalker, M., et al.[2018]

The study identified that the GSK-3β signaling pathway plays a crucial role in the differentiation of fibroblasts into myofibroblasts, which contributes to the progression of idiopathic pulmonary fibrosis (IPF).

The novel inhibitor 9-ING-41 effectively blocked myofibroblast differentiation and improved lung function in mouse models of pulmonary fibrosis, suggesting its potential as a therapeutic option for patients with IPF.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Glycogen Synthase Kinase-3β Inhibition with 9-ING-41 Attenuates the Progression of Pulmonary Fibrosis. Jeffers, A., Qin, W., Owens, S., et al.[2021]

Chronic lung injury leads to the inactivation of the A20 enzyme, resulting in the accumulation of the C/EBPβ transcription factor in alveolar macrophages, which promotes the development of pulmonary fibrosis (PF).

Restoring A20 activity through pharmacological means or ectopic expression can enhance the degradation of C/EBPβ and shows strong therapeutic potential against experimental PF, suggesting that targeting the GSK-3β-A20-C/EBPβ pathway may be an effective strategy for treating PF.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Targeting Degradation of the Transcription Factor C/EBPβ Reduces Lung Fibrosis by Restoring Activity of the Ubiquitin-Editing Enzyme A20 in Macrophages. Liu, SS., Lv, XX., Liu, C., et al.[2019]

A new orally active drug that selectively inhibits the kinase activity of ALK5, a receptor for TGF-beta, shows promise in treating pulmonary fibrosis by blocking both the initiation and progression of the disease in a rat model.

The drug was effective not only when given at the start of fibrosis development but also when administered to rats with established fibrosis, suggesting it could be a potential therapeutic option for patients with idiopathic pulmonary fibrosis (IPF).

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Progressive transforming growth factor beta1-induced lung fibrosis is blocked by an orally active ALK5 kinase inhibitor. Bonniaud, P., Margetts, PJ., Kolb, M., et al.[2022]

References

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

DSP rs2076295 variants influence nintedanib and pirfenidone outcomes in idiopathic pulmonary fibrosis: a pilot study. [2022]

2. Netherlands pubmed.ncbi.nlm.nih.gov

TRIB3‒GSK-3β interaction promotes lung fibrosis and serves as a potential therapeutic target. [2021]

3. Switzerland pubmed.ncbi.nlm.nih.gov

Longitudinal "Real-World" Outcomes of Pirfenidone in Idiopathic Pulmonary Fibrosis in Greece. [2022]

4. England pubmed.ncbi.nlm.nih.gov

Anti-fibrotic effects of pirfenidone by interference with the hedgehog signalling pathway in patients with systemic sclerosis-associated interstitial lung disease. [2020]

5. Germany pubmed.ncbi.nlm.nih.gov

Safety, tolerability and pharmacokinetics of GSK3008348, a novel integrin αvβ6 inhibitor, in healthy participants. [2018]

6. England pubmed.ncbi.nlm.nih.gov

Glycogen Synthase Kinase-3β Inhibition with 9-ING-41 Attenuates the Progression of Pulmonary Fibrosis. [2021]

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

Targeting Degradation of the Transcription Factor C/EBPβ Reduces Lung Fibrosis by Restoring Activity of the Ubiquitin-Editing Enzyme A20 in Macrophages. [2019]

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

Progressive transforming growth factor beta1-induced lung fibrosis is blocked by an orally active ALK5 kinase inhibitor. [2022]