Ensifentrine for COPD

Recruiting at 1 trial location

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: Verona Pharma plc

Must be taking: Bronchodilators

Disqualifiers: Asthma, Lung diseases, Cancer, 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

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

Compensation: Varies

Number of Visits: 7

50 Participants Needed

Trial Summary

What is the purpose of this trial?

This is a randomized, double-blind, placebo-controlled, two-period cross-over study of nebulized ensifentrine (3 mg) or placebo administered BID for two 8-week Treatment Periods. All participants with receive both ensifentrine and placebo during participation. There are 7 in-clinic visits over a total duration of up to 24 weeks participation.

Will I have to stop taking my current medications?

The trial requires participants to use the study-supplied COPD Maintenance Therapy once daily, but it does not specify if you must stop other medications. It's best to discuss your current medications with the study team to understand any specific requirements.

What data supports the effectiveness of the drug Ensifentrine for COPD?

Ensifentrine has shown to improve lung function and reduce the rate of moderate or severe exacerbations in patients with COPD, as demonstrated in Phase III trials. It also improved symptoms and quality of life in some studies, with a safety profile similar to placebo. ^{1 2 3 4 5}

Is Ensifentrine safe for humans?

Ensifentrine has been tested in clinical trials for COPD and has shown a satisfactory safety profile, with fewer effects on heart rate and blood pressure compared to some other treatments, and no significant side effects reported. ^{1 2 3 6 7}

What makes the drug Ensifentrine unique for treating COPD?

Ensifentrine is unique because it is an inhaled drug that acts as a dual inhibitor of phosphodiesterase (PDE) 3 and 4, providing both bronchodilator (helps open airways) and anti-inflammatory effects, which is different from most current COPD treatments that focus mainly on bronchodilation or inflammation separately. ^{1 2 3 4 8}

Eligibility Criteria

This trial is for COPD patients aged 40-80 who have a history of smoking and moderate to severe lung function impairment. They must be using regular bronchodilator therapy, able to use a nebulizer correctly, and produce sputum samples. Exclusions include significant liver enzyme elevations, recent cancer (except certain skin cancers), immunodeficiency, recent experimental drug/device use or other serious health issues.

Inclusion Criteria

COPD Severity: Pre- and Post-albuterol/salbutamol FEV1/FVC ratio of <0.70; Post-albuterol/salbutamol FEV1 ≥30 % and ≤80% of predicted normal calculated using the National Health and Nutrition Examination Survey III.

Regular use of bronchodilator COPD therapy, in any form (e.g., LAMA, LABA, LAMA+LABA), for at least 4 weeks prior to Screening and agrees to use study supplied COPD Maintenance Therapy once daily through the final study visit.

You are between 40 and 80 years old, have smoked at least 10 packs of cigarettes in your life, and have been diagnosed with COPD based on specific guidelines.

Exclusion Criteria

Alanine aminotransferase (ALT) ≥ 2 x upper limit of normal (ULN), alkaline phosphatase and/or bilirubin > 1.5 x ULN (isolated bilirubin >1.5 x ULN is acceptable if bilirubin is fractionated and direct bilirubin <35%). HIV infection or other immunodeficiency. History of cancer within the last 5 years, except for well-treated basal cell carcinoma and squamous cell carcinoma of the skin.

Taking prohibited medication. Prior receipt of blinded nebulized study medication in an ensifentrine (RPL554) study. Note: Other ensifentrine formats (e.g., DPI, MPI) are not exclusionary.

Use of an experimental drug within 30 days or 5 half-lives of Screening, whichever is longer, and/or participation in a study treatment-free follow-up phase of a clinical trial within 30 days prior to Screening. Use of an experimental medical device or participation in a follow-up phase of an experimental medical device clinical trial within 30 days prior to Screening. Any other medical history, chronic uncontrolled diseases that the investigator considers clinically significant, examination or laboratory findings or reason that the Investigator considers makes the patient unsuitable to participate at Screening.

Timeline

Screening and Run-in

Participants are screened for eligibility to participate in the trial and enter a run-in period to ensure a stable background on a once daily COPD Maintenance Therapy

2-4 weeks

1 visit (in-person)

Treatment Period 1

Participants receive 8 weeks of treatment with blinded, nebulized ensifentrine or placebo + once daily COPD Maintenance Therapy

8 weeks

3 visits (in-person)

Washout

Participants will only take once daily COPD Maintenance Therapy. There will be a follow-up phone call about 1 week after finishing Treatment Period 1

4 weeks

Treatment Period 2

Participants receive 8 weeks of treatment with Study Medication (opposite of Treatment Period 1) + once daily COPD Maintenance Therapy

8 weeks

3 visits (in-person)

Safety Follow-up

Safety follow-up call 1 week after Treatment Period 2

1 week

Treatment Details

Interventions

• Ensifentrine

Trial Overview The study tests the effect of ensifentrine versus placebo on inflammation in COPD patients. It's a double-blind study where participants receive both treatments across two periods totaling up to 24 weeks with seven clinic visits. Ensifentrine is administered twice daily via nebulization.

Participant Groups

Group I: Treatment Sequence 2 Experimental Treatment 2 Interventions

Treatment Period 1 (blinded Placebo) followed by Treatment Period 2 (blinded Ensifentrine)

Group II: Treatment Sequence 1 Experimental Treatment 2 Interventions

Treatment Period 1 (blinded Ensifentrine) followed by Treatment Period 2 (blinded Placebo)

Ensifentrine is already approved in United States for the following indications:

Approved in United States as Ohtuvayre for:

• Chronic obstructive pulmonary disease (COPD)

Who Is Running the Clinical Trial?

Verona Pharma plc

Lead Sponsor

Trials

16

Recruited

3,000+

University of Alabama at Birmingham

Collaborator

Trials

1,677

Recruited

2,458,000+

Findings from Research

Ensifentrine (RPL554) is an inhaled medication that acts as a dual inhibitor of phosphodiesterase 3 and 4, providing both bronchodilation and anti-inflammatory effects, making it a promising treatment for chronic obstructive pulmonary disease (COPD).

Currently under clinical development, it is uncertain whether ensifentrine will serve as an add-on therapy for acute COPD exacerbations or as a standalone maintenance treatment, indicating the need for further research to clarify its optimal use.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Ensifentrine (RPL554): an inhaled 'bifunctional' dual PDE3/4 inhibitor for the treatment of asthma and chronic obstructive pulmonary disease. Cazzola, M., Page, C., Calzetta, L., et al.[2019]

In a study involving 416 patients with moderate-to-severe COPD, adding nebulized ensifentrine to tiotropium significantly improved lung function, with dose-dependent increases in peak FEV1 observed over 4 weeks.

Ensifentrine also led to meaningful improvements in quality of life, as measured by the St. George's Respiratory Questionnaire, without increasing the frequency of adverse events compared to placebo.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A Dose-Ranging Study of the Novel Inhaled Dual PDE 3 and 4 Inhibitor Ensifentrine in Patients with COPD Receiving Maintenance Tiotropium Therapy. Ferguson, GT., Kerwin, EM., Rheault, T., et al.[2023]

Roflumilast, an oral PDE4 inhibitor, can help prevent exacerbations in certain COPD patients, but it has side effects like nausea and diarrhea, highlighting the need for better treatment options.

RPL554/ensifentrine, an inhaled dual PDE3/4 inhibitor, shows promise in improving symptoms and quality of life for COPD patients with a favorable safety profile, but further Phase III trials are necessary to confirm its efficacy and safety on a larger scale.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Inhaled Dual Phosphodiesterase 3/4 Inhibitors for the Treatment of Patients with COPD: A Short Review. Martin, C., Burgel, PR., Roche, N.[2021]

Ensifentrine, a dual phosphodiesterase inhibitor, significantly improved lung function in patients with chronic obstructive pulmonary disease (COPD) in two phase III trials, with an average increase in FEV1 of 87 ml and 94 ml compared to placebo.

The treatment also reduced the rate of moderate or severe exacerbations and increased the time to first exacerbation, while showing a safety profile similar to that of placebo, indicating its potential as an effective therapy for COPD.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Ensifentrine, a Novel Phosphodiesterase 3 and 4 Inhibitor for the Treatment of Chronic Obstructive Pulmonary Disease: Randomized, Double-Blind, Placebo-controlled, Multicenter Phase III Trials (the ENHANCE Trials). Anzueto, A., Barjaktarevic, IZ., Siler, TM., et al.[2023]

Nebulised ensifentrine showed a clear dose-response relationship in improving lung function (FEV1) in asthma patients, outperforming placebo and demonstrating effectiveness comparable to salbutamol, a standard asthma treatment.

All doses of ensifentrine were well tolerated with no significant adverse effects on heart rate or potassium levels, unlike salbutamol, which caused dose-related reductions in potassium and increased heart rates.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Efficacy and safety of a first-in-class inhaled PDE3/4 inhibitor (ensifentrine) vs salbutamol in asthma. Bjermer, L., Abbott-Banner, K., Newman, K.[2020]

Cilomilast showed some improvement in lung function (FEV1) in COPD patients compared to placebo, but only one of the studies demonstrated a statistically significant and clinically meaningful difference, leading to mixed results regarding its efficacy.

While cilomilast was associated with more gastrointestinal side effects, safety assessments did not reveal serious safety concerns, but the overall lack of consistent efficacy led to the termination of its development.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The efficacy and safety of cilomilast in COPD. Rennard, S., Knobil, K., Rabe, KF., et al.[2021]

Roflumilast, when combined with inhaled corticosteroids and long-acting β2 agonists, significantly improves lung function in severe COPD patients, as shown by increased forced expiratory volume (FEV1) and reduced exacerbation rates in a meta-analysis of 9,715 patients.

While roflumilast is effective, it is associated with a higher incidence of adverse effects such as diarrhea, headache, and nausea compared to placebo, indicating the need for careful monitoring of side effects in patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Effects of Roflumilast on Patients with Chronic Obstructive Pulmonary Disease Treated with Inhaled Corticosteroid/Long-Acting &#946;2 Agonist: A Meta-analysis. Zeng, S., Bai, H., Zou, M.[2022]

Ensifentrine is a new inhaled medication that effectively targets both airway inflammation and bronchodilation, showing significant improvements in symptoms and quality of life for patients with COPD during Phase 2 studies.

In these studies, ensifentrine provided clinically meaningful bronchodilation whether used alone or alongside standard treatments, indicating its potential as a valuable maintenance therapy for COPD patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Ensifentrine as a Novel, Inhaled Treatment for Patients with COPD. Donohue, JF., Rheault, T., MacDonald-Berko, M., et al.[2023]

References

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

Ensifentrine (RPL554): an inhaled 'bifunctional' dual PDE3/4 inhibitor for the treatment of asthma and chronic obstructive pulmonary disease. [2019]

2. New Zealand pubmed.ncbi.nlm.nih.gov

A Dose-Ranging Study of the Novel Inhaled Dual PDE 3 and 4 Inhibitor Ensifentrine in Patients with COPD Receiving Maintenance Tiotropium Therapy. [2023]

3. New Zealand pubmed.ncbi.nlm.nih.gov

Inhaled Dual Phosphodiesterase 3/4 Inhibitors for the Treatment of Patients with COPD: A Short Review. [2021]

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

Ensifentrine, a Novel Phosphodiesterase 3 and 4 Inhibitor for the Treatment of Chronic Obstructive Pulmonary Disease: Randomized, Double-Blind, Placebo-controlled, Multicenter Phase III Trials (the ENHANCE Trials). [2023]

5. England pubmed.ncbi.nlm.nih.gov

Efficacy and safety of a first-in-class inhaled PDE3/4 inhibitor (ensifentrine) vs salbutamol in asthma. [2020]

6. New Zealand pubmed.ncbi.nlm.nih.gov

The efficacy and safety of cilomilast in COPD. [2021]

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

Effects of Roflumilast on Patients with Chronic Obstructive Pulmonary Disease Treated with Inhaled Corticosteroid/Long-Acting &#946;2 Agonist: A Meta-analysis. [2022]

8. New Zealand pubmed.ncbi.nlm.nih.gov

Ensifentrine as a Novel, Inhaled Treatment for Patients with COPD. [2023]