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BRENSOCATIB

Brensocatib (also known as INS1007 or AZD7986) is an investigational medication currently being studied in various clinical trials. It works as a selective, competitive, and reversible inhibitor of dipeptidyl peptidase 1 (DPP1), which plays a role in activating neutrophil serine proteases. These proteases are involved in inflammatory processes in multiple conditions. This article provides an overview of the ongoing clinical trials evaluating Brensocatib’s effectiveness, safety, and potential applications in conditions such as bronchiectasis, COVID-19, hidradenitis suppurativa, and chronic rhinosinusitis.

Table of Contents

What is Brensocatib?

Brensocatib (also known as INS1007 or AZD7986) is an investigational medication being developed for various inflammatory conditions [1]. It is not yet fully approved for widespread use, but is currently undergoing extensive clinical testing to determine its effectiveness and safety for several medical conditions. Brensocatib is being studied primarily as an oral medication (taken by mouth) that works differently from many existing treatments by targeting a specific enzyme in the body [2].

How Does Brensocatib Work?

Brensocatib works through a unique mechanism of action. It is a selective, competitive, and reversible inhibitor of an enzyme called dipeptidyl peptidase 1 (DPP1, also known as cathepsin C) [3]. This enzyme plays an important role in activating certain proteins called neutrophil serine proteases during the maturation of neutrophils (a type of white blood cell) in the bone marrow.

When Brensocatib blocks DPP1, it prevents the activation of neutrophil proteases like neutrophil elastase, proteinase-3, and cathepsin-G. These proteases are normally released by neutrophils during inflammation and can cause tissue damage. By reducing the activity of these proteases, Brensocatib aims to decrease inflammation and tissue damage in various inflammatory conditions [4].

Unlike many anti-inflammatory treatments that work immediately, Brensocatib takes some time to show its full effect. This is because it needs time to replace the existing neutrophils with new ones that have lower levels of active proteases. Clinical studies have shown that significant reductions in neutrophil elastase concentrations can be observed after 14 days of treatment, with even greater reductions after 28 days [3].

Medical Conditions Being Treated with Brensocatib

Non-Cystic Fibrosis Bronchiectasis (NCFBE)

The most advanced research on Brensocatib is for the treatment of non-cystic fibrosis bronchiectasis (NCFBE). Bronchiectasis is a chronic condition where the airways in the lungs become damaged and widened, leading to symptoms such as chronic cough, excessive mucus production, and recurring lung infections [2].

In a Phase 2 clinical trial known as the WILLOW study, Brensocatib showed promising results in reducing the rate of pulmonary exacerbations (sudden worsening of symptoms) in people with NCFBE over a 24-week treatment period. This study tested doses of 10 mg and 25 mg once daily [2].

The research has progressed to Phase 3 with the ASPEN study, which is evaluating the effects of Brensocatib (10 mg and 25 mg) compared to placebo over a 52-week treatment period. This study is measuring how Brensocatib affects the rate of pulmonary exacerbations, lung function, and quality of life in NCFBE patients [5].

Cystic Fibrosis

Brensocatib is also being studied for potential benefits in people with cystic fibrosis, a genetic disorder that affects the lungs and digestive system. A Phase 2a study is evaluating the safety, tolerability, and pharmacokinetics (how the drug moves through the body) of Brensocatib in adults with cystic fibrosis at doses of 10 mg, 25 mg, 40 mg, and potentially 65 mg [6].

COVID-19

During the COVID-19 pandemic, Brensocatib was studied as a potential treatment for severe COVID-19. The STOP-COVID19 trial investigated whether Brensocatib could reduce the incidence of acute lung injury and acute respiratory distress syndrome (ARDS) in hospitalized COVID-19 patients by blocking damaging neutrophil proteases [3].

Hidradenitis Suppurativa

More recently, Brensocatib is being evaluated for hidradenitis suppurativa, a chronic inflammatory skin condition that causes painful bumps under the skin in areas where skin rubs together. The CEDAR study is a Phase 2b trial evaluating the efficacy and safety of Brensocatib at doses of 10 mg and 40 mg in adults with moderate to severe hidradenitis suppurativa [7].

Chronic Rhinosinusitis Without Nasal Polyps

Brensocatib is being studied for chronic rhinosinusitis without nasal polyps (CRSsNP), a condition characterized by inflammation of the sinuses that lasts 12 weeks or longer. The BiRCh study is examining whether Brensocatib (10 mg and 40 mg) can improve clinical symptoms of CRSsNP when used alongside mometasone furoate nasal spray [8].

Dosage Forms Available

Based on the clinical trials, Brensocatib is being developed in several dosage forms:

  • Oral tablets: Most studies are using film-coated tablets at doses of 10 mg, 25 mg, or 40 mg taken once daily [5] [7].
  • Oral solution: A pediatric oral solution is being developed and compared to the tablet form in bioavailability studies [9].
  • Different oral liquid formulations: Studies are evaluating the palatability (taste) and acceptability of different Brensocatib oral liquid formulations [1].

Overview of Clinical Studies

Brensocatib is undergoing extensive clinical testing to evaluate its effectiveness, safety, and how it works in the body:

Efficacy Studies

  • WILLOW Study: A completed Phase 2 study in NCFBE that showed Brensocatib could extend the time to first pulmonary exacerbation and reduce the frequency of exacerbations [2].
  • ASPEN Study: An ongoing Phase 3 study in NCFBE evaluating the effect of Brensocatib on the rate of pulmonary exacerbations over 52 weeks [5].
  • CEDAR Study: A Phase 2b study in hidradenitis suppurativa evaluating whether Brensocatib can reduce the number of inflammatory nodules and abscesses [7].
  • BiRCh Study: A Phase 2b study in chronic rhinosinusitis without nasal polyps measuring improvements in sinus symptoms [8].

Pharmacokinetic and Safety Studies

Several studies are investigating how Brensocatib is processed by the body and potential interactions with other medications:

  • Studies in participants with kidney impairment [10]
  • Studies in participants with liver impairment [11]
  • Studies of drug interactions with medications like clarithromycin (an antibiotic) [12], rifampin, and esomeprazole [13]
  • Studies of the absorption, metabolism, and excretion of Brensocatib [4]
  • Studies evaluating potential effects on heart rhythm (QT interval) [14]

Safety and Potential Side Effects

As Brensocatib is still being investigated in clinical trials, the full safety profile and list of side effects are not yet fully established. The clinical trials mentioned are carefully monitoring for adverse events, which are any undesirable experiences associated with the use of the medication.

The safety evaluation includes monitoring:

  • Number of participants who experience adverse events [5]
  • Laboratory tests of blood counts, liver function, and kidney function [3]
  • Specific adverse events of special interest, which in some studies include hyperkeratosis (thickening of the skin), infections, and dental complications [3]

Since Brensocatib works by affecting neutrophil function, which is important for fighting infections, researchers are carefully monitoring for any increased risk of infections in study participants.

Special Considerations

Kidney and Liver Function

Specific studies are being conducted to understand how Brensocatib affects patients with impaired kidney or liver function. These studies will help determine if dose adjustments are needed for these populations [10] [11].

Drug Interactions

Studies are investigating potential interactions between Brensocatib and other medications, particularly those that affect specific liver enzymes called CYP3A4, which are involved in processing many medications. For example, a study is looking at how clarithromycin, a strong CYP3A4 inhibitor, affects Brensocatib levels in the body [12].

Administration with Food

Some studies specify that Brensocatib should be taken before breakfast, suggesting that food might affect how the drug is absorbed [2]. However, specific recommendations will be based on the results of ongoing studies.

Ongoing Research

Brensocatib research is ongoing across multiple fronts:

  • Expanding to new patient populations, including children (pediatric formulations are in development) [9] [1]
  • Testing in new medical conditions
  • Long-term safety and efficacy monitoring
  • Investigating optimal dosing regimens
  • Developing new formulations for different patient needs

An expanded access program has been established for NCFBE patients who completed the ASPEN clinical trial, allowing them continued access to Brensocatib while research continues [15].

As research progresses, more information will become available about the effectiveness and safety of Brensocatib for various conditions. Patients interested in Brensocatib should discuss with their healthcare provider whether participation in a clinical trial might be appropriate for their specific situation.

Aspect Details
Drug Classification Brensocatib (also known as INS1007 or AZD7986) is a selective, competitive, and reversible inhibitor of dipeptidyl peptidase 1 (DPP1)
Mechanism of Action Inhibits DPP1, which reduces activation of neutrophil serine proteases (including neutrophil elastase), thereby potentially reducing inflammation and tissue damage
Conditions Under Investigation – Non-cystic fibrosis bronchiectasis (NCFBE)
– Cystic fibrosis
– COVID-19
– Hidradenitis suppurativa
– Chronic rhinosinusitis without nasal polyps
Formulations Studied – Oral tablets (most common: 10 mg, 25 mg, 40 mg)
– Pediatric oral solutions
– Administration typically once daily
Key Clinical Trials – WILLOW study: Phase 2 trial in NCFBE (completed)
– ASPEN study: Phase 3 trial in NCFBE (ongoing)
– CEDAR study: Phase 2b trial in hidradenitis suppurativa
– BiRCh study: Phase 2b trial in chronic rhinosinusitis
– STOP-COVID19: Trial in COVID-19 patients
Phase of Development – Phase 3 for non-cystic fibrosis bronchiectasis
– Phase 2 for most other indications
– Multiple Phase 1 studies for drug interactions, special populations
Special Population Studies – Renal impairment
– Hepatic impairment
– Drug-drug interaction studies (with clarithromycin, rifampin, esomeprazole)
Safety Assessments – QT interval studies
– Adverse events monitoring
– Laboratory parameters
– Special interest: dental complications, infections, hyperkeratosis
Notable Results – Phase 2 WILLOW study met primary endpoint (time to first pulmonary exacerbation)
– Reduced neutrophil elastase concentrations in sputum
– Results from other indications are pending or ongoing

FAQ

  • What is Brensocatib and how does it work? Brensocatib (also known as INS1007 or AZD7986) is an investigational drug that works as a selective, competitive, and reversible inhibitor of dipeptidyl peptidase 1 (DPP1). This enzyme is responsible for activating neutrophil serine proteases during neutrophil maturation in the bone marrow. By inhibiting DPP1, Brensocatib reduces the activity of neutrophil proteases like neutrophil elastase, which are involved in inflammatory processes. This mechanism may help reduce inflammation and tissue damage in various conditions where neutrophil activity contributes to disease progression.
  • What conditions is Brensocatib being studied for? Brensocatib is being studied in clinical trials for several conditions, including: non-cystic fibrosis bronchiectasis (NCFBE), cystic fibrosis, COVID-19, hidradenitis suppurativa (a chronic inflammatory skin condition), and chronic rhinosinusitis without nasal polyps. The most advanced studies appear to be in non-cystic fibrosis bronchiectasis, where Phase 3 trials are underway following promising results in earlier phase studies.
  • What have studies shown about Brensocatib's effectiveness so far? In the Phase 2 WILLOW study for non-cystic fibrosis bronchiectasis, Brensocatib showed promising results by prolonging the time to first pulmonary exacerbation and reducing neutrophil elastase concentration in sputum compared to placebo. This study met its primary endpoint and supported further investigation in larger Phase 3 trials. The ASPEN study is an ongoing Phase 3 trial evaluating Brensocatib's effect on the rate of pulmonary exacerbations over 52 weeks. Studies in other conditions like hidradenitis suppurativa, COVID-19, and chronic rhinosinusitis are still ongoing, with results yet to be fully determined.
  • What are the most common forms of Brensocatib being tested? Brensocatib is being tested in several forms across different trials. The most common form is oral tablets at various doses (primarily 10 mg, 25 mg, and 40 mg), taken once daily. Some studies are also evaluating pediatric oral solutions and comparing their bioavailability to tablet formulations. Trials are examining different dosages to determine the optimal balance between efficacy and safety. Most studies administer Brensocatib once daily, and some trials specify taking it under fasted conditions.
  • What should patients know about participating in Brensocatib clinical trials? Patients considering participation in Brensocatib clinical trials should understand that the drug is still investigational and not yet approved for general use. Trial participation involves regular monitoring of safety and efficacy measures, including blood tests, symptom assessments, and possibly imaging studies. Different trials have specific eligibility criteria regarding disease severity, previous treatments, and other health conditions. Some trials compare Brensocatib to placebo, while others may investigate drug interactions or effects in specific populations like those with liver or kidney impairment. The trials vary in duration from single-dose studies to treatment periods of up to 52 weeks.

Ongoing Clinical Trials on BRENSOCATIB

  • Study on the Effectiveness and Safety of Brensocatib for Patients with Chronic Rhinosinusitis Without Nasal Polyps

    Not recruiting

    1 1
    Investigated drugs:
    Belgium Bulgaria Czechia Denmark France Germany +5

  • Study on the Effectiveness and Safety of Brensocatib for Adults with Moderate to Severe Hidradenitis Suppurativa

    Not recruiting

    1
    Investigated drugs:
    Bulgaria France Germany Greece The Netherlands Poland +1

Glossary

  • Brensocatib: An investigational drug (also known as INS1007 or AZD7986) that inhibits dipeptidyl peptidase 1 (DPP1), reducing neutrophil protease activity, which may help in treating inflammatory conditions.
  • DPP1 (Dipeptidyl Peptidase 1): An enzyme (also known as cathepsin C) that activates neutrophil serine proteases during neutrophil maturation in the bone marrow. Brensocatib works by inhibiting this enzyme.
  • Neutrophil Elastase: A protease enzyme released by neutrophils (a type of white blood cell) that can cause tissue damage in inflammatory conditions. Brensocatib indirectly reduces its activity.
  • Non-Cystic Fibrosis Bronchiectasis (NCFBE): A chronic lung condition characterized by permanent widening of airways, mucus production, and recurrent infections. It's one of the main conditions being studied in Brensocatib trials.
  • Pulmonary Exacerbation: A worsening of respiratory symptoms in lung conditions like bronchiectasis, often requiring antibiotic treatment. Reducing these events is a key outcome measure in Brensocatib trials.
  • Pharmacokinetics (PK): The study of how a drug moves through the body, including its absorption, distribution, metabolism, and excretion. Many Brensocatib trials measure these parameters.
  • Bioavailability: The proportion of a drug that enters circulation when introduced into the body and is available at the site of action. Some trials compare bioavailability between different Brensocatib formulations.
  • Neutrophil Serine Proteases: Enzymes released by neutrophils that contribute to inflammation and tissue damage in various conditions. Brensocatib reduces their activity by inhibiting DPP1.
  • Hidradenitis Suppurativa (HS): A chronic inflammatory skin condition that causes painful lumps under the skin, typically in areas where skin rubs together. Brensocatib is being studied as a potential treatment.
  • Chronic Rhinosinusitis Without Nasal Polyps (CRSsNP): Inflammation of the sinuses that lasts for 12 weeks or longer, without the presence of nasal polyps. Brensocatib is being evaluated for this condition in the BiRCh study.
  • QT Interval: A measurement on an electrocardiogram representing the time between the start of the Q wave and the end of the T wave, indicating ventricular electrical activity. Some trials assess Brensocatib's effect on this interval.
  • CYP3A4: An enzyme involved in drug metabolism. Some Brensocatib trials study interactions with drugs that affect this enzyme, like clarithromycin (an inhibitor) or rifampin (an inducer).
  • Neutrophil Extracellular Traps (NETs): Web-like structures released by neutrophils composed of DNA and proteins that can trap pathogens but also contribute to tissue damage in inflammatory conditions.
  • ARDS (Acute Respiratory Distress Syndrome): A serious lung condition causing fluid buildup in the air sacs, leading to low blood oxygen levels. A potential complication of COVID-19 that Brensocatib aims to prevent in clinical trials.

References

  1. https://clinicaltrials.gov/study/NCT06178783
  2. https://clinicaltrials.gov/study/NCT03218917
  3. https://clinicaltrials.gov/study/NCT04817332
  4. https://clinicaltrials.gov/study/NCT05652257
  5. https://clinicaltrials.gov/study/NCT04594369
  6. https://clinicaltrials.gov/study/NCT05090904
  7. https://clinicaltrials.gov/study/NCT06685835
  8. https://clinicaltrials.eu/trial/study-on-the-effectiveness-and-safety-of-brensocatib-for-patients-with-chronic-rhinosinusitis-without-nasal-polyps/
  9. https://clinicaltrials.gov/study/NCT06344728
  10. https://clinicaltrials.gov/study/NCT05673603
  11. https://clinicaltrials.gov/study/NCT05517525
  12. https://clinicaltrials.gov/study/NCT05965570
  13. https://clinicaltrials.gov/study/NCT05826574
  14. https://clinicaltrials.gov/study/NCT05355935
  15. https://clinicaltrials.gov/study/NCT05344508