New England Journal of Medicine Publishes Positive Results from Phase 2 WILLOW Study of Brensocatib in Patients with Non-Cystic Fibrosis Bronchiectasis
BRIDGEWATER, N.J., Sept. 7, 2020 /PRNewswire/ -- Insmed Incorporated (Nasdaq:INSM), a global biopharmaceutical company on a mission to transform the lives of patients with serious and rare diseases, today announced that final results from the Phase 2 WILLOW study of brensocatib in patients with non-cystic fibrosis bronchiectasis (NCFBE) were published online in the New England Journal of Medicine (NEJM). New data from subgroup analyses of the WILLOW study also were presented today during a late-breaking clinical trials session at the virtual European Respiratory Society (ERS) International Congress 2020. Brensocatib is a novel, first-in-class, oral, reversible inhibitor of dipeptidyl peptidase 1 (DPP1) being developed by Insmed for the treatment of bronchiectasis and other inflammatory diseases.
"We are very pleased that NEJM has recognized the significance of the Phase 2 WILLOW data for patients with NCFBE. These results demonstrate the potential clinical benefits of directly reducing neutrophil-mediated inflammation in bronchiectasis—a critical finding for patients who currently suffer from severe outcomes in the absence of an approved therapy," said Martina Flammer, M.D., MBA, Chief Medical Officer of Insmed. "We eagerly anticipate initiating our Phase 3 program for brensocatib in bronchiectasis later this year as we work to bring this urgently needed solution to patients."
The results published today showed that brensocatib significantly prolonged time to first pulmonary exacerbation, the primary endpoint, over the 24-week treatment period for both treatment doses versus placebo (p=0.03 for the 10 mg group; p=0.04 for the 25 mg group). The risk of exacerbation at any time during the trial was reduced by 42% for the 10 mg group versus placebo (HR 0.58, p=0.03) and by 38% for the 25 mg group versus placebo (HR 0.62, p=0.046).
Treatment with brensocatib also reduced the rate of pulmonary exacerbations, a key secondary endpoint. Patients treated with brensocatib experienced a 36% reduction in the 10 mg arm (p=0.04) and a 25% reduction in the 25 mg arm (p=0.17), compared with the placebo arm. In addition, mean concentrations of active neutrophil elastase (NE) in sputum showed dose-dependent reductions compared with placebo over the 24-week treatment period.
Importantly, study results were consistent among subgroups based on age, baseline NE concentrations, prior exacerbation history, bronchiectasis severity index, and lung function.
"The WILLOW study demonstrated that among patients with NCFBE who have a history of frequent exacerbations, treatment with brensocatib significantly prolonged the time to first exacerbation and reduced the risk of exacerbation over the treatment period. Annualized rates of exacerbation were also lower compared to placebo," said lead author James Chalmers, MBChB, Ph.D., Professor and Consultant Respiratory Physician at the School of Medicine, University of Dundee, UK. "These results are critically important given the lack of approved pharmaceutical therapies to reduce the risk of exacerbation—the major driver of morbidity and mortality in patients with bronchiectasis. The results also validate the novel mechanism of action of brensocatib and highlight the potential benefits of reducing neutrophil serine protease activity."
In addition to the results published in NEJM, new data from the WILLOW study were presented today at the ERS International Congress. Subgroup analyses showed that brensocatib consistently prolonged time to first exacerbation and reduced rates of exacerbation among patient subgroups analyzed by baseline disease severity, P. aeruginosa infection, and sputum NE concentration. Further, brensocatib reduced the sputum concentrations of all three neutrophil serine proteases (NSPs) assessed (NE, proteinase 3, and cathepsin G).
Brensocatib was generally well-tolerated in the WILLOW study. Rates of adverse events (AEs) leading to drug discontinuation in patients treated with placebo, brensocatib 10 mg, and brensocatib 25 mg were 11%, 7%, and 7%, respectively. The most common AEs in patients treated with brensocatib were cough, headache, sputum increase, dyspnea, infective exacerbation of bronchiectasis, and diarrhea.
Rates of adverse events of special interest (AESIs) in patients treated with placebo, brensocatib 10 mg, and brensocatib 25 mg, respectively, were as follows: rates of skin events (including hyperkeratosis) were 12%, 15%, and 24%; rates of dental events were 4%, 16%, and 10%; and rates of infections considered AESIs were 18%, 14%, and 17%. Hyperkeratosis was reported in 1/85, 3/81, and 1/89 patients treated with placebo, brensocatib 10 mg, and brensocatib 25 mg, respectively. The study included extensive dental evaluations to closely monitor progression of periodontal disease. The results did not raise a signal about dental safety. The percentage of patients with change in periodontal pocket depth ≥2 mm and absolute value of ≥5 mm (the threshold of concern for periodontal disease) were 12%, 11%, and 12% for placebo, brensocatib 10 mg, and brensocatib 25 mg, respectively. No skin or dental adverse events were considered serious.
Brensocatib received breakthrough therapy designation from the U.S. Food and Drug Administration in June 2020 for the treatment of adult patients with NCFBE for reducing exacerbations. Insmed plans to initiate a Phase 3 program for brensocatib in bronchiectasis by the end of 2020.
WILLOW was a randomized, double-blind, placebo-controlled, parallel-group, multi-center, multi-national, Phase 2 study to assess the efficacy, safety and tolerability, and pharmacokinetics of brensocatib administered once daily for 24 weeks in patients with non-cystic fibrosis bronchiectasis (NCFBE). WILLOW was conducted at 116 sites and enrolled 256 adult patients diagnosed with NCFBE who had at least two documented pulmonary exacerbations in the 12 months prior to screening. Patients were randomized 1:1:1 to receive either 10 mg or 25 mg of brensocatib or matching placebo. The primary efficacy endpoint was the time to first pulmonary exacerbation over the 24-week treatment period in the brensocatib arms compared to the placebo arm.
Brensocatib is a small molecule, oral, reversible inhibitor of dipeptidyl peptidase I (DPP1) being developed by Insmed for the treatment of patients with bronchiectasis. DPP1 is an enzyme responsible for activating neutrophil serine proteases (NSPs), such as neutrophil elastase, in neutrophils when they are formed in the bone marrow. Neutrophils are the most common type of white blood cell and play an essential role in pathogen destruction and inflammatory mediation. In chronic inflammatory lung diseases, neutrophils accumulate in the airways and result in excessive active NSPs that cause lung destruction and inflammation. Brensocatib may decrease the damaging effects of inflammatory diseases such as bronchiectasis by inhibiting DPP1 and its activation of NSPs.
About Non-Cystic Fibrosis Bronchiectasis
Non-cystic fibrosis bronchiectasis (NCFBE) is a severe, chronic pulmonary disorder in which the bronchi become permanently dilated due to a cycle of infection, inflammation, and lung tissue damage. The condition is marked by frequent pulmonary exacerbations requiring antibiotic therapy and/or hospitalizations. Symptoms include chronic cough, excessive sputum production, shortness of breath, and repeated respiratory infections, which can worsen the underlying condition. NCFBE affects approximately 340,000 to 520,000 patients in the U.S. Today, there are no approved therapies specifically targeting NCFBE in the U.S., Europe, or Japan.
Insmed Incorporated is a global biopharmaceutical company on a mission to transform the lives of patients with serious and rare diseases. Insmed's first commercial product, ARIKAYCE® (amikacin liposome inhalation suspension), is the first and only therapy approved in the United States for the treatment of refractory Mycobacterium avium complex (MAC) lung disease as part of a combination antibacterial drug regimen for adult patients with limited or no alternative treatment options. MAC lung disease is a chronic, debilitating condition that can cause severe and permanent lung damage. Insmed is also advancing brensocatib, a novel oral reversible inhibitor of dipeptidyl peptidase 1 with therapeutic potential in bronchiectasis and other inflammatory diseases, and treprostinil palmitil, an inhaled formulation of a treprostinil prodrug that may offer a differentiated product profile for rare pulmonary disorders, including pulmonary arterial hypertension. For more information, visit www.insmed.com.
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