Insmed Presents Positive Patient-Reported Outcomes and Microbiologic Data from Phase 3 ARISE Study Of ARIKAYCE® (Amikacin Liposome Inhalation Suspension) in Patients with NTM Lung Disease Caused by MAC at American Thoracic Society 2024 International Conference Plenary Session
—Patients Treated with ARIKAYCE Plus Macrolide-Based Background Regimen Had Meaningfully Greater Improvements in Respiratory Symptoms vs. Macrolide-Based Background Regimen Alone, As Measured By the QOL-B Respiratory Domain Instrument—
— QOL-B Respiratory Domain Scores for ARIKAYCE Patients Showed Improvement Through Month 6 and Continued to Improve Through Month 7 (1 Month Off Treatment), While Improvements in the Comparator Arm Plateaued After Month 3 and Worsened After Month 6 —
—Microbiologic Data Presented Showed Patients in the ARIKAYCE-treated Arm Had Numerically Greater Rates of Culture Conversion By Month 6, and Nominally Statistically Significantly Higher Rates By Month 7, With Earlier Time to First Culture Conversion vs. Comparator Arm—
— No Study Patients Developed MAC with Resistance to ARIKAYCE or Macrolides—
"The inclusion of late-breaking ARISE data in both a plenary and in two oral sessions at ATS highlights the importance of these study results for the NTM community and the exciting potential for ARIKAYCE to reach a broader population of people living with MAC lung disease," said
As previously announced, data from ARISE demonstrated that the Quality of Life-Bronchiectasis (QOL-B) respiratory domain may be an effective patient-reported outcome (PRO) tool in patients with MAC lung disease. The ARISE study was designed to help support the validation of a PRO tool to be used in ENCORE, the ongoing Phase 3b registrational study evaluating the efficacy and safety of an ARIKAYCE-based regimen in patients with newly diagnosed or recurrent MAC lung disease who have not received antibiotics for their current infection.
In ARISE, ARIKAYCE-treated patients performed better than those in the comparator arm (a macrolide-based multi-drug regimen) as measured by the QOL-B instrument, with 43.8% of patients achieving an improvement in QOL-B respiratory score above or equal to the estimated meaningful within-subject score difference of 14.8, compared with 33.3% of patients in the comparator arm. While the study was not powered to show a statistically significant difference between treatment arms, a strong trend toward significance was observed for improvement from baseline at Month 7 (least-squares mean change from baseline 12.24 vs. 7.76, p=0.1073).
New data presented showed that patients in the ARIKAYCE treatment arm experienced continued improvement in QOL-B scores to Month 7, which included one month off treatment (observed mean QOL-B score change from baseline: 14.1). In contrast, in patients randomized to the comparator arm, QOL-B scores plateaued between Month 3 and Month 6 and worsened after stopping treatment at Month 6 through Month 7 (observed mean QOL-B score change from baseline: 6.9).
In a separate abstract presented, microbiologic evaluation of sputum samples showed that a greater proportion of patients treated with the ARIKAYCE plus macrolide-based background regimen achieved culture conversion by Month 6 versus patients in the comparator arm (80.6% vs. 63.9%, p=0.0712). Patients in the ARIKAYCE arm also achieved nominally statistically significantly higher culture conversion rates at Month 7 versus patients in the comparator arm (78.8% vs. 47.1%, p=0.0010) with culture conversion more likely to persist by Month 7.
Of those patients who achieved culture conversion by Month 6, more patients in the ARIKAYCE arm achieved culture conversion by Month 1 versus the comparator arm (74.3% vs. 46.7%, respectively) and median time to first culture conversion event was 1.0 month in the ARIKAYCE arm and 2.0 months in the comparator arm. Notably, no patients in this study developed a MAC isolate with resistance to ARIKAYCE and/or macrolide.
"These findings are very important given that NTM lung disease is a challenging and complex disease to treat with limited therapeutic options. Based on the positive results from ARISE, I look forward to seeing the results from the ongoing Phase 3 registrational study ENCORE and the impact they may have on the NTM patient community," said lead study investigator
The discontinuation rate of ARIKAYCE or the placebo used in the comparator arm was 22.9% in the ARIKAYCE arm and 7.8% in the comparator arm. Study completion rates were 91.7% in the ARIKAYCE arm and 94.1% in the comparator arm. No new safety signals were observed in the ARIKAYCE arm, and the safety profile in general was as expected in both treatment arms. Treatment-emergent adverse events (TEAEs) were reported by 91.7% of patients in the ARIKAYCE arm and 80.4% of patients in the comparator arm. The most common TEAEs were dysphonia (41.7% for the ARIKAYCE arm vs. 3.9% for the comparator arm), cough (27.1% vs. 7.8%), diarrhea (27.1% vs. 25.5%), and COVID-19 (12.5% vs. 9.8%). Of the treatment-emergent serious adverse events observed in the trial, none were determined to be related to ARIKAYCE and none were deemed related to COVID-19.
In addition to the ARISE results, the following
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About the ARISE & ENCORE Clinical Trial Program
ARIKAYCE was granted accelerated approval by the FDA in September of 2018 for the treatment of MAC lung disease as part of a combination antibacterial drug regimen for adult patients who have limited or no alternative treatment options. It is the first and only therapy approved in the
ARISE was a global, randomized, double-blind, placebo-controlled, Phase 3b study in adult patients with newly diagnosed or recurrent MAC lung disease who had not received antibiotics for their current infection that aimed to generate evidence demonstrating the domain specification, reliability, validity, and responsiveness of PRO-based scores. Patients were randomized 1:1 to receive ARIKAYCE plus background regimen or placebo plus background regimen once daily for six months. Patients then discontinued all study treatments and remained in the trial for one month for the continued assessment of PRO endpoints. The study enrolled 99 patients.
The ongoing ENCORE trial is a randomized, double-blind, placebo-controlled, Phase 3b study to evaluate the efficacy and safety of an ARIKAYCE-based regimen in patients with newly diagnosed or recurrent MAC lung disease who have not started antibiotics. Patients are randomized 1:1 to receive ARIKAYCE plus background regimen or placebo plus background regimen once daily for 12 months. Patients will then discontinue all study treatments and remain in the trial for three months for the assessment of durability of culture conversion. The primary endpoint is change from Baseline to Month 13 in respiratory symptom score. The key secondary endpoint is the proportion of patients achieving durable culture conversion at Month 15.
About ARIKAYCE
ARIKAYCE is approved in
About PARI Pharma and the Lamira® Nebulizer System
ARIKAYCE is delivered by a novel inhalation device, the Lamira® Nebulizer System, developed by PARI. Lamira® is a quiet, portable nebulizer that enables efficient aerosolization of ARIKAYCE via a vibrating, perforated membrane. Based on PARI's 100-year history working with aerosols, PARI is dedicated to advancing inhalation therapies by developing innovative delivery platforms to improve patient care.
About Brensocatib
Brensocatib is a small molecule, oral, reversible inhibitor of dipeptidyl peptidase 1 (DPP1) being developed by
IMPORTANT SAFETY INFORMATION AND BOXED WARNING FOR ARIKAYCE IN THE
WARNING: RISK OF INCREASED RESPIRATORY ADVERSE REACTIONS
ARIKAYCE has been associated with an increased risk of respiratory adverse reactions, including hypersensitivity pneumonitis, hemoptysis, bronchospasm, and exacerbation of underlying pulmonary disease that have led to hospitalizations in some cases. |
Hypersensitivity Pneumonitis has been reported with the use of ARIKAYCE in the clinical trials. Hypersensitivity pneumonitis (reported as allergic alveolitis, pneumonitis, interstitial lung disease, allergic reaction to ARIKAYCE) was reported at a higher frequency in patients treated with ARIKAYCE plus background regimen (3.1%) compared to patients treated with a background regimen alone (0%). Most patients with hypersensitivity pneumonitis discontinued treatment with ARIKAYCE and received treatment with corticosteroids. If hypersensitivity pneumonitis occurs, discontinue ARIKAYCE and manage patients as medically appropriate.
Hemoptysis has been reported with the use of ARIKAYCE in the clinical trials. Hemoptysis was reported at a higher frequency in patients treated with ARIKAYCE plus background regimen (17.9%) compared to patients treated with a background regimen alone (12.5%). If hemoptysis occurs, manage patients as medically appropriate.
Bronchospasm has been reported with the use of ARIKAYCE in the clinical trials. Bronchospasm (reported as asthma, bronchial hyperreactivity, bronchospasm, dyspnea, dyspnea exertional, prolonged expiration, throat tightness, wheezing) was reported at a higher frequency in patients treated with ARIKAYCE plus background regimen (28.7%) compared to patients treated with a background regimen alone (10.7%). If bronchospasm occurs during the use of ARIKAYCE, treat patients as medically appropriate.
Exacerbations of underlying pulmonary disease has been reported with the use of ARIKAYCE in the clinical trials. Exacerbations of underlying pulmonary disease (reported as chronic obstructive pulmonary disease (COPD), infective exacerbation of COPD, infective exacerbation of bronchiectasis) have been reported at a higher frequency in patients treated with ARIKAYCE plus background regimen (14.8%) compared to patients treated with background regimen alone (9.8%). If exacerbations of underlying pulmonary disease occur during the use of ARIKAYCE, treat patients as medically appropriate.
Anaphylaxis and Hypersensitivity Reactions: Serious and potentially life-threatening hypersensitivity reactions, including anaphylaxis, have been reported in patients taking ARIKAYCE. Signs and symptoms include acute onset of skin and mucosal tissue hypersensitivity reactions (hives, itching, flushing, swollen lips/tongue/uvula), respiratory difficulty (shortness of breath, wheezing, stridor, cough), gastrointestinal symptoms (nausea, vomiting, diarrhea, crampy abdominal pain), and cardiovascular signs and symptoms of anaphylaxis (tachycardia, low blood pressure, syncope, incontinence, dizziness). Before therapy with ARIKAYCE is instituted, evaluate for previous hypersensitivity reactions to aminoglycosides. If anaphylaxis or a hypersensitivity reaction occurs, discontinue ARIKAYCE and institute appropriate supportive measures.
Ototoxicity has been reported with the use of ARIKAYCE in the clinical trials. Ototoxicity (including deafness, dizziness, presyncope, tinnitus, and vertigo) were reported with a higher frequency in patients treated with ARIKAYCE plus background regimen (17%) compared to patients treated with background regimen alone (9.8%). This was primarily driven by tinnitus (7.6% in ARIKAYCE plus background regimen vs 0.9% in the background regimen alone arm) and dizziness (6.3% in ARIKAYCE plus background regimen vs 2.7% in the background regimen alone arm). Closely monitor patients with known or suspected auditory or vestibular dysfunction during treatment with ARIKAYCE. If ototoxicity occurs, manage patients as medically appropriate, including potentially discontinuing ARIKAYCE.
Nephrotoxicity was observed during the clinical trials of ARIKAYCE in patients with MAC lung disease but not at a higher frequency than background regimen alone. Nephrotoxicity has been associated with the aminoglycosides. Close monitoring of patients with known or suspected renal dysfunction may be needed when prescribing ARIKAYCE.
Neuromuscular Blockade: Patients with neuromuscular disorders were not enrolled in ARIKAYCE clinical trials. Patients with known or suspected neuromuscular disorders, such as myasthenia gravis, should be closely monitored since aminoglycosides may aggravate muscle weakness by blocking the release of acetylcholine at neuromuscular junctions.
Embryo-Fetal Toxicity: Aminoglycosides can cause fetal harm when administered to a pregnant woman. Aminoglycosides, including ARIKAYCE, may be associated with total, irreversible, bilateral congenital deafness in pediatric patients exposed in utero. Patients who use ARIKAYCE during pregnancy, or become pregnant while taking ARIKAYCE should be apprised of the potential hazard to the fetus.
Contraindications: ARIKAYCE is contraindicated in patients with known hypersensitivity to any aminoglycoside.
Most Common Adverse Reactions: The most common adverse reactions in Trial 1 at an incidence ≥5% for patients using ARIKAYCE plus background regimen compared to patients treated with background regimen alone were dysphonia (47% vs 1%), cough (39% vs 17%), bronchospasm (29% vs 11%), hemoptysis (18% vs 13%), ototoxicity (17% vs 10%), upper airway irritation (17% vs 2%), musculoskeletal pain (17% vs 8%), fatigue and asthenia (16% vs 10%), exacerbation of underlying pulmonary disease (15% vs 10%), diarrhea (13% vs 5%), nausea (12% vs 4%), pneumonia (10% vs 8%), headache (10% vs 5%), pyrexia (7% vs 5%), vomiting (7% vs 4%), rash (6% vs 2%), decreased weight (6% vs 1%), change in sputum (5% vs 1%), and chest discomfort (5% vs 3%).
Drug Interactions: Avoid concomitant use of ARIKAYCE with medications associated with neurotoxicity, nephrotoxicity, and ototoxicity. Some diuretics can enhance aminoglycoside toxicity by altering aminoglycoside concentrations in serum and tissue. Avoid concomitant use of ARIKAYCE with ethacrynic acid, furosemide, urea, or intravenous mannitol.
Overdosage: Adverse reactions specifically associated with overdose of ARIKAYCE have not been identified. Acute toxicity should be treated with immediate withdrawal of ARIKAYCE, and baseline tests of renal function should be undertaken. Hemodialysis may be helpful in removing amikacin from the body. In all cases of suspected overdosage, physicians should contact the
LIMITED POPULATION: ARIKAYCE® is indicated in adults, who have limited or no alternative treatment options, for the treatment of Mycobacterium avium complex (MAC) lung disease as part of a combination antibacterial drug regimen in patients who do not achieve negative sputum cultures after a minimum of 6 consecutive months of a multidrug background regimen therapy. As only limited clinical safety and effectiveness data for ARIKAYCE are currently available, reserve ARIKAYCE for use in adults who have limited or no alternative treatment options. This drug is indicated for use in a limited and specific population of patients.
This indication is approved under accelerated approval based on achieving sputum culture conversion (defined as 3 consecutive negative monthly sputum cultures) by Month 6. Clinical benefit has not yet been established. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials.
Limitation of Use : ARIKAYCE has only been studied in patients with refractory MAC lung disease defined as patients who did not achieve negative sputum cultures after a minimum of 6 consecutive months of a multidrug background regimen therapy. The use of ARIKAYCE is not recommended for patients with non-refractory MAC lung disease.
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