Full Press Release Details
INSMED ANNOUNCES POSITIVE TOPLINE RESULTS FROM PHASE 3 ARISE STUDY OF ARIKAYCE (AMIKACIN LIPOSOME INHALATION SUSPENSION) IN PATIENTS WITH NTM LUNG
DISEASE CAUSED BY MAC
-QOL-B Respiratory Domain Shown to Work Effectively as Patient-Reported Outcome Tool in Patients with MAC Lung Disease; to be Proposed to FDA as Primary Endpoint in ENCORE with
-Patients Treated with ARIKAYCE Plus Macrolide-Based Background Regimen Had
Meaningfully Larger Improvements in QOL-B Respiratory Score with Strong Trend Toward Significance vs. Macrolide-Based Background Regimen Alone-
-ARIKAYCE-Treated Patients Had Nominally Statistically
Significantly Higher Culture Conversion Rates at Month 7 vs. Comparator (78.8% vs. 47.1%, p=0.0010); Culture Conversion Began Earlier and Was More Likely to Persist Through Month 7 with ARIKAYCE Regimen-
-No New or Unexpected Safety Signals Observed-
-Insmed to Explore Accelerating Filing for ARIKAYCE in Newly Infected MAC Lung Disease Patients with Global Regulators on Basis of ARISE Data-
-Insmed to Host Investor Call at 8:30 a.m. ET on Tuesday, September 5-
BRIDGEWATER, N.J., Sept. 5, 2023 /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 positive topline results from its Phase 3 ARISE study of ARIKAYCE in patients with newly diagnosed or recurrent nontuberculous mycobacterial (NTM) lung infection caused by Mycobacterium avium complex (MAC) who had not started antibiotics.
The study met its primary objective of demonstrating that the Quality of Life - Bronchiectasis (QOL-B) respiratory domain works effectively as a patient-reported outcome (PRO) instrument
in patients with MAC lung disease. Based on these results, Insmed plans to propose to the U.S. Food and Drug Administration (FDA) that the QOL-B respiratory domain PRO be the primary endpoint for the ENCORE study without any modifications.
Patients in ARISE (N=99) were randomized 1:1 to treatment with ARIKAYCE plus macrolide-based background regimen (ARIKAYCE arm) or placebo plus macrolide-based background regimen
(comparator arm) for six months, followed by one month off treatment. ARIKAYCE-treated patients performed better than those in the comparator arm as measured by the QOL-B instrument, with 43.8% of patients achieving an improvement in QOL-B
respiratory score above 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 (12.24 vs. 7.76, p=0.1073).
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), and culture conversion was faster and more likely to persist through Month 7 for the ARIKAYCE arm.
"The ARISE study represents a clear and unambiguous win for the entire NTM community. We are thrilled that these results not only validate a PRO tool in NTM lung disease, but also show
that patients treated with an ARIKAYCE-based regimen felt better versus patients in the comparator arm, as measured by this instrument. Coupled with extraordinary culture conversion outcomes, these findings give us great confidence that our Phase 3
registrational trial, ENCORE, is well-positioned to achieve both statistically and clinically meaningful results, leading to a sizeable increase in the number of patients who could hope to benefit from ARIKAYCE," said Martina Flammer, M.D., MBA,
Chief Medical Officer of Insmed.
Based on the results of ARISE, Insmed plans to explore with global regulators accelerating the filing for approval of ARIKAYCE in newly infected patients with MAC lung disease. In parallel, the Company continues to enroll patients in ENCORE, which will use the PRO tool that has been validated in ARISE, with 250 patients expected to be enrolled by the end of 2023. Enrollment in ENCORE is expected to continue into 2024 to ensure a high degree of statistical
powering and Insmed anticipates reporting topline data from ENCORE in 2025.
"I want to thank the many patients, caregivers, and investigators who participated in ARISE and made this impressive outcome possible. We look forward to discussing these excellent results
from this well-executed study in the near future with regulators," noted Kevin Mange, M.D., M.S.C.E., Chief Development Officer of Insmed.
Additional ARISE Study Findings
Insmed reported the following additional results from the ARISE study:
Consistent with prior clinical studies, a higher proportion of patients in the ARIKAYCE arm achieved culture
conversion by Month 6 (defined as negative cultures at Months 5 and 6) compared to patients in the comparator arm (80.6% vs. 63.9%, p=0.0712). Among patients who achieved
culture conversion by Month 6, more patients in the ARIKAYCE arm achieved the first of their two required monthly negative cultures for clinical conversion at Month 1 versus
the comparator arm (74.3% vs. 46.7%). As reported above, at Month 7 (one month following the cessation of treatment), 47.1% of patients in the comparator arm were culture-converted vs. 78.8% of patients in the ARIKAYCE arm, suggesting that
ARIKAYCE-treated patients are more likely to remain negative.
Correlation Between Culture Conversion and QOL-B Performance
Patients in the ARIKAYCE arm who achieved culture conversion at both Month 6 and Month 7 had nominally statistically significantly greater improvements in QOL-B
respiratory domain scores at Month 7 compared to patients in the ARIKAYCE arm who did not achieve culture conversion (15.74 vs. 3.53, p=0.0167 at Month 6 and 14.89 vs. 4.50, p=0.0416 at Month 7).
PROMIS Fatigue-Short Form 7a
The Patient-Reported Outcome Measurement Information System (PROMIS) Fatigue-Short Form 7a was also assessed in the study. While both treatment arms showed improvements in the PROMIS
Fatigue scores from Baseline to Month 7, the difference between treatment groups was not significant, with 35.5% of ARIKAYCE patients achieving a within-subject meaningful difference of at least a 4-unit decrease (a negative change signifies
improvement) compared to 29.4% of subjects in the comparator arm. As previously noted, the study was not powered to show a statistically significant difference between treatment arms.
Safety and Tolerability
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 events 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 by investigators and none were deemed related to COVID-19.
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 U.S. for the treatment of MAC lung disease. The ARISE and ENCORE clinical trial program is intended to fulfill the FDA's post-marketing requirement
to allow for full approval of ARIKAYCE in the U.S. and to support a supplemental new drug application for the use of ARIKAYCE as a treatment for patients with a MAC lung infection.
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 started antibiotics 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 the Validation of PRO Tools in MAC Lung Disease
Today, there are no established clinical endpoints to evaluate the benefits of treatment in patients with MAC lung disease. The QOL-B instrument is a self-administered PRO questionnaire
used to assess symptoms, functioning, and health-related quality of life in adults with non-cystic fibrosis bronchiectasis. Insmed's clinical trial program to establish that the Respiratory Symptom Domain of the QOL-B is reliable for measuring
respiratory symptoms in patients with MAC lung disease generated evidence to support content validity based on concept elicitation and cognitive interviews with patients, and generated evidence to support measurement properties based on
cross-sectional analyses using screening and baseline blinded data from both ARISE and a subset of patients from ENCORE (first 131 patients enrolled). Longitudinal analyses were based on ARISE data. Researchers used the Patient Global Impression of
Severity (PGI-S) questionnaire, a simple, one-question categorical rating of symptom severity, as an anchor to estimate a range of meaningful within-subject score differences. The PROMIS Fatigue Short Form 7a was also evaluated in this clinical
trial program using an identical approach.
Insmed management will host a conference call for investors beginning at 8:30 a.m. ET on Tuesday, September 5, 2023, to discuss the ARISE results. Shareholders and other interested
parties may participate in the conference call by dialing (888) 210-2654 (U.S. and international) and referencing access code 7862189. The call will also be webcast live on the Company's website at www.insmed.com.
A replay of the conference call will be accessible approximately one hour after its completion through October 5, 2023, by dialing (800) 770-2030 (U.S. and international) and referencing
access code 7862189. A webcast of the call will also be archived for 90 days under the Investor Relations section of the Company's website at www.insmed.com.
About MAC Lung Disease
Mycobacterium avium complex (MAC) lung disease is a rare and
serious disorder that can significantly increase morbidity and mortality. Patients with MAC lung disease can experience a range of symptoms that often worsen over time, including chronic cough, dyspnea, fatigue, fever, weight loss, and chest
pain. In some cases, MAC lung disease can cause severe, even permanent damage to the lungs, and can be fatal. MAC lung disease is an emerging public health concern worldwide with significant unmet need.
ARIKAYCE is approved in the United States as ARIKAYCE (amikacin liposome inhalation suspension), in Europe as ARIKAYCE Liposomal 590 mg Nebuliser Dispersion, and in
Japan as ARIKAYCE inhalation 590 mg (amikacin sulfate inhalation drug product). Current international treatment guidelines recommend the use of ARIKAYCE for appropriate patients. ARIKAYCE is a novel, inhaled, once-daily formulation of
amikacin, an established antibiotic that was historically administered intravenously and associated with severe toxicity to hearing, balance, and kidney function. Insmed's proprietary PULMOVANCE liposomal technology enables the delivery
of amikacin directly to the lungs, where liposomal amikacin is taken up by lung macrophages where the infection resides, while limiting systemic exposure. ARIKAYCE is administered once daily using the Lamira Nebulizer System
manufactured by PARI Pharma GmbH (PARI).
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.
IMPORTANT SAFETY INFORMATION FOR ARIKAYCE IN THE U.S.
| 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