The phase 2 study evaluated ARIKAYCE in patients with nontuberculous mycobacterial lung infections who had been unable to achieve culture conversion to negative despite receiving a multi-drug guideline-based regimen for six or more months. Although the primary endpoint was not reached, data from the study suggest that the addition of ARIKAYCE to the guideline-based multi-drug regimen can achieve early and sustained negative sputum cultures. In addition, culture conversion resulting from ARIKAYCE plus multi-drug treatment was associated with improvements in the six-minute walk test. ARIKAYCE is currently being evaluated in a global phase 3 randomized open-label clinical study designed to evaluate the culture conversion results observed in the phase 2 clinical study. The phase 3 study, which is known as the CONVERT study, is enrolling adult non-cystic fibrosis patients with an NTM lung infection caused by Mycobacterium avium complex (MAC).
"Pulmonary nontuberculous mycobacterial disease is a chronic, progressive infection associated with irreversible lung damage and mortality," said
Insmed's clinical development program in refractory NTM lung disease represents the largest and most comprehensive program conducted to date.
The phase 2 study was a randomized, double-blind, placebo-controlled study that evaluated the efficacy and safety of ARIKAYCE in adults with NTM lung disease due to MAC or Mycobacterium abscessus (M. abscessus) that was refractory to guideline-based therapy. Eligibility for the study required patients to have been on the
Eighty-nine subjects were randomized and dosed in the study. Of the 80 subjects who completed the 84-day double-blind phase, 78 subjects entered the open-label phase during which all patients received ARIKAYCE plus a multi-drug regimen for 84 days. Seventy-six (76) percent (59/78) of subjects who entered the open-label phase of the study completed the open-label study.
The primary efficacy endpoint of the study was the change from baseline (day 1) to the end of the double-blind phase of the trial (day 84) in a semi-quantitative measurement of mycobacterial density on a seven-point scale. The primary endpoint did not reach statistical significance; however, a positive numerical trend in favor of ARIKAYCE was observed (p=0.072). The p-value for the key secondary endpoint of culture conversion to negative at Day 84 was 0.003, in favor of ARIKAYCE. A shorter time to first negative sputum culture was also observed with ARIKAYCE relative to placebo during the double-blind phase (p=0.013).
The microbiologic outcomes from the study were also explored post hoc using a more stringent definition of culture conversion, which is defined as at least three consecutive monthly sputum samples that test negative for NTM. This definition of culture conversion is in the guidelines and used in clinical practice.
Twenty-three subjects achieved at least three consecutive negative monthly sputum samples by the 28-day follow-up assessment, of which four started to convert at baseline prior to administration of study drug. For the 19 patients who achieved culture conversion, 17 achieved culture conversion after receiving ARIKAYCE, 10 who were randomized to ARIKAYCE in the double-blind phase and seven after entering the open-label phase. Two patients achieved culture conversion while receiving placebo in the double-blind phase.
The majority of patients who achieved culture conversion (three consecutive negative monthly sputum samples) during the double-blind phase continued to have negative cultures through the open-label and follow-up phases.
At the end of the double-blind phase, the ARIKAYCE group improved from baseline in mean distance walked in the six-minute walk test. At the end of the open-label phase, patients in the ARIKAYCE group continued to improve in the mean distance walked in the six-minute walk test while the patients who previously received placebo in the double-blind phase and subsequently received ARIKAYCE in the open-label phase demonstrated a reduced rate of decline from baseline.
The majority (90 percent) of patients in both treatment groups experienced at least one treatment-emergent adverse event with most events either mild or moderate in severity. During the double-blind phase a greater percentage of patients treated with ARIKAYCE experienced dysphonia, bronchiectasis exacerbation, cough, oropharyngeal pain, fatigue, chest discomfort, wheezing, and infective pulmonary exacerbation of cystic fibrosis. No clinically relevant changes were detected in laboratory values and vital signs.
About Nontuberculous Mycobacteria Lung Disease
NTM is a rare and serious disorder associated with increased morbidity and mortality. There is an increasing rate of lung disease caused by NTM and this is an emerging public health concern worldwide. Patients with NTM lung disease may experience a multitude of symptoms such as fever, weight loss, cough, lack of appetite, night sweats, blood in the sputum, and fatigue. Patients with NTM lung disease frequently require lengthy hospital stays to manage their condition. There are no products specifically indicated for the treatment of NTM lung disease in the US,
The prevalence of human disease attributable to NTM has increased over the past two decades. In a decade long study (1997 to 2007), researchers found that the prevalence of NTM in the US is increasing at approximately 8% per year and that NTM patients on
For more information about NTM lung disease, visit NTMfacts.com.
ARIKAYCE, or liposomal amikacin for inhalation, is a novel, once daily formulation of amikacin that is in late-stage clinical development for patients with NTM lung disease. Amikacin solution for parenteral administration is an established drug that is effective against a variety of NTM; however, its use is limited by the need to administer it intravenously and by toxicity to hearing, balance, and kidney function. Insmed's advanced pulmonary liposome technology uses charge neutral liposomes to deliver amikacin directly to the lung where it is taken up by the lung macrophages where the NTM infection resides. This prolongs the release of amikacin in the lungs while minimizing systemic exposure thereby offering the potential for decreased systemic toxicities. ARIKAYCE's ability to deliver high levels of amikacin directly to the lung distinguishes it from intravenous amikacin. ARIKAYCE is administered once daily using an optimized, investigational eFlow® Nebulizer System manufactured by
About PARI Pharma and the eFlow® Electronic Nebulizer
Arikayce is delivered by a novel, inhalation device, the eFlow® Electronic Nebulizer, developed by
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