Insmed (INSM) Announces Publication of ARIKAYCE Phase 2 Data in NTM Lung Disease; Primary Endpoint Missed

October 18, 2016 8:11 AM EDT

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Insmed Incorporated (Nasdaq: INSM) announced the online publication of data from its phase 2 study of ARIKAYCE™ (liposomal amikacin for inhalation or LAI) in the American Journal of Respiratory and Critical Care Medicine. ARIKAYCE is a novel formulation of amikacin administered once-daily using an optimized eFlow® Electronic Nebulizer (PARI Pharma GmbH). ARIKAYCE is being studied in treatment-refractory nontuberculous mycobacterial (NTM) lung disease.

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 Eugene Sullivan, MD, chief medical officer of Insmed. “Current treatment options are not approved for pulmonary NTM and are limited to lengthy multi-drug regimens that are associated with intolerance, treatment failures, and problematic multi-drug interactions. The novel drug formulation of liposomal amikacin for inhalation delivers high levels of a potent aminoglycoside directly to the lung macrophages where the infection resides. There is an important unmet need among patients with refractory NTM lung disease and data from this phase 2 study suggest that liposomal amikacin could be a treatment option.”

Insmed’s clinical development program in refractory NTM lung disease represents the largest and most comprehensive program conducted to date. Insmed has received multiple designations for ARIKAYCE from the U.S. Food and Drug Administration (FDA) for the treatment of NTM, including: orphan, breakthrough therapy, Qualified Infectious Disease Product (QIDP), and Fast Track status. Products in development under QIDP status gain certain incentives if they are approved by the FDA, which include a five-year extension of data exclusivity provisions and priority review of its NDA. Fast Track status is intended to facilitate development and expedite review of drugs to treat serious and life-threatening conditions.

Study Design

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 American Thoracic Society/Infectious Disease Society of America (ATS/IDSA) guideline therapy for at least six months prior to screening and to have had persistently positive mycobacterial cultures. The study included an 84-day double-blind phase in which subjects were randomized 1:1 either to ARIKAYCE once-daily plus a multi-drug regimen or to placebo once-daily plus a multi-drug regimen. After completing the 84-day double-blind phase, subjects had the option of continuing in an 84-day open-label phase during which all subjects received ARIKAYCE plus a multi-drug regimen. The study also included 28-day and 12-month off-ARIKAYCE follow-up assessments.

Study Results

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.

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