Insmed Incorporated (Nasdaq GS:INSM) today reported results from the Company's phase 2 clinical trial of ARIKAYCETM, or liposomal amikacin for inhalation, for the treatment of patients with treatment resistant nontuberculous mycobacterial (NTM) lung infections. The randomized, double-blind, placebo-controlled phase 2 clinical trial compared ARIKAYCE (590 mg delivered once daily), added to standard of care treatment, versus standard of care treatment plus placebo, in 90 adult patients with treatment resistant NTM lung disease. 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 continue to have persistently positive mycobacterial cultures.
The primary efficacy endpoint of the study was a semi-quantitative measurement of the change in mycobacterial density on a seven-point scale from baseline (day one) to the end of the randomized portion of the trial (day 84). ARIKAYCE did not meet the pre-specified level for statistical significance although there was a positive trend (p=0.148) in favor of ARIKAYCE. However, ARIKAYCE did achieve statistical significance with regard to the clinically relevant key secondary endpoint of culture conversion, with 11 out of 44 patients treated with ARIKAYCE (added to standard of care treatment) demonstrating negative cultures by day 84 of the study as compared to 3 out of 45 patients treated with placebo (added to standard of care treatment) (p=0.01).
Patients receiving ARIKAYCE experienced a greater number of adverse events than those receiving placebo. All adverse events experienced with ARIKAYCE were consistent with those seen in similar patient populations receiving inhaled antibiotics. The most common side effect was laryngeal irritation.
The Company plans to incorporate these results into discussions with the regulatory agencies in the United States and Europe to determine next steps for ARIKAYCE. The Company also intends to apply for Breakthrough Therapy Designation for ARIKAYCE in the United States based upon the culture conversion results. ARIKAYCE has already received Orphan Drug, Qualified Infectious Disease Product (QIDP) and Fast Track designations from the U.S. Food and Drug Administration (FDA) for the treatment of NTM lung infections and recently received Orphan Drug Designation from the European Medicines Agency (EMA).
"The results relating to the key secondary endpoint of culture conversion are encouraging, and I believe demonstrate that ARIKAYCE has the potential to be an option for treating even the most difficult treatment resistant patients with NTM lung infections," said David Griffith, M.D., Professor of Medicine, W.A and E. B. Moncrief Distinguished Professor at The University of Texas Health Sciences Center and a co-Principal Investigator on the study.
"We are encouraged by the achievement of culture conversion in this trial, which we believe is the ultimate goal in the treatment of mycobacterial infections," said Dr. Renu Gupta, Executive Vice President, Development and Chief Medical Officer of Insmed. "The design of this trial was such that the patients who entered the trial and received drug were clearly resistant to guideline therapy, making them the most treatment-challenged NTM patients. Therefore the hurdle for showing any improvement with a therapy is extremely high."
"While ARIKAYCE did not achieve statistical significance on the primary endpoint of bacterial density reduction, we are very pleased by the greater number of culture conversions among patients receiving ARIKAYCE," stated Will Lewis, President and Chief Executive Officer of Insmed. "We now look forward to the regulatory discussions in the US and Europe that will guide our path forward."
"We extend our gratitude to the investigators and their patients who participated in this study," concluded Mr. Lewis.
The objective of the primary endpoint was to show a reduction in the density of bacteria of at least one step along a seven point scale as a means of identifying whether a trend suggestive of ultimate culture conversion could be established. The number of patients showing at least a one-step reduction in the treatment arm versus those in the placebo arm was not statistically significants primary endpoint was not culture conversion because it was assumed that culture conversion would not be achievable in 84 days treatment, particularly given the severe, treatment-resistant patient population that was the subject of this study.
ARIKAYCE achieved statistical significance with regard to the secondary outcome of culture conversion, with 11 out of 44 patients treated with ARIKAYCE demonstrating negative cultures by day 84 of the study as compared to 3 out of 45 patients treated with placebo arm (standard of care therapy only)>
Patients receiving ARIKAYCE experienced adverse events consistent with those seen in similar patient populations receiving inhaled antibiotics. Overall, mild to moderate throat irritation was more common in the ARIKAYCE arm compared to the placebo arm. One Suspected Unexpected Serious Adverse Reaction (SUSAR) was observed in the ARIKAYCE arm, but there was no difference in severe serious adverse reactions or hemoptysis between the two arms. Instances of hearing loss or tinnitus, a side effect more commonly associated with intravenous dosing of amikacin, were evenly balanced between the ARIKAYCE and placebo arms. The study population was chronically ill with a mean age of 61.
Clinical Trial Design
Mycobacterial density is a measurement currently used in clinical practice to assess the progress or decline of those patients with recalcitrant NTM. Following the randomized portion of the study, all eligible patients had the option to receive ARIKAYCE once daily for an additional 84 days in an open-label design.
Patients in the trial were stratified for either Mycobacterium avium complex (MAC) infections or Mycobacterium abscessus infections. These pathogens collectively account for approximately 85% of all patients with NTM lung disease in the U.S. Stratification was also performed based on patients with cystic fibrosis versus those who do not have cystic fibrosis.