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Background Analysis: US FDA Advisory Committee to Review Insmed’s Amikacin for the Treatment of Nontuberculous Mycobacterial Lung Disease – AUG 7, 2018 (AMDAC)

Announcement

The US FDA has scheduled an Antimicrobial Drugs Advisory Committee (AMDAC) meeting for Tuesday, August 7, 2018 to a discuss a new drug application (NDA) for amikacin liposome inhalation suspension, sponsored by Insmed, Inc. (Insmed), for the proposed indication of treatment of nontuberculous mycobacterial (NTM) lung disease caused by Mycobacterium avium complex in adults, as part of a combination antibacterial drug regimen.

Indication Background

Description of Indication

NTM lung disease that is caused by Mycobacterium avium complex (MAC) is a rare and serious disease that can be fatal. Symptoms of the disease include fever, weight loss, cough, lack of appetite, night sweats, blood in the sputum, and fatigue. Patients often require treatment in a hospital setting.

In the US, Insmed estimates there will be between 75,000 and 105,000 patients with diagnosed NTM lung disease in 2018, of which the Company expects 40,000 to 50,000 will be treated for NTM lung disease caused by MAC.  Insmed expects that between 10,000 and 15,000 of these patients will be refractory to treatment.  In Japan, Insmed estimates there will be between 125,000 and 145,000 patients with diagnosed NTM lung disease in 2018, with approximately 60,000 to 70,000 of those patients being treated for NTM lung disease caused by MAC and 15,000 to 18,000 of these treated patients being refractory to treatment. Insmed also estimates there will be approximately 14,000 patients with diagnosed NTM lung disease in the EU5 (comprised of France, Germany, Italy, Spain, and the United Kingdom) in 2018, of which the Company estimates approximately 4,400 will be treated for NTM lung disease caused by MAC and approximately 1,400 of these treated patients will be refractory to treatment. 

Product Background

Description of Product

Amikacin liposome inhalation suspension (ALIS) is a novel, inhaled, once-daily formulation of the aminoglycoside drug amikacin. ALIS was designed to be administered once daily using an investigational eFlow® Nebulizer System, a portable aerosol delivery system manufactured by PARI Pharma GmbH (PARI).. Another formulation of amikacin, an amikacin solution for intravenous (IV) administration, is already FDA-approved for the treatment of certain serious infections. The IV formulation carries a Boxed Warning for neurologic and renal toxicity.

Insmed's liposome technology is intended to deliver amikacin directly to the lung where it is taken up by the lung macrophages where the NTM infection resides. This system aims to extend the release of amikacin in the lungs while minimizing systemic exposure, thereby potentially decreasing systemic toxicities.

 Clinical Trials of Proposed Indication

The NDA is based primarily on the results of a phase 2 trial named INS-212 and a phase 3 trial named CONVERT. Comprehensive data from the clinical development program (CDP) for ALIS, including detailed analyses by the Company and by the FDA, will be presented in briefing materials that will be posted ahead of the meeting. The briefing materials for the meeting will be summarized on the day they are posted, in our subsequent report, the Briefing Summary. Presented below are top-line results from the INS-212 and CONVERT trials based on press releases made by Insmed.

INS-212 (Clinicaltrials.Gov Identifier: NCT01315236)

Results of the INS-212 trial were announced by Insmed in October 2016. Although the primary endpoint was not met, the Company asserted their analysis of the trial data nonetheless suggests benefits of treatment with ALIS use. The trial evaluated the drug’s use in adults with NTM lung disease due to MAC or Mycobacterium abscessus (M. abscessus) that was refractory to Guideline-Based Therapy (GBT) established by American Thoracic Society and the Infectious Disease Society of America (ATS/IDSA). Eligibility for the trial required patients to have been on ATS/IDSA GBT for at least six months prior to screening and to have had persistently positive mycobacterial cultures.

The trial included an 84-day double-blind phase in which subjects were randomized 1:1 either to ALIS once-daily plus GBT or to placebo once-daily plus GBT. 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 ALIS plus GBT. The trial also included 28-day and 12-month off-ALIS follow-up assessments.

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 ALIS plus GBT 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, Insmed says a positive numerical trend in favor of ALIS 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 ALIS. A shorter time to first negative sputum culture was also observed with ALIS 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. Insmed notes that this definition of culture conversion is in relevant guidelines and used in clinical practice. This outcome was later used as the primary endpoint in the subsequent phase 3 trial named CONVERT.

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 ALIS, 10 who were randomized to ALIS 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, Insmed reports that the ALIS 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 ALIS 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 ALIS 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 ALIS 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.

CONVERT (Clinicaltrials.Gov Identifier: NCT02344004)

The CONVERT trial was an open-label, Phase 3 trial that enrolled 336 adult patients with NTM lung disease caused by MAC who were refractory to at least six months of GBT. Patients were randomized 2:1 to receive ALIS plus GBT versus GBT alone. The primary endpoint was the proportion of patients achieving culture conversion by Month 6 (defined as 3 consecutive negative monthly sputum cultures).

Insmed has reported that the CONVERT trial met its primary endpoint of culture conversion by Month 6 with statistical significance. In particular, the Company has reported that the addition of ALIS to GBT eliminated evidence of NTM lung disease caused by MAC in sputum by Month 6 in 29% of patients, compared to 9% of patients on GBT alone (p < 0.0001). The trial was powered to detect a treatment effect of 15% between the two treatment groups.

Insmed has also reported top-line data for several secondary endpoints, including the 6-month timepoint. Although top-line data for the 6-minute walk test indicates no statistically significant difference between patients in the two arms, the Company says an analysis of these data (per a pre-specified endpoint) shows that patients who achieved culture conversion in either arm demonstrated an improvement in 6-minute walk distance when compared to patients who did not culture convert (p=0.0108). Top-line data for the secondary endpoint of time to conversion demonstrated that patients on GBT took approximately 30% longer to convert when compared to patients on ALIS plus GBT (p < 0.0001). The Company is continuing its analysis of the impact of conversion on a variety of other clinical measures.

In the study, serious treatment emergent adverse events were similar between treatment arms. There were no distinctions between treatment arms due to hearing loss or renal impairment, side effects commonly associated with IV use of amikacin. The overall dropout rate was 16.1%, with an 8.9% dropout rate in the GBT arm and a 19.6% rate in the ALIS plus GBT arm. Overall, the rate of reported adverse events in the ALIS plus GBT arm was higher, and these events were predominately mild or moderate in nature and generally declined after the second month of treatment. The Company says these findings are consistent with the Phase 2 study results and demonstrate adverse events similar to those seen in other clinical studies of inhaled antibiotics.

Regulatory Background

US Regulatory Background

September 28, 2018 – PDUFA date

March 29, 2018 – Insmed announced the submission of the NDA (NDA 207356),

Priority Review

Ex-US Regulatory Background

Insmed appears to be planning to submit marketing applications for ALIS in the EU and Japan.

What’s Next?

Tarius will send a Briefing Summary after briefing materials are posted to FDA’s website (typically within 2 days of the meeting). This report will provide a summary of the FDA and the Sponsor’s briefing materials.

Tarius will send a Results Wire soon after the meeting. This report will include the voting outcomes, if applicable, and key outcomes of the discussion.

METADATA: Sponsor: Insmed, Inc. Drug Name: amikacin liposome inhalation suspension n Drug Class: aminoglycoside Indication: nontuberculous mycobacterial (NTM) lung disease


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DISCLAIMER: The information in this document is for informational purposes only. The SAC Tracker Background Analysis contains information from publicly available sources, including FDA, sponsor, scientific, and clinical websites. Tarius A/S assumes no liability for any inaccurate or incomplete information, or for any actions taken in reliance thereon. © Tarius A/S. All rights reserved.