FDA AdComm #2 on inhaled ciprofloxacin (11 Jan 2018); IMI Call for AMR diagnostics (28 Feb 2018 deadline)

Dear All: Two new events on the near-term horizon.

First, FDA has announced an Antimicrobial Drugs Advisory Committee for 11 Jan 2018  (and materials from the meeting can now be found here). Per the FR notice, this AMDAC will cover Aradigm’s inhaled ciprofloxacin for non-CF bronchiectasis and is almost certainly a discussion of the results Aradigm’s ORBIT-3 and ORBIT-4 trials of their once daily ciprofloxacin for inhalation. I have not seen detailed data but instead provide key excerpts from their press release just below my signature. You will recall that Bayer’s inhaled ciprofloxacin for that indication struggled at its 16 Nov 2017 AMDAC with votes of 6-9 (Yes-No) and 1-14 (Yes-No) on whether safety and efficacy evidence was adequate for proposed 14-day and 28-day treatment regimens. It is important that the community learn how to develop such products and I look forward to hearing the discussion.

Second, IMI2 Call 13 is now out and includes as its Topic 3 an exciting call for work on “The value of diagnostics to combat antimicrobial resistance by optimising antibiotic use.” I’ve been aware of discussions on this Topic for some time: it has variously been referred to as DRIVE-DX or VALUE-DX, alluding to the somewhat analogous DRIVE-AB topic. Whatever its final name, the main goal of the Topic is to understand, demonstrate, and quantify the value of diagnostics and the obstacles to their adoption and use in the framework of a Standardised Care Network in order to combat antimicrobial resistance (AMR) by optimising antibiotic use in Europe.

I am delighted to see this Call come to fruition and I look forward to seeing the project itself come to life! Details on this project can be found on the IMI website and the application deadline is 28 Feb 2018. 

All best wishes, –jr

John H. Rex, MD | Chief Medical Officer, F2G Ltd. | Expert-in-Residence, Wellcome Trust. Follow me on Twitter: @JohnRex_NewAbx. See past newsletters and subscribe for the future: https://amr.solutions/blog/

From Aradigm’s 1 Dec 2016 online press release about ORBIT-3 and ORBIT-4:
HAYWARD, Calif.–(BUSINESS WIRE)– Aradigm Corporation (NASDAQ:ARDM) (the “Company”) today announced top-line results from its two Phase 3 clinical trials (ORBIT-3 and ORBIT-4) evaluating the safety and efficacy of Pulmaquin®, the Company’s investigational proprietary formulation of once daily ciprofloxacin for inhalation, in patients with non-cystic fibrosis bronchiectasis (“non-CF BE”) with chronic lung infections with Pseudomonas aeruginosa (P. aeruginosa).

The ORBIT-3 and ORBIT-4 pivotal trials were identical in design except for a pharmacokinetics sub-study that was conducted in one of the trials. The primary endpoint in both ORBIT-3 and ORBIT-4 was an increase in the median time to first mild, moderate or severe pulmonary exacerbation (“PE”). The key secondary efficacy endpoint in both trials was the frequency of PE’s over the 48-week double-blind treatment period.

In ORBIT-4 the median time to first mild, moderate or severe PE was 230 days in the Pulmaquin treatment group as compared to 163 days in the placebo group. This increase in the median time to first PE was statistically significant (p=0.0462) using non-stratified log-rank analysis. In the key secondary efficacy endpoint, there was a 37% reduction in the frequency of PE’s over the 48-week treatment period in the Pulmaquin treatment group as compared to the placebo group. This result was statistically significant (p=0.0007) with a Hazard Ratio of Pulmaquin/placebo of 0.63 using non-stratified binomial regression.

In ORBIT-3 the median time to first mild, moderate or severe PE was 221 days in the Pulmaquin treatment group as compared to 136 days in the placebo group. This increase in the median time to first PE was similar to ORBIT-4 but was not statistically significant (p=0.8488) using non-stratified log-rank analysis. In the key secondary efficacy endpoint, there was a 13% reduction in the frequency of PE’s over the 48-week treatment period in the Pulmaquin treatment group as compared to the placebo group. This result was not statistically significant (p=0.3125) with a Hazard Ratio of Pulmaquin/placebo of 0.87 using non-stratified binomial regression.

The analyses of combined data from both studies resulted in a statistically significant reduction in the number of PE’s over the 48-week double-blind period (Hazard Ratio Pulmaquin/placebo: 0.73; p=0.0015), representing a 27% reduction in PE’s over the period.

Upcoming meetings of interest to the AMR community:

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