Background Analysis: US FDA Advisory Committee to Review Shionogi’s Cefiderocol for the Treatment of Complicated Urinary Tract Infections – OCT 16, 2019 (AMDAC)

Announcement

The US FDA has scheduled an Antimicrobial Drugs Advisory Committee (AMDAC) meeting for Wednesday, October 16, 2019 to discuss a new drug application (NDA) for cefiderocol [lyophilized powder for intravenous (IV) use], by Shionogi, Inc. (Shionogi), for treatment of complicated urinary tract infections, including pyelonephritis due to gram-negative bacteria in patients with limited or no alternative treatment options.

Indication Background

FDA Guidance defines complicated urinary tract infection (cUTI) as a clinical syndrome characterized by pyuria (pus in the urine) and a documented microbial pathogen on culture of urine or blood, accompanied by local and systemic signs and symptoms, including fever (i.e., oral or tympanic temperature greater than 38 degrees Celsius), chills, malaise, flank pain, back pain, and/or costovertebral angle pain or tenderness, that occur in the presence of a functional or anatomical abnormality of the urinary tract or in the presence of catheterization. Patients with pyelonephritis (inflamed kidney), regardless of underlying abnormalities of the urinary tract, are considered a subset of patients with cUTI. Usually, one or more of the following conditions that increase the risk of developing a cUTI are present:

• In-dwelling urinary catheter

• 100 milliliters (mL) or more of residual urine after voiding (neurogenic bladder)

• Obstructive uropathy (nephrolithiasis, fibrosis)

• Azotemia caused by intrinsic renal disease

• Urinary retention, including retention caused by benign prostatic hypertrophy.

The syndrome can become life-threatening, particularly when it is caused by multi-drug resistant microbial pathogens.

Product Background

Cefiderocol is a novel cephalosporin proposed to penetrate the cell membrane of Gram-negative pathogens through a unique iron transport mechanism.

Clinical Trials of Proposed Indication

A summary of the design and top-line results of the pivotal, phase 2 registrational trial is provided below, based on information provided in a press release by Shionogi on October 25, 2018. A comprehensive summary of the full data package submitted to the FDA, and detailed analyses by both Shionogi and the FDA, will be made available two days prior to the AMDAC meeting, in meeting materials posted by the FDA. These materials will be summarized on the day they are posted, in our subsequent report, the Briefing Summary. At the time of publishing this report, trial results were not yet posted at the ClinicalTrials.Gov database (ClinicalTrials.Gov ID: NCT02321800).

Shionogi has reported that their phase 2, registrational trial demonstrated that treatment with cefiderocol met non-inferiority versus imipenem/cilastatin (IPM/CS) in patients with cUTI at test of cure (TOC). In the study, 73 percent (183/252) of patients in the cefiderocol group met the primary endpoint (combination of clinical response and microbiological response at TOC) versus 55 percent (65/119) in the IPM/CS group, with an adjusted treatment difference of 18.58 percent. These results in a post-hoc analysis showed that cefiderocol was superior to IPM/CS. The study enrolled 452 patients with cUTI and patients were randomly assigned 2:1 to cefiderocol and IPM/CS with a median duration of treatment of nine days for both groups.

The microbiologic response rate at TOC for the cefiderocol group was 73 percent (184/252) versus 56 percent (67/119) in the IPM/CS group, with the difference between groups at TOC at 17.25 percent. Although the study was designed to determine non-inferiority, Shionogi reported the findings showed that cefiderocol resulted in a clinically meaningful microbiological eradication rates and outperformed IPM/CS.

The company has also reported that cefiderocol exhibited a safety profile consistent with that of other cephalosporins.

Regulatory Background

US Regulatory Background

unknown – PDUFA date

unknown – NDA submission date (NDA 209445)

December 13, 2016 – The Limited Population Pathway for Antibacterial and Antifungal Drugs (LPAD pathway) was added to the Federal Food, Drug, and Cosmetic (FD&C) Act through section 3042 of the 21st Century Cures Act (section 506(h) of the FD&C Act).

February 2015 – The FDA issued Guidance for Industry, entitled “Complicated Urinary Tract Infections: Developing Drugs for Treatment.”

Ex-US Regulatory Background

April 1, 2019 – Shionogi announced that a Marketing Authorization Application (MAA) submission for cefiderocol was accepted for review by the European Medicines Agency (EMA). The MAA submission seeks an indication for the treatment of infections due to aerobic Gram-negative bacteria in adult patients with limited treatment options.

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: Shionogi, Inc. Drug Name: cefiderocol Drug Class: antibiotic, cephalosporin Indication: complicated urinary tract infection

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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.