Regulatory Decision Summary for Xenleta

Review decision

The Regulatory Decision Summary explains Health Canada’s decision for the product seeking market authorization. The Regulatory Decision Summary includes the purpose of the submission and the reason for the decision.


Product type:

Drug

Medicinal ingredient(s):

lefamulin acetate

Therapeutic area:

Antibacterials for Systemic Use

Type of submission:

Priority New Drug Submission (New Active Substance)

Control number:

233292
What was the purpose of this submission?

 

This New Drug Submission (NDS) - New Active Substance (NAS) for Priority Review was filed to obtain market authorization for Xenleta (lefamulin acetate) for the treatment of adults with community-acquired pneumonia (CAP) caused by susceptible microorganisms [Streptococcus pneumoniae including multi-drug resistant S. pneumoniae (MDRSP), Staphylococcus aureus (methicillin-susceptible isolates), Haemophilus influenzae, Haemophilus parainfluenzae, Moraxella catarrhalis, Legionella pneumophila, Mycoplasma pneumoniae, and Chlamydophila pneumoniae].

 

Why was the decision issued?

 

Xenleta (lefamulin acetate), a novel semi-synthetic pleuromutilin antibacterial agent, is the first compound of the pleuromutilin class of antibiotics to be developed for systemic use (oral [PO] and intravenous [IV]) in humans.

Two phase 3 pivotal multicentre, randomized, double-blind, double-dummy, active-controlled, parallel-group, non-inferiority studies support the market authorization of Xenleta for the treatment of community-acquired bacterial pneumonia (CAP) caused by susceptible microorganisms. In Study 3101, patients were randomized to receive either IV Xenleta or IV moxifloxacin (with or without adjunctive linezolid) with the option to switch to oral Xenleta or oral moxifloxacin, respectively, after 3 days. In Study 3102, patients were randomized to receive either oral Xenleta or oral moxifloxacin.

In both studies, Xenleta was non-inferior to moxifloxacin for the primary endpoint of early clinical response (ECR) rates at 72 to 120 hours after the first dose of study drug in the Intent-to-treat (ITT) Analysis Set. In Study 3101, the ECR responder rate was 87.3% in the Xenleta group and 90.2% in the moxifloxacin group. In Study 3102, the ECR responder rate was 90.8% in the Xenleta group and 90.8% in the moxifloxacin group. Investigator-assessed Clinical Response (IACR) rates at the Test of Cure (TOC) Visit (that is [i.e.] 5 to 10 days after the last dose of study drug) in the modified ITT (mITT) Analysis Set and in the Clinically Evaluable at TOC (CE-TOC) Analysis Set (key secondary endpoints) were supportive of findings with the primary endpoint.

In in vitro studies, lefamulin demonstrated antibacterial activity (expressed as MIC90, or concentration required to inhibit 90% of isolates) against the most relevant respiratory pathogens associated with CAP and their resistant isolates.

The primary safety database included 641 patients with CAP who received at least one dose of IV or oral Xenleta at the proposed dosing regimen in the pivotal studies. In the pooled analysis, rates of adverse reactions, serious adverse reactions, treatment discontinuations due to adverse reactions, and deaths were similar between treatment groups. In Study 3101, the most common adverse reactions were administration site reactions experienced during the IV dosing period, while in Study 3102, the most common adverse reactions were gastrointestinal disorders, most notably diarrhea. In the pooled safety analysis, electrocardiogram (ECG) findings reported as adverse reactions included ECG QT prolonged (0.6% Xenleta, 0.8% moxifloxacin). There were a small number of relatively severe hepatic elevation events, however, no Xenleta patient met the laboratory criteria for potential Hys Law. Based on findings from animal studies, Xenleta may cause fetal harm when administered to pregnant women. Animal studies indicate that lefamulin was concentrated in the milk of lactating rats.

Concomitant administration of oral Xenleta with sensitive CYP3A4 substrates that prolong the QT interval is contraindicated. While a thorough QT interval study was not conducted, the overall body of data was sufficient to draw the conclusion that administration of lefamulin increases the risk of QT interval prolongation at clinically relevant doses. Co-administration of oral lefamulin with CYP3A4 substrates increases exposure of the CYP3A4 substrates.

Health Canada recommended issuance of marketing authorization for Xenleta for the treatment of adults with CAP caused by: Streptococcus pneumoniae (S. pneumoniae) including multi-drug resistant S. pneumoniae (MDRSP), Staphylococcus aureus (methicillin-susceptible isolates), Haemophilus influenzae, Haemophilus parainfluenzae, Moraxella catarrhalis, Legionella pneumophila, Mycoplasma pneumoniae, and Chlamydophila pneumoniae.

 

Decision issued

Approved; issued a Notice of Compliance in accordance with the Food and Drug Regulations.