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Merck starts pivotal trials of new antibiotic combination

Continues testing after positive phase II results for relebactam addition 

Merck & CoAfter positive phase II results, Merck & Co has decided to take a novel antibiotic into phase III testing.

Beta-lactamase inhibitor relebactam is a welcome addition to the late-stage antibiotics pipeline, which remains fairly sparse despite high levels of concern worldwide about multidrug resistant (MDR) infections.

The drug is designed to inhibit a key resistance mechanism that inhibits the effectiveness of beta lactam antibiotics, and will be studied in phase III in combination with Merck's Primaxin (imipenem), a broad-spectrum carbapenem that is generally reserved to treat serious and resistant infections.

In some cases, carbapenems are the last-line therapy for MDR infections, but there has been a progressive increase in resistance to the class in bacterial families such as the Enterobacteriaceae, which includes clinically important pathogens such as Pseudomonas aeruginosa, Klebsiella pneumoniae, Salmonella species and Escherichia coli.

In the phase II trial, more than 300 adults with complicated urinary tract infections or acute pyelonephritis were given one of two doses of relebactam or placebo on top of imipenem plus cilastatin, another drug designed to tackle resistance.

The main efficacy measure was the proportion of patients with a microbiological response at the point when intravenous antibiotics were discontinued - generally after between 4 and 14 days of treatment.

The trial showed adding relebactam treatment to imipenem/cilastatin was not inferior to imipenem/cilastatin plus placebo - an important initial finding which shows the beta lactamase inhibitor does not impede the effect of the antibiotic. There were also no safety issues with the drug, according to Merck (known as MSD outside the US and Canada).

Merck has now started two trials of the combination in imipenem-resistant patient populations to see if the combination can help restore the antibiotic's efficacy.

The first is comparing treatment with relebactam/imipenem to   piperacillin/tazobactam in patients with hospital-acquired bacterial pneumonia or ventilator-associated bacterial pneumonia (HAP/VAP).

The second will pit the combination against colistimethate sodium in combination with imipenem in the treatment of imipenem-resistant bacterial infections, including those caused by P. aeruginosa.

AstraZeneca (AZ) recently secured CHMP backing in Europe for Zavicefta - which combines established cephalosporin antibiotic ceftazidime with new-generation beta lactamase inhibitor avibactam. The combination has also been approved in the US - where it is sold by Actavis - as Avycaz.

An independent UK review estimated in 2014 that by 2050 MDR infections could claim 10m lives a year and result in a cumulative loss from global output of $100trn.

Article by
Phil Taylor

22nd June 2016

From: Research



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