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Merck preps regulatory filings for much-needed antibiotic combo

The regimen combines Merck’s own Primaxin with new beta lactamase inhibitor relebactam

MerckMerck & Co has reported positive late-stage data for an antibiotic combination that could provide a new treatment option for serious and hard-to-treat Gram negative infections.

The regimen combines Merck’s imipenem/cilastatin duo - sold as Primaxin as a broad-spectrum antibiotic for decades - with a new beta lactamase inhibitor called relebactam that is designed to restore susceptibility to imipenem in resistant strains.

If licensed, the new triple antibiotic would provide a new treatment option for patients who have acquired a serious infection caused by multi-drug resistant (MDR) and carbapenem-resistant Gram-negative bacteria, which are a huge problem for the NHS, prolonging hospital stays and increasing healthcare costs.

The pivotal phase III trial showed that imipenem/cilastatin/relebactam was comparable to the combination of imipenem/cilastatin plus colistin - a drug first introduced in the 1950s that has been resurrected to help fight challenging Gram-negative infections - with both regimens around 70% effective at day 28. It’s a significant result, as colistin has been held up as a ‘last-line’ therapeutic for Gram-negative infections, despite having fallen out of favour in the 1970s due mainly to toxicity issues including kidney damage.

Three years ago, reports of colistin resistance in bacteria that could be transferred between organisms via plasmids raised concerns that the drug’s activity could be compromised much sooner than expected.

The new data suggests relebactam can provide an alternative option, says Merck, and it intends to file for approval of a fixed-dose combination of the drug with imipenem and cilastatin as soon as possible. Importantly, the new cocktail was also less likely to cause kidney toxicity than colistin, and all-cause mortality was lower at day 28.

“Infections caused by Gram-negative bacteria continue to be a major problem for hospitalised patients,” commented Amanda Paschke, senior principal scientist, infectious disease clinical research, at Merck Research Laboratories.

“The prevalence of carbapenem-resistant pathogens is increasing globally, highlighting the need for effective new antibacterial agents with Gram-negative coverage,” she added. Merck is also carrying out a phase III trial comparing the relebactam regimen with piperacillin/tazobactam, another widely-used antibiotic for hospital-acquired infections.

Merck - known as MSD in Europe - is not the only company trying to bring new agents to market for Gram-negative infections. In February, Allergan won US approval for its fixed-dose combination antibiotic Avycaz, which became the first new drug to treat pneumonia caused by Gram-negative bacterial infections in the US in more than 15 years. It’s been sold in Europe by Pfizer as Zavicefta since 2016.

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

Meanwhile, the need for new antibiotics for resistant infections is also exemplifiedby the recent case in the UK of a man who contracted ‘super gonorrhoea’ - caused by Gram-negative bacteria Neisseria gonorrhoeae that proved to be incurable using first-choice antibiotics (azithromycin and ceftriaxone).

Eventually he was able to shake the infection with Merck’s Invanz (ertapenem) given intravenously as a last-line option, but with 78 million people worldwide infected with gonorrhoea and escalating rates of multidrug resistant (MDR) strains, the need for new treatment options is apparent.

The World Health Organization (WHO) notes there are just three drugs in development for resistant gonorrhoea, namely Cempra’s solithromycin, for which a phase III study has recently been completed but missed its primary endpoint, as well as Entasis/AstraZeneca’s zoliflodacin and GlaxoSmithKline’s gepotidacin, which are in phase II.

Article by
Phil Taylor

23rd April 2018

From: Research



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