The RESTORE-1 trial, results and real world repercussions – an interview with Keith Kaye

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The RESTORE-1 study recently assessed Merck’s (NJ, USA) investigational beta-lactamase inhibitor, relebactam, in combination with imipenem and results were presented at ID Week this week (3–7 October, CA, USA).

In light of this, we spoke to Principle Investigator Keith Kaye, from the University of Michigan (MI, USA) about the trial, its results and the importance of assessing new drugs in a real world setting.

First could you just introduce yourself and your background?

I’m an Infectious Diseases Physician at the University of Michigan where I’m the Director of Research for the Infectious Diseases Division. My background has been historically in infection control and antibiotic stewardship and my research is focused mostly on antimicrobial-resistant bacteria, specifically multi-drug and extremely-drug resistant Gram-negatives. I’ve also done a lot of work with healthcare-associated infections and am interested in old antibiotics for new indications, such as colistin, and new antibiotics for new indications.

Could you just introduce the RESTORE-1 study and tell us a bit about the rationale behind it?

The RESTORE-1 trial assessed a novel antibiotic; it coupled a carbapenem (imipenem), which is an old, relied-upon antibiotic, with a novel beta-lactamase inhibitor (relebactam), which is a particularly effective at inhibiting carbapenemase production, particularly Klebsiella pneumoniae carbapenemases (KPCs). Relebactam also inhibits a broad category of other types of beta-lactamases, including extended spectrum beta-lactamases (ESBLs) and it really enhances imipenem’s activity, which is a benefit particularly against these extremely-drug resistant pathogens.

RESTORE-1 was significant because it mimicked a ‘real world’ use of imipenem–relebactam (IMI/REL). A typical US FDA or EU Phase III study will often study an indication like urinary tract infections (UTIs), for example, where many of the patients who are enrolled don’t actually have the very resistant type pathogens. So while those studies provide very good safety data and some overall efficacy they don’t really give us real world data for how IMI/REL would perform against standard-of-care treatment for highly resistant Gram-negative infections such as carbapenem resistant enterobacteriaceae (CREs) or resistant pseudomonas.

The RESTORE-1 study really focused specifically on patients that had, or were at high-risk for, the extremely-drug resistant infections. As a clinician these are the kind of studies we get particularly excited about because they give us a true indication of how IMI/REL will perform in real world settings and in the types of patients where we might want to use this drug, and really need this drug.

Could you outline some of your key findings?

The first major finding is that IMI/REL performs extremely well in terms of efficacy compared with the comparator, which here was imipenem plus colistin (IMI/COL). In terms of outcomes like mortality, clinical cure and overall response IMI/REL either performed better than IMI/COL or at least as-well-as IMI/COL, particularly in critically ill patients such as pneumonia patients or those with invasive infections.

The other major category of results was safety. One of the major limitations of colistin-based therapy is nephrotoxicity or acute kidney injury. One of the big advantages of IMI/REL is it’s relatively safety in terms of kidney toxicity. If you look specifically at safety outcomes, no matter how you slice the data IMI/REL was really superior to IMI/COL with regards to safety – particularly with regards to acute kidney injury as a significantly smaller percentage of patients in the IMI/REL than the IMI/COL group experienced protocol-defined nephrotoxicity (% difference: -45.9 [95% CI: -69.1, -18.4]; P=.002).

The other big advantage of IMI/REL compared with polymyxin-based therapy is its pharmacokinetics and pharmacodynamics, which seem to be very reliable, dependable and favorable.

So the key takeaways are that in patients where we have few (if any) treatment options available IMI/REL worked well; it was efficacious, patients did very well in terms of overall response, clinical cure and mortality. In addition, it was a very safe treatment compared with colistin-based therapy, demonstrating significantly reduced rates of acute kidney injury. This is a safe and efficacious treatment option that we’re very excited to have available hopefully in the near future.

Could you outline some of the impacts these findings might have for patients and clinicians in the future?

Polymyxin-based therapy, which is colistin-based therapy in this study, used to be our only choice for some resistant infections. If you go back as recently as 5 years ago there was absolutely nothing, even on the horizon, for treatment of infections due to pathogens like CRE and drug-resistant pseudomonas so providers were often forced to use colistin and in some cases they still are, for example, against Acinetobacter.

Nephrotoxicity is a major disadvantage of colistin-based therapy, leading to a need for additional options that are safe and effective. IMI/REL is a very important new treatment option that has been efficacious against resistant bacteria in a well-designed study mimicking that type of situations that will occur in real world settings. So, I think it’s a very important study and I think it provides very informative results for clinicians.

However, I think we need as many different and unique and effective treatment options for these resistant Gram-negatives as possible because these bacteria tend to find ways to develop resistance. New agents that have a novel mechanism of overcoming resistance and are safe and efficacious are very much needed, not only in places like the USA but also in parts of Europe where there’s a lot of carbapenem resistance, such as Greece and Italy, and also in other parts of the world such as India and South-East Asia.

Do you think there’s a need for more studies like RESTORE-1?

The really nice thing about the RESTORE study is that it is a very high-level, well-designed, randomized, controlled, blinded study and it’s great to have that sort of data and those sorts of studies performed on these types of critically ill patients – it really I think adds a lot of credibility and importance to the results that we get. We should really cherish these results and try to apply it as much as we can to the real world clinical settings.

There is actually an additional study, RESTORE-II, ongoing and this is specifically looking at bacterial pneumonia and ventilator-associated bacterial pneumonia, again this is comparing IMI/REL with the standard-of-care in types of patients who are classically managed in intensive care units, who are at high-risk for Gram-negative infections and often have poor outcomes. I think these sort of real world data are going to be very valuable as well. Pneumonia patients are unfortunately somewhat understudied because they’re hard to study, you often have a hard time getting good microbiological data and outcomes are poor, but this is where a lot of the most serious Gram-negative infections occur. So I think these sorts of studies for IMI/REL are going to also be extremely informative.

Could you give a broader perspective on new drugs and/or drug combinations for Gram-negative infections specifically?

We do have more options now. For example, meropenem–vaborbactam, which compared with colistin has enhanced KPC activity and also has enhanced safety, or plazomicin, which came to market recently indicated for UTIs.

In addition, there are two agents that have been out now for a couple of years, ceftazidime–avibactam, which enhances CRE activity but not really activity against pseudomonas, and ceftolozaone-tazobactam, which enhances pseudomonal activity but doesn’t do a lot for enhancing CRE activity.

However, unfortunately we’re already seeing resistance emerge to many of these newer options that have been out for months to years. I think that IMI/REL brings something new in that it offers a unique profile of activity, particularly against both pseudomonas and CRE.

For treating resistant Gram-negatives it’s a very different scenario than 20 years ago where you could pick imipenem out of your toolbox and it was a ‘hammer’ that was effective against all sorts of Gram-negative ‘nails’. Now we have a toolbox where we have different shaped hammers for different shaped nails.

We need a variety of different agents and we need to understand how to most effectively use these and which of our agents are going to be the most effective for different types of resistant Gram-negatives. I think it’s really a new age for antimicrobial stewardship; it’s not only about limiting use and limiting durations of therapy but I think it’s also about choosing what we think is going to be the most effective and the safest agent out of some new options, and also the agents that will have the least collateral damage in terms of antimicrobial resistance and C. difficile infection.

So it’s a very exciting time, drugs like IMI/REL are desperately needed and are extremely important hammers, so to speak, in the toolbox, and it’s up to us to learn how to safely and effectively use IMI/REL in ways that will benefit patients the most and benefit society the most.

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Sources: Brown M, Motsch J, Kaye K et al. Nephrotoxicity associated with imipenem/cilastatin/relebactam (IMI/REL) versus imipenem/cilastatin plus colistin (IMI+CST) in patients with imipenem-nonsusceptible (NS) bacterial infections. ID Week 2018. San Francisco, CA, USA, 3–7 October 2018 (Poster 1951)

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