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(+Video) Phase 3 trial of bezlotoxumab to prevent recurrence of Clostridium … – Nature World Report

Phase III results of studies have been released recently by Merck & Co Inc. of its antibody, bezlotoxumab, to prevent of recurrent Clostridium difficile. This was annnounced at the International Conference on Antimicrobials and Chemotherapy and the International Congress of Chemotherapy (ICAAC/ICC) 2015 annual meeting.

The A single infusion of bezlotoxumab cut down the recurrence of C. difficile infection in a month’s time, from 25 percent to 15 percent. On the basis of the results of this trial, Merck plans to file for approval of the antibody in the EU, Canada and the U.S.

There is a change in the field that is similar to goal orinted agents in oncology in some ways, where a classification of cancer is being backed by a treatment that focuses on the genetics of the drug target, whether that target is a bacterium or a cancer cell.

There are three differences between classical antibiotics and Bezlotoxumab. It is an antibody and it is aimed at a toxin produced by C. difficile rather than C. difficile itself, it is primarily made to prevent recurrence.

During an interactive Saturday session on “Solving the Riddle of Developing Agents with Novel Approaches to Antimicrobial Therapy” featuring speakers from industry and U.S. and European regulatory authorities, discussions were held on the broader problems of how to gain approval for antibiotics that do not abide by the classical model.

Paratek’s president, Evan Loh, informed BioWorld Today that “theoretically, narrow is great.” Paratek Pharmaceuticals Inc. has both a broad and a narrow-spectrum antibacterial in phase III trials.

 

In practice, narrow-spectrum agents “certainly have a role, and they really have a role if you know what the bug is.” But therein lies the rub: “when people come into your office [with an infection], you never know what it is.”

When it comes to bezlotoxumab, creating a narrow-spectrum agent was easy since C. difficile infections are simple to find. Other infectious agents like noroviruses, can lead to diarrhea. Merck’s Nicholas Kartsonis, associate vice president, Clinical Research, told BioWorld Today, “once you are in a hospital with recurrent diarrhea, it’s due to C. difficile.

This is exactly opposite to the situation in infections like pneumonia that are caused by several bacteria.

Loh said that “it’s very hard to find a specific pneumonia infection that’s caused by Pseudomonas,” or whatever other bacterium a trial might be looking at.

The situation is made worse by the speed by which treatment is supposed to begin. The most dangerous case is severe sepsis, where hourly delay of treatment increased the death rate by 7 percent to 8 percent.

Also in some less severe infections, time is much more of the essence than it is for cancer patients. An example is: A lung cancer patient can be tested for the EML-ALK fusion gene mutation and a decision to treat with Xalkori (crizotinib, Pfizer Inc.) can be based on results that are returned three days later, a patient with a severe infection can be dead within those three days.

Those issues slow down enrollment of trials overall. “That was limited to a particular bacterial species could take five to seven years. And a lot can happen in those five to seven years,” said the Medicines Company’s chief medical officer, Jeffery Loutit, at the symposium that enrolling a trial for an indication of ventilator-acquired pneumonia (VAP). He acknowledged, as bacteria continue to develop resistance and competitors continue to develop their own drugs.

The EMA’s chair of Infectious Disease Working Party, Mair Powell, told the audience at the symposium, “A randomized trial is always preferred. But we completely accept that it may not always be possible to power it for inferential statistics.”

Treatment that particularly targets resistant strains of bacteria, the problems of enrollment can be such that the EMA does not necessarily need trials to be powered for the ability to statistically compare the experimental agent. She explained, “the randomization step is considered by us to be a really important issue.”

However, in a trial of a new agent for a multidrug resistant bacterial strain, the number of treated patients could be so less that “the focus is not really on these data, the focus is on supporting the evidence of the dose.”

The FDA is stricter, on this point and need inferential statistics making large scale trials a must. The agency plans to release draft guidelines for developing antibiotics for unmet medical needs. But those will not change the fact that inferential statistics are required, said the FDA’s Deputy Director for Safety Sumathi Nambiar.

Statistical issues pin-point another prominent issue that is specific to antibiotic trials in shifting from anatomically based indications to specific pathogens. While tumors in different anatomical locations are evaluated by the same criteria – basically, tumor shrinkage – the outcomes used to measure antibiotic success are different for different infections.

Nambiar said that given those differences the FDA could be prepared to accept a wider margin when determining non-inferiority of an experimental drug.

She added that if a trial does pool across body sites, the sponsors should “make every attempt” to have 50 percent patient with serious form of the infection in question – that is, one that is hospital acquired and/or multidrug resistant.

Source: Press Release

 

(+Video) Phase 3 trial of bezlotoxumab to prevent recurrence of Clostridium … – Nature World Report

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