A race to the top for the new C Difficile treatment class

If the adage “competition breeds success” is correct, then there will be several living microbiota treatments available for you. Clostridium difficile infections (CDI) in the years to come. At least 3 companies have presented advanced stage data on their own new therapies in 2021.

In fact, it was a banner year for Ferring Pharmaceuticals with RBX2660, Finch Therapeutics with CP101, and Seres Therapeutics with SER-109, all of which presented data at major gastroenterology meetings.

The 3 products are all based on the underlying science of fecal microbiota transplantation (FMT) – already considered a leading treatment method for recurrent CDI, with evidence suggesting that human metabolic profiles could be influenced by the treatment, leading to the creation of these therapies of the living microbiota. .

And the advent of these products comes at a time when the United States Food and Drug Administration (FDA) has given up on formally approving FMT, which is currently only used at the discretion of the clinician. Additionally, the need will continue to grow for these types of treatments as the country’s largest stool bank closes at the end of the year.

Switching from FMT to live microbiota therapies

Paul Feuerstadt, MD, Yale University School of Medicine, who is involved in the research of RBX2660, said HCPLive® all 3 treatments show promise and have the potential to truly improve CDI care in the years to come.

“We are moving from fecal microbiota transplantation to more sophisticated living microbiota-based biotherapy,” Feuerstadt said. “And what we saw in 2021 was the end of the big tests. We are now seeing the subgroup analyzes, the mechanisms of action, the fundamental science, all supporting what we have theorized.

“With a product approved by the FDA, this will open the door for all clinicians,” he added. “So this will almost become a side-treatment with antimicrobials in anyone who has recurrent C difficile, because why not? “

The 3 therapies

RBX2660 is a standardized, stabilized and experimental living therapy based on the microbiota.

In data presented at the 2021 American College of Gastroenterology (ACG) annual meeting, researchers, including Feuerstadt, found high clinical efficacy in reducing rCDI with a sustained clinical response for up to 6 months with a 82.8% treatment success rate (n = 53). There was no difference between patients who received 1 dose (83.3%; n = 20) versus 2 doses (82.5%; n = 33).

For those patients who initially responded, 88.7% (n = 47) maintained a clinical response at 6 months.

CP101 is an investigational orally administered microbiome treatment designed to restore microbiome diversity and provide early intervention in the management of recurrent CDI. In data also presented in the ACG of the PRISM3 phase 2, randomized, double-blind, placebo-controlled trial.

Finally, the SER-109 also made the buzz in 2021, especially at ACG.

The data presented are from the multicenter, randomized, placebo-controlled phase 3 ECOSPOR III trial where initial data showed that SER-109 was superior to placebo in reducing CDI recurrence at 8 weeks to meet the endpoint. main evaluation of effectiveness. Treatment resulted in a sustained clinical response rate of approximately 88% at 8 weeks after treatment and a 27% absolute reduction in CDI recurrence, representing a relative risk reduction of 68%.

Research errors delayed progress

While the genesis of the new treatments was FMT, Feuerstadt said that when FMT first appeared years ago, it was pretty obvious that it was working well in treating CDI. As a result, researchers began to study the therapy as a potential option for other gastrointestinal illnesses, as well as some neurological and liver diseases, instead of relying on this science.

This resulted in 3 or 4 years of unsuccessful or inconclusive studies, but companies quickly realized that they could draw on the underlying science of FMT to really focus on developing treatments for it. ICD. This is where the era of living microbiota therapy began.

Jessica R. Allegretti, MD, MPH, FACG, director of the fecal microbiota transplant program and associate director of the Crohn’s and Colitis Center at Brigham and Women’s Hospital, and assistant professor of medicine at Harvard Medical School, said HCPLive these promising products were born out of a need in the field.

“I think it was clear that FMT was working and that it was the most effective therapy in this space, however, as it is not FDA approved and probably never will be,” said Allegretti. “I am happy that there have been several companies who say they have seen the need for these products. “

Off-label use

In some ways, the competition might resemble the advent of biologics to treat inflammatory bowel disease (IBD). And similar to this trend, there could be off-label use and research that explores the treatment of other diseases with a living microbiota.

Depending on how the FDA approaches the approval of these products, there may be non-compliant uses for RBX2660 and CP101, including for IBD and certain neurological diseases.

Feuerstadt said that for normal drug approvals, off-label use is quite open to interpretation by clinicians. However, he believes that with the approval of these types of therapies there will likely be more advice on off-label use.

But once approval is obtained, it is highly likely that researchers and clinicians will innovate in testing the capacity of new therapies.

“I think like with all products, when we’re finally approved by the FDA, I think we’re going to start seeing off-label use, we’re going to start seeing new trials using these indications and other diseases,” ”Said Allegretti. “I think there certainly could be many other utilities for these whole stool products, just as we’re seeing the use of in FMT.”

But unlike the emergence of the new class of treatment for IBD, Allegretti, who leads research for CP101, said the 3 treatments in development all have similar mechanisms of action and safety profiles, which was not really true for organic products.

“Especially the ones that are really complete saddle products, you know these will work in theory the same in recurring C diff, we are already starting to see very good safety profiles in all areas”, a- she declared.

The need for new therapies

At present, there is a need for a new class of treatments in this space, because with the probable disappearance of FMT, it’s hard infections are largely caused by the use of antibiotics.

And for primary CDI, the majority of patients will still be treated effectively with antibiotics.

“So I don’t think in the next few years we’re going to see them being used as a whole for all C diff therapy, although I imagine a world in the future where we don’t rely on antibiotics for it. processing. of this disease at all, ”Allegretti said. “And I hope we prevent it.”

Ultimately, Allegretti predicts that all 3 development products will ultimately gain FDA approval and be used; in the end, it will be the patients who will benefit the most.

“I don’t think it’s a race to the finish and the others are over,” she said. “I think there is room for each of them in this space. And I think they will have all their pros and cons. And then, as a clinician, you’ll be sitting in front of the patient and deciding which one to prescribe, based on that patient’s individual preferences and, unfortunately, of course, what their payer will cover as with many of our decisions.

Feuerstadt also predicts that at least 1 of these 3 options will gain FDA approval in 2022.

And they couldn’t have come at a better time because even with a decrease in nosocomial infections due to some of the COVID-19 mitigation techniques in place, there is still an issue with the spread of C difficile, both in the community and in hospitals.

CDI remained the most common nosocomial infection for almost 10 years.

“Better infection control measures, better antimicrobial stewardship have led to a decrease in the proportion of infections associated with health care or infections associated with hospitals, but the infection associated with the community has remained stable,” Feuerstadt said. “And I think we’ve probably maximized our ability at the hospital to minimize the spread of C difficile. “

But the level of spread remaining in the community is cause for concern, and Feuerstadt said the way to curb the spread is to not allow the infection to reoccur.

“It shouldn’t be an infection that we treat 3 and 4 times in an individual, it should be a first, if you come back we will stop it,” he said. “When patients come into my office, my name is closest to me. But really, I have the tools and I’m comfortable with the tools to stop this infection and minimize future occurrences. “

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