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 live microbiota treatments available for Clostridium difficile infections (CDI) in the coming years. At least 3 companies have presented later-stage data on their own novel therapeutics in 2021.

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

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

And the advent of these products comes at a time of need as the US Food and Drug Administration (FDA) has shied away from ever officially approving FMT, which is currently only used at the discretion of the clinician. In addition, the need will continue to grow for these types of therapeutics as the largest stool bank in the country is closing operations at the end of the year.

Making the Leap from FMT to Live Microbiota Therapies

Paul Feuerstadt , MD, Yale University School of Medicine, who is involved in the research of RBX2660, told HCPLive® all 3 treatments are promising and have the potential to really improve CDI care in the coming years.

“We're making the leap from fecal microbiota transplantation to a more sophisticated microbiota based live biotherapeutic,” Feuerstadt said. “And what we saw in 2021, was the finishing of the major trials. We now see the subgroup analyses, the mechanisms of action, the basic science data, all supporting what we theorized.

“With an FDA approved product, it's going to open the door for all clinicians,” he added. “So this will become almost a side by side treatment with antimicrobials in anybody that has recurrent C difficile, because why not?”

The 3 Therapies

RBX2660 is a standardized, stabilized, investigational microbiota-based live therapeutic.

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

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

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

Finally, SER-109 has also gained buzzed in 2021, including at ACG.

The data presented comes from the multicenter, randomized, placebo-controlled phase 3 ECOSPOR III trial where topline data showed SER-109 was superior to placebo in reducing CDI recurrence at 8 weeks to achieve the primary efficacy endpoint. The treatment resulted in a sustained clinical response rate of approximately 88% at 8 weeks following treatment and a 27% absolute reduction of recurrence of CDI, which is a relative risk reduction of 68%.

Research Mistakes Delayed Progress

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

That resulted in 3 or 4 years of failed or inconclusive studies, but soon companies realized they could build on the underlying science of FMT to really hone in on developing treatments for CDI. That is where the era of live microbiota therapeutics 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, told HCPLive these promising products were borne out of a necessity in the field.

“I think it was clear that FMT worked that it is the most effective therapy in this space, however, it is not FDA approved and likely never will be FDA approved,” Allegretti said. “I'm glad that there have been several companies that saw 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 that trend, there might be some off-label use and research that explores the treatment of other diseases with live microbiota.

Depending on how the FDA approaches approval for these products, there might be some off-label uses for RBX2660 and CP101, including for IBD and some neurological diseases.

Feuerstadt said for normal medication approvals, the off-label use is pretty open to the interpretation of the clinicians. However, he believes with the approval of these types of therapeutics there will likely be more guidance on off-label usage.

But once an approval does happen it is highly likely investigators and clinicians will get innovative in testing out the capability of the new therapies.

“I think as with all products, when they eventually become FDA approved, I think we are going to start to see some off label usage, and we're going to start to see some novel trials in these and other disease indications,” Allegretti said. “I think that there certainly could be many other utilities for these whole stool products, just like we're seeing use in FMT.”

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

“Especially the ones that are really whole stool products, you know, those in theory will function similarly in recurrent C diff. We're already starting to see very good safety profiles across the board,” she said.

The Need for New Therapies

Right now there is a need for a new class of treatments in this space, because along with the likely demise of FMT, C difficile infections are largely caused by the use of antibiotics.

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

“So I don't think in the next few years, we're going to see these used as a whole for all C diff therapy, although I do imagine a world in the future where we are not relying on antibiotics for the treatment of this disease at all,” Allegretti said. “And hopefully, we're preventing it.”

Ultimately, Allegretti predicts all 3 of the developmental products will ultimately garner FDA approval and will be utilized; ultimately, it will be the patients who benefit the most.

“I don't think it's a race to the finish and then the others are done,” she said. “I think there is room for all of them in this space. And I think they all will have their own pros and cons. And then you as a clinician will be sitting in front of the patient and making the decision as to which one, you're going 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 anticipates at least 1 of these 3 options will gain FDA approval in 2022.

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

CDI has still remained the most common hospital-acquired infection for the better part of 10 years.

“Better infection control measures, better antimicrobial stewardship led to a decrease in the proportion of health care associated infections or hospital associated infections, but the community associated infection stayed level,” Feuerstadt said. “And I think we've probably maximized our ability in the hospital to minimize the spread of C difficile.”

But the community spread remaining level is concerning and Feuerstadt said the way to curb the spread is by not allowing the infection to reoccur.

“This shouldn't be an infection that we treat 3 and 4 times in one individual, that should be an initial, if you recur, we're going to shut it down,” he said. “When patients come into my office, I call myself the closer. But really, I have the tools and I'm comfortable using the tools to shut down that infection and minimize future occurrences.”