Issue: June 2021
Source: Healio Interview
Disclosures: Allegretti reports consulting for Finch Therapeutics and serving as a scientific advisor to OpenBiome. Khoruts reports receiving a grant from Finch Therapeutics and patents on preparation of microbiota-based therapeutics. Grinspan, Kelly and Yen report no relevant financial disclosures.
June 24, 2021
11 min read
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Future of FMT for recurrent C. difficile infection still unclear

Issue: June 2021
Source: Healio Interview
Disclosures: Allegretti reports consulting for Finch Therapeutics and serving as a scientific advisor to OpenBiome. Khoruts reports receiving a grant from Finch Therapeutics and patents on preparation of microbiota-based therapeutics. Grinspan, Kelly and Yen report no relevant financial disclosures.
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Fecal microbiota transplantation is not yet FDA approved for treating recurrent Clostridioides difficile despite several studies showing it to be efficacious and safe.

Currently, FMT exists under a policy of enforcement discretion of the FDA, allowing it to be used for the treatment of C. difficile.

Source: Adobe Stock.
Source: Adobe Stock.

In a study conducted by Colleen R. Kelly, MD, and colleagues, FMT cured C. difficile in 90% of patients in the FMT National Registry, which included 20 FMT practice sites in North America. Safety and efficacy were similar between real-world experience and research studies. After 6 months follow up after initial FMT, only four of the 112 patients had recurrent C. difficile.

Healio Gastroenterology spoke with experts who use FMT in their practice. They shared their experiences, latest updates, impact from the COVID-19 pandemic and what’s next in alternative therapies.

Alexander Khoruts, MD, from the University of Minnesota, explained FMT as a procedure was originally introduced into Western medicine in the 1950s, but gained momentum only in the recent decade. He said few practitioners implemented the procedure into their clinical practice because it was not an easy thing to do.

Alexander Khoruts, MD
Alexander Khoruts

Khoruts said his program was the first to describe how FMT is made, and they never lost the independence to perform the treatment.

“After doing a handful of cases using patient-directed donors, I thought this was crazy,” he said. “There had to be a better way to do it, and we had to find a way to standardize donor selection and material preparation. A key procedural step was the ability to cryopreserve the transplant material.”

Then, OpenBiome opened its doors and became the dominant supplier or stool bank, Khoruts said.

“This is how it went mainstream,” he said.

Colleen R. Kelly, MD, Warren Alpert School of Medicine at Brown University, said she fears stool banks will be seen as unnecessary when FMT alternatives become available but there is still a need for the procedure for certain patients.
Colleen R. Kelly, MD, Warren Alpert School of Medicine at Brown University, said she fears stool banks will be seen as unnecessary when FMT alternatives become available but there is still a need for the procedure for certain patients.

Source: Colleen R. Kelly, MD.

OpenBiome is one of, if not the only, centralized stool banks in the United States. It is the main source of FMT materials.

In an interview with Healio Gastroenterology, Justin Chen, director of External Affairs at OpenBiome, said it takes a lot of time and care for OpenBiome to find a donor for FMT. He said less than 3% of applicants pass the health screenings and quality to be stool donors.

“Logistically, donors need to donate at least three times a week for 2 months,” Chen said. “Donations occur on-site, which requires donors to come into OpenBiome’s donation facility to provide stool.”

OpenBiome limits its donors to individuals who live in the Boston metropolitan area. They evaluate the donors with blood tests, stool tests, nasal swab tests and clinical exams at a minimum of every 60 days, according to Chen.

“From a safety perspective, OpenBiome rigorously screens our donors to determine if FMT derived from their stool is suitable for treating patients who are often very sick,” Chen said. “This involves screening donors for infectious pathogens such as multidrug-resistant organisms and potentially microbiome-mediated conditions such as gastrointestinal or metabolic conditions.”

Ari Grinspan, MD
Ari Grinspan

“OpenBiome is essentially the only available stool FMT product that’s available across the country and when they had to shut down because of an FDA safety alert, it dramatically reduced the capability and availability to perform FMT,” Ari Grinspan, MD, associate professor in the department of medicine, division of gastroenterology at Mount Sinai, told Healio Gastroenterology. “Most of the clinicians who use FMT were getting products from OpenBiome, so once the supplier was gone, there was really no readily available product we could obtain for our patients.”

COVID-19 Impact on FMT

OpenBiome allowed only emergency use once the COVID-19 pandemic started.

“OpenBiome has implemented new donor screening protocols for mitigating the risk for transmission of SARS-CoV-2 via FMT,” Chen said.

These protocols are compliant with FDA COVID-19 guidance, he said. OpenBiome tested every stool sample provider since Dec. 2019 for SARS-CoV-2 and as of March 2020, it tested all donors by nasopharyngeal swab. It screened donors at a minimum every 28 days and in June 2020, they screened donors at a minimum of every 14 days.

OpenBiome also evaluates a donor’s potential exposure, symptoms, reported testing and travel every time they visited the facility.

Kelly, from Warren Alpert School of Medicine at Brown University, told Healio Gastroenterology that OpenBiome was no longer recruiting new donors due to COVID-19. OpenBiome said it had enough materials on hand to ship out to units treating patients. However, Kelly noted the stool bank may eventually run out of FMT materials.

“They are winding down,” she said.

While practices have found it difficult to get access to FMT materials in general and now more than ever with COVID-19, Khoruts said he is still able to function as normal at the University of Minnesota because they have their own supply. He noted throughout the pandemic, the university began to receive more referrals from private clinics that were no longer able to perform FMT.

Kelly said she was receiving materials from the University of Minnesota and has been able to operate and perform FMT over the past few months. However, many physicians have not been able to do the same.

Eugene Yen, MD
Eugene Yen

In an interview with Healio Gastroenterology, Eugene Yen, MD, clinical associate professor of medicine at the University of Chicago/NorthShore University Health System, said, “We have our own internal stool bank. It has not been a problem for us, because our donors can be tested and submit multiple samples during their testing period, which can sustain our supply for a long time. The main issue is that the centralized stool banks have not been able to provide stool to their clients who do FMT.”

Yen said there needs to be greater access to fecal material to be able to perform FMT in patients with recurrent C. difficile. There needs to be a way health care providers can access the material if they do not have their own stool bank, according to Yen.

Yen said many health care providers use central banks like OpenBiome for their FMT materials so when it became unavailable, there was not another source of donor stool to take the place of OpenBiome.

Kelly said the University of Minnesota does not have the same bandwidth as OpenBiome to supply the whole country with FMT materials. She said there are a few local banks across the United States; however, not every practice is affiliated with them and so not many FMTs have been performed.

“It’s a real problem and we won’t have any of these products approved in the immediate future,” Kelly said. “It’s not like we are going to have them in the next 6 months. There is going to be a period where there’s a bit of a lag.”

FDA Approval

Jessica Allegretti, MD, MPH
Jessica Allegretti

Speaking with Healio Gastroenterology, Jessica Allegretti, MD, MPH, from Brigham and Women’s Hospital Crohn’s and Colitis Center, noted FMT is not yet approved by the FDA. FMT is performed under the enforcement discretion policy put in place by the FDA stating it is still an experimental procedure. She said many physicians feel FMT should be approved because it works and it is also safe.

Khoruts believes the FDA will never approve FMT.

“It doesn’t necessarily fall under FDA oversight anyway,” Khoruts said. “It’s clinical practice.

He said if it is treated like a drug, it will have a different name and it will then need to be approved by the FDA. Khoruts also said an emerging drug is probably not far from being developed and approved by the FDA.

When the COVID-19 pandemic began, the FDA said only FMT material made prior to Dec. 2019 could be used to perform the procedure, according to Allegretti. She said at the time OpenBiome had material stored so they were still able to supply FMT material.

“However, the FDA changed their recommendation after the virus was identified in stool. Banked samples therefor needed to be retroactively tested for SARS-CoV-2 to be certain that the aliquot was negative,” Allegretti said. “OpenBiome had to halt both manufacturing and shipping of material to comply with the FDA’s requirements.”

Allegretti said a test was developed and validated to test the stool for SARS-CoV-2 but there was a lot of material to be tested, limiting availability.

Like Khoruts, Allegretti believes that FMT will never be approved by the FDA.

There are products under investigation that are FMT-like products, Allegretti said.

“It is very encouraging that there is already positive trial data for potential future FDA approved products,” Allegretti said. “Once we have FDA approved products, the enforcement discretion policy is likely to go away. [The FDA] has not said that, but that’s what many of us assume will happen.”

“Providers had become very reliant on the OpenBiome stool bank and when it wasn’t available there wasn’t a large source of donor stool to take that place,” Kelly said.

Kelly also said FMT is being considered as a drug by the FDA. FMT needs to go through many clinical trials, she said, which is costly. Kelly shared that many hoped the FDA would categorize FMT similarly to a blood bank; however, that is not the plan.

FMT Material May Run Out

Kelly said an FMT-like product needs to be approved soon or made available soon before OpenBiome possibly runs out of FMT materials.

“[OpenBiome] already liquidated some of their production supplies and they anticipate they have enough doses to last over the next year, but it’s a little bit of a race,” Kelly said. “If they run out of doses and we don’t have a product yet, providers are going to have to just use fresh donor FMT, the way we had a long time ago.”

Kelly noted apart from getting fresh donor material being complicated, she feels fresh donor screening is not as safe. There is a limit to the amount of testing you can do with fresh donor material compared with a stool bank where each dose can be thoroughly tested.

Justin Chen
Justin Chen

On May 3rd, OpenBiome expanded availability of FMT preparations from emergency use to patients who were scheduled to undergo the procedure, according to Chen. It anticipates the number of FMT procedures being performed to increase.

While OpenBiome plans to serve patients with FMT through 2021, despite stopping production, it anticipates an FDA-approved product will be available. Physicians are eager yet nervous because they fear OpenBiome may run out before the FDA product is approved but look forward to a product.

“Our goal is to provide access to our FMT material, which is an investigational product, for patients with recurrent C. difficile until they have access to an FDA-approved treatment,” Chen said. “We do not have any special insight into the approval process but from the announcements made this past summer of positive data from three pivotal trials, we expect to see an approval in early 2022.”

Chen said OpenBiome aims to provide FMT preparations until the end of year; however, they do not have a definite end date. OpenBiome has a large inventory that is expected to last until early 2022.

“The exact end date depends on few factors — mainly the size of our inventory and demand for FMT — that we can generally account for but not to the certainty of a specific date or month,” Chen said.”

OpenBiome plans to provide FMT preparations to researchers running clinical trials, with pre-existing collaborations with the company that were put on pause due to COVID-19, according to Chen.

“OpenBiome has notified these researchers that we have reserved FMT preparations for their trials, which will be available until the end of 2022 to allow more time for enrollment,” Chen said. “OpenBiome is no longer starting new collaborations with researchers and the vast majority of our inventory will be used to treat patients.”

Alternatives to FMT

The most common way to perform FMT is currently via a colonoscopy, but a few companies have been conducting clinical trials on oral alternatives.

Finch Therapeutics and OpenBiome have collaborated to develop CP101, a freeze-dried oral FMT capsule, expanding long-term access to FMT for recurrent C. difficile. It is a product based on technology that was developed at the University of Minnesota, Khoruts said.

Researchers are still conducting trials on CP101.

Allegretti presented results from the PRISM3 trial at UEG Week Virtual. She noted CP101 helped increase microbiome diversity and was well-tolerated by patients. The drug prevented recurrence of C. difficile infection in patients aged at least 65 years with first C. difficile recurrence who were at high risk for further recurrence, or patients who had two or more recurrences.

Seres Therapeutics has developed SER-109, an investigational, oral, biologically derived microbiome therapeutic intended to prevent recurrence of C. difficile infection.

In a pivotal phase 3 clinical trial of SER-109, results demonstrated that patients who took SER-109 were less likely to have infection recurrence compared with those treated with antibiotics alone. These results also showed that SER-109 significantly decreased the risk for recurrence of C. difficile. Only 11.1% of patients who received SER-109 experienced a recurrence vs. 41.3% of patients who received placebo.

Researchers are currently enrolling patients with recurrent C. difficile into an open-label clinical study of SER-109.

“These are FMT-like products, it serves the same purpose as FMT for the traditional donor-to-patient way but in capsule formulation,” Grinspan said. “The hope is that these products will be approved around the same time that OpenBiome closes its doors so that we can continue to provide microbial-based therapy for our patients with recurrent C. difficile.”

Health Care Provider Fears

Kelly said she hopes the new products that become available are priced within reach to the masses and not so costly that patients will not be able to use them. Her hope is the FDA will understand that all patients will not be able to be treated with these new products and will find a “loophole” for the existence of stool banks and not completely take FMT off the table.

When other products become available, Kelly speculates the FDA may say stool banks are no longer necessary.

“That makes me a little nervous because I can already foresee that there will be people who may not be candidates for treatment with some of these encapsulated products,” Kelly said. “For instance, I have patients who can’t swallow, they’ve had a stroke, or they have some swallowing difficulties. If you can’t swallow that’s not going to be helpful for you. Direct colonoscopic delivery is superior in critically ill patients with acute/severe or fulminant C. difficile who may also have an ileus. I’d hate to see stool banks disappear.”

Yen said there is a large unmet need for material and providers for patients with recurrent C. difficile, despite the advent of other stool substitutes being studied.

“The key thing is the whole field is moving from direct human-provided product into a more pharmaceutical-grade product that can be mass produced,” Grinspan, the director of the GI Microbial Therapeutics, said. “[In addition,] we have all the safety regulations and protocols to avoid not just COVID; but there are also concerns about multidrug-resistant organisms. So, by having a more [pharmaceutical]-grade product, a more defined product or one that has rigorous protocols involved, you can screen for all these things to make sure the product we’re providing is as safe as it possibly can be.”

“It’s unfortunate because patients are really the ones suffering,” Allegretti said. “If OpenBiome is not able to provide material anymore, many of us are asking the question, what will replace it? We actually don’t know what the answer to that question is yet.”