After big 2016 setback, field of microbiome-based drugs gets injection of promise with positive signal from Rebiotix pivotal study
Several years ago, as companies capitalizing on science that suggests flushing ‘good’ gut bacteria into the system can treat a plethora of conditions — from C. diff infections to obesity — began to gain traction, the opportunities to harness the microbiome garnered feverish promise and generous funding. Then, in 2016, Seres Therapeutics’ failure in a mid-stage trial evaluating its “crapsule” — donor-derived processed fecal material encapsulated in a pill — derailed the emerging field, relegating the microbiome from hero to zero status.
The money has since begun to trickle back in, but the expectations are now more down to earth. A number of significant data readouts from key players this year are expected to generate concrete evidence that the ecosystem of gut bacteria has a crucial role to play in health. On Wednesday, Rebiotix offered the first glimpse of positive data from its ongoing late-stage study.
The company’s poop-derived frozen formulation, RBX2660, which is delivered into patients via an enema, is being developed to reduce recurrent infections of C. diff, a stubborn infection that has grown resistant to existing antibiotics and kills more than 29,000 Americans each year.
The 270 patient placebo-controlled study has met the main goal — the proportion of patients with treatment success with RBX2660 to prevent recurrent C. diff within 8 weeks versus placebo, but the full dataset is still to come, the company said, without disclosing any specifics.
“It has been a long time coming through a number of obstacles to be able to provide the data that demonstrates that this is a therapeutic option for patients and can be developed as a drug product and can meet the requirements,” said Lee Jones, chief, and founder of Rebiotix, in an interview.
“It signals to the field that this is real.”
Rebiotix, founded in 2011, was swallowed by Swiss drugmaker Ferring Pharmaceuticals in 2018.
“I spent the better part of 34 years either as a grad student or as a scientist or as an investor in this game, so I know how it has evolved,” said Ferring’s CSO Per Falk in an interview. “And this is clearly the closest we have ever gotten to see a real application of the knowledge that has been building for so long.”
The field of microbiome-based therapeutics has grown to be a fecund field for drug developers — big and small — using different therapeutic modalities, some of which are designed to sidestep the “ick” factor associated with traditional stool transfer or FMT.
The intervention requires a stool sample to be screened, liquefied, and delivered to the colon by nasal or rectal tube. Patients must either find their own donor, obtain viable stool from a licensed health care provider, or turn to a stool bank, such as OpenBiome. Fewer than 3% of the population qualify as healthy donors, according to the Fecal Transplant Foundation.
Originally pioneered in China, FMT has been used in the United States for years now as a way to combat recurrent C.diff, as the perpetrating bacteria have mutated to increasingly render traditional antibiotics obsolete. However, the FDA considers the intervention an investigational treatment with an unproven safety and efficacy profile. In 2013, the US regulator implemented a policy of “enforcement discretion” in relation to FMT for treatment-refractory C. diff: While developers are working on advancing products under an IND, physicians can use FMT products after securing reasonable consent from patients.
Jones has been a vocal critic of the enforcement discretion policy, suggesting that the FDA has in a way generated a pathway for patients and doctors to conduct stool transfers, without the requisite safety and oversight. In addition, she said, the policy has slowed the process of trial enrollment for companies like Rebiotix and others in the field.
“What it (enforcement discretion) did was it changed the referral patterns,” she said. “It set the whole field back because nobody really knows now how those products work, or if they were safe … I would say there was a fivefold decrease in enrollment rates through the course of our programs based on the enforcement discretion issues. We would have had a safe product out to the for patient use well before the timeframe that we’re talking about now.”
Others in the field, such as Finch Therapeutics CEO Mark Smith (who helped co-found OpenBiome) have asserted that while enrollment in placebo-controlled studies is difficult when patients have open-label access to FMT, it is still feasible, pointing out many patients do not even qualify for clinical trial enrollment due to comorbidities or because they have no access to sites.
Rebiotix’s full late-stage dataset is expected by this fall, but the coronavirus pandemic has put somewhat of a question mark on that timeline, Lee said.
“Unfortunately, C. diff keeps going on and in fact, with the advent of a lot of people heading into the ICU, we expect to see an uptick in this,” she said of the ongoing Phase III study. “So for those sites that are still accepting patients, and they’re still doing the clinical program. What’s difficult is that a lot of clinical people are grounded in terms of traveling to the site … and so access to the clinical sites to do data monitoring is tricky at this point in time.”
While drug developers such as Rebiotix, Finch and Seres continue on with their quest to develop drugs from bugs using donated stool, since last summer, a handful of safety issues related to the raw material have caused a stir.
Last year, the death of an immuno-compromised 73-year old patient in an FMT trial conducted by Massachusetts General Hospital (MGH) struck a chord with researchers, after post-mortem testing revealed the stool donation used contained a rare type of E. coli bacteria. The incident shed light on the non-standardized methods different researchers have been employing in order to screen and purify the stool used in such trials.
Making matters worse, the FDA issued a safety alert in March after E. coli-tainted stool from the widely used non-profit stool bank OpenBiome made six patients sick, four of whom were hospitalized. Two other FMT recipients whose transplants comprised OpenBiome’s product also died. Weeks later, the FDA issued another safety alert highlighting the risk of potential transmission of the new coronavirus from fecal matter derived from donors used in FMT and said that additional safety measures are necessary.
Companies in the field are now highlighting these incidents as another reason to wait for their products, which may still be harnessed from the same raw material, but must undergo the same rigorous safety and efficacy testing as any other chemical or biologic therapy does before hitting the market.
What these FDA alerts show is that with FMT, there will always be an issue that must be chased, said Seres’ chief technology officer John Aunins in a previous interview. “You didn’t test previous agents, or you use the test that wasn’t sensitive enough or a pathogen emerges and you don’t have a test for it,” he said. “So it’s, it’s just an inherent situation with that kind of a product.”
Jones echoed the sentiment, saying she believes the company’s provisions for safety will hold it in good stead. “We haven’t had the same issues that they’ve (OpenBiome) had in terms of safety,” she said.