DUBLIN – Top-line data from a phase II pivotal trial of CP-101, Finch Therapeutics Group Inc.’s oral microbiome therapy for chronic Clostridioides difficile infection (CDI), are technically good, but how good is the big question.

The study, which recruited 206 patients, attained the primary endpoint – defined as the proportion of patients with no CDI recurrence eight weeks after receiving a single CP-101 capsule – with statistical significance (p<0.05). Those in the treatment arm achieved a cure rate of 74.5% as compared with 61.5% for those in the placebo arm. All participants also received standard-of-care antibiotics. The safety profile was benign – no serious treatment-related adverse events were reported.

Expectations for microbiome therapy have been buoyed by what appear to be extraordinarily high cure rates – typically 80% to 90% – for hospital procedures, although for the most part those studies comprise open-label rather than randomized controlled trials.

There are plenty more data to unpack from this study, which will happen in due course. For now, Somerville, Mass.-based Finch is touting its significance as the first clinical trial of an oral microbiome treatment to meet its primary endpoint, while conceding that it will not be sufficient for an approval. “Our expectation is we’re going to do a second study,” CEO Mark Smith told BioWorld.

Mark Smith, CEO Finch

The trial readout is, he said, “an important milestone for the maturation of this new modality.” For the wider microbiome field, this is the year when the rubber finally hits the road, after a decade or more of scientific buzz, high expectations and not a little hype.

Last month, Rebiotix Inc., of Roseville, Minn., reported what it termed “positive preliminary results” from a phase III trial in CDI of its enema-based microbiome therapy, RBX-2660, without releasing any actual numbers. Cambridge, Mass.-based Seres Therapeutics Inc. is due shortly to report data from a phase III trial of its oral microbiome therapy, SER-109, also in CDI. Its Cambridge neighbour, Vedanta Biosciences Inc., is also in the frame, with data from a phase II trial in CDI of VE-303, another oral microbiome product, expected later this year.

Comparisons will probably be unavoidable but would also be invidious given the differences in study populations. Seres, for example, has recruited patients with a minimum of three CDI recurrences, whereas both Finch and Vedanta have included patients after just one recurrence. Finch’s Prism3 study included a “meaningful” number of such patients, Smith said. It is easier to obtain a large separation between treatment and control groups in later-stage patients, as the benefits of sustained antibiotic therapy start to wane and recurrence occurs more frequently in the control population. “You’re going to have a high event rate,” he said.

Seres also requires participants to have a positive test for C. diff. toxin, whereas neither Finch nor Vedanta do. A positive toxin test is the more stringent test for active disease. However, Finch opted, Smith said, to follow real-world clinical practice by permitting either test, as more than 80% of patients are diagnosed on the basis of polymerase chain reaction (PCR), even if that method does not distinguish between active and inactive disease. Seres has attributed the previous failure of a phase II trial of SER-109 to the use of PCR, which probably led to the inclusion of patients without active disease.

The actual therapies differ markedly. CP-101, which has both fast track and breakthrough therapy designations, comprises full-spectrum donor-derived microbiota, which is defined on the basis of its potency rather than its composition. “The real focus is on the total viable cells being delivered,” Smith said. A single capsule contains 1011 viable bacterial cells. SER-109 is enriched for spore-forming Firmicute bacteria by exposing the donated microbiome to a biocidal step, which eliminates bacteria that do not form spores. Patients receive four capsules per day (equivalent to 3 x 107 colony-forming units) over three days. VE-303 comprises eight types of clonal human commensal strains sourced from bacterial cell banks rather than donated fecal material. In the ongoing phase II trial, participants are receiving either a high dose, comprising 10 capsules per day over 14 days, a low dose, comprising two capsules per day over 14 days, or placebo.

Finch has not yet finalized the timing of a second pivotal trial. The COVID-19 pandemic will probably lead to many more new CDI cases, given the widespread use of antibiotic therapy in hospitalized patients. “That is one of the primary risk factors for developing C. diff.,” Smith said. Its precautionary step to hold all drug substance for at least one year before release for clinical use provided it with a time buffer, which will allow it to include SARS-CoV-2 testing in its safety testing. It’s been a core element of its safety strategy, to allow for changes in the microbial threat environment. Not doing so could have had very serious repercussions. “COVID has really been an instrumental example,” Smith said.

Finch is also gearing up for a clinical trial of CP-101 in patients with chronic hepatitis B infection. The presumed mechanism in that setting is immunomodulatory, whereas recolonization of the gut mucosa is the goal in CDI. That study is due to get underway early next year, and interim data are expected by the end of 2021.

But for now, CDI is where the action is. Although Finch has been the first to report data this summer, it will not be the last. “A lot of people have been waiting for this moment in the field,” said Smith.

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