乌鸦传媒

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Two bacteria-based treatments for recurrent Clostridioides difficile infection showed positive results in late-stage randomized trials, bringing them a step closer to the clinic.

The studies tested proprietary mixtures of bacterial agents that colonize the intestinal tract and prevent C. difficile from thriving, and were reported on at the Digestive Disease Week (DDW) virtual meeting.

One, RBX2660, comprises live bacteria and delivered via enema. Its manufacturer, a Ferring unit known as Rebiotix, has said little publicly about its exact composition. The other product, SER-109, is an oral mixture of Firmicutes bacterial spores.

In a Rebiotix-sponsored media briefing, an investigator in the RBX2660 trials said the treatment is similar in concept to fecal microbiota transplantation but overcomes some of that approach's limitations.

Fecal transplant, in which the material is obtained from human donors, is inherently variable, meaning that results are difficult to reproduce reliably, noted Paul Feuerstadt, MD, of Yale University in New Haven, Connecticut. "What we're striving for is a more predictable safety and efficacy profile," he said, with "a pharmaceutically produced product" that provides consistent results. The same could be said for SER-109, developed by Seres Therapeutics.

At DDW, Christine Lee, MD, of the Vancouver Island Health Authority in British Columbia, presented results from RBX2660's main phase III trial, called , involving 320 patients randomized 2:1 to single doses of the active product or saline placebo. Patients showing recurrence within 8 weeks were considered treatment failures and were reassigned to either open-label RBX2660 or another C. diff therapy. Those without short-term recurrence -- just under 270 -- were followed through 6 months.

Rates of treatment success were 70.4% (95% CI 63.7%-76.8%) with RBX2660 versus 58.1% (95% CI 48.4%-68.2%) with placebo, leading to a 98.6% probability of superiority in a Bayesian model, Lee reported.

Numerically greater differences in recurrence risk were seen in patients ages 65 and older compared with those younger (12.7 vs 7.3 points, not statistically significant). The raw data also suggested that the benefit was concentrated in men -- with an efficacy advantage of 18.7 percentage points over placebo, compared with only 4.4 points among women -- but this difference, too, did not reach statistical significance.

And, similarly, there was no statistically significant difference in efficacy between patients with more than three prior C. diff episodes versus three or fewer, even as point estimates suggested that patients with more than three previous bouts were more likely to respond to RBX2660 (16.1 vs 5.4 percentage point differences from placebo). Overall, it appeared that the trial was underpowered for these subgroup analyses.

Lee said "no meaningful difference" was seen in adverse events (AEs) between RBX2660 and placebo. Among 267 patients evaluated for safety, a total of 368 events occurred, mostly mild to moderate gastrointestinal symptoms (Lee did not separate these by treatment assignment). Two patients in the RBX2660 group withdrew prematurely because of diarrhea, but the investigators determined it was not treatment-related in either case.

Interim results from a separate open-label RBX2660 trial, , were also reported at DDW in a poster presentation. This trial is using "less restrictive" eligibility criteria than in the randomized trial in an attempt to capture more of a "real-world patient population," the investigators (including Feuerstadt) explained in the poster. In particular, patients with irritable bowel syndrome and inflammatory bowel disease were allowed to enroll, whereas they were excluded from PUNCH CD3, said co-author Sahil Khanna, MBBS, of the Mayo Clinic in Rochester, Minnesota.

With 125 treated thus far in the study -- enrollment is ongoing with an ultimate goal of about 500 -- efficacy appears to be very similar to that seen in the main PUNCH CD3 trial, the poster indicated. Some 75% of those initially enrolled remained recurrence-free at 8 weeks, and 74% of those had no episodes through 6 months. Safety findings were similar as well, with no serious AEs related to treatment.

Results with SER-109, the oral bacterial spore product, were largely the same. These came from a trial called , in which 182 patients were randomized 1:1 to the active agent or placebo.

As reported by Louis Korman, MD, of Capital Digestive Care in Washington, and colleagues in a poster, the randomization resulted in patients assigned to SER-109 trending younger and more female, and also more likely to have three or more previous C. diff episodes.

As with the RBX2660 trials, patients were initially evaluated at 8 weeks after initial dosing (patient received four capsules daily for 3 days after randomization), at which point 40% of the placebo group had developed recurrence, compared with 13% of those receiving SER-109, for a relative risk of 0.32 (95% CI 0.18-0.58).

SER-109 maintained this advantage through week 24 in the study: 47% recurrence with placebo versus 21% with the active agent (RR 0.46, 95% CI 0.30-0.73). Subgroup analyses confirmed the advantage for participants ages 65 and older and for those who had previously received vancomycin or fidaxomicin.

Nearly all participants showed treatment-related AEs, but these occurred at similar rates in both study arms, both overall and for specific symptoms. No special safety signal for SER-109 was observed.

Neither Rebiotix nor Seres has announced specific plans for submitting applications for marketing approval.