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PUNCH CD2: Microbiome drug safely prevents C. difficile recurrence

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RBX2660, a microbiome-based drug candidate, safely prevented recurrent Clostridium difficile infection after a standard course of antibiotics, according to results from the PUNCH CD2 trial presented at UEG Week 2016.

RBX2660 (Rebiotix) is a microbiota-based drug produced from live human-derived microbes, which has received orphan drug status, fast track status and breakthrough therapy designation from the FDA.

“Based on the results of the PUNCH CD2 study, our plan is to advance the clinical development of RBX2660 into a phase 3 trial in recurrent C. diff with the ultimate goal of bringing to market a drug product that addresses this critically important and potentially life-threatening disease,” Lee Jones, co-founder, president and CEO of Rebiotix, said in a press release.

Erik R. Dubberke

Christine Lee

In this randomized, double blind, placebo-controlled trial, Erik R. Dubberke, MD, MSPH, of the division of infectious diseases, Washington University School of Medicine, Christine Lee, MD, of the division of infectious disease at St. Joseph’s Hospital in Hamilton, Ontario, and colleagues evaluated two doses of RBX2660, two doses of placebo, or one dose of RBX2660 and one dose of placebo.

These were administered by enema 1 week apart in 127 patients (median age, 63 years; 62% women; median prior CDI episodes, 4) who were treated with antibiotics for CDI, which were discontinued 1 to 2 days before treatment with RBX2660. Patients who failed treatment were also able to receive up to two doses of open-label RBX2660.

In the masked phase, 66.7% of patients who received only one dose of RBX2660 were treated successfully (defined as absence of diarrhea for 8 weeks after the last dose) compared with 45.5% of the placebo group (P = .048). Patients who received two doses of RBX2660 had comparable success rates as the single dose group (61%), and the pooled success rate in both RBX2660 groups was superior to placebo (63.9% vs. 45.5%; P = .046).

Among the 30 treatment failures who received open-label RBX2660, 21 were successfully treated, for a combined success rate of 89.2% (P < .0001 vs. placebo).

There were no unexpected adverse events at 8 weeks, and they occurred in comparable proportions across groups, most of which were gastrointestinal.

The researchers concluded that RBX2660 is a safe and effective treatment for preventing recurrent CDI.

Universal donor pool appropriate

Additional data from the PUNCH CD2 trial were also presented at ACG 2016.

One poster presentation reported findings suggesting that the universal donor pool used to develop RBX2660 does not affect patient outcomes.

Because RBX2660 is manufactured from human-derived microbes that can be tracked to specific donors and patients, the researchers were able to evaluate associations between donors and the outcomes of the 83 patients who received at least one dose of the drug.

Ultimately, they found that the donor was not a significant predictor of treatment response (P > .99). Success and failure rates were the same for each donor, which was consistent with previous study results.

“Thus, the data from two clinical studies demonstrate that RBX2660 prepared from a universal donor pool is appropriate without donor-to-patient matching,” the researchers wrote. “However, this may not be the case for indications other than CDI.”

High placebo response

Sahil Khanna

Another poster, presented by Sahil Khanna, MBBS, MS, from the Mayo Clinic in Rochester Minn., and colleagues, found a higher than expected placebo response in the PUNCH CD2 trial and a similar study.

Among the 44 patients treated with placebo, 45.5% responded. However, there were no significant differences between responders and non-responders in terms of age, sex, median prior CDI episodes, median prior metronidazole courses or median prior vancomycin courses, and 90% of responders received vancomycin just before enrolling in the study compared with 87.5% of non-responders.

Further studies are needed to identify reasons for this placebo response, the researchers concluded.

Durable response

Khanna and colleagues also presented a post hoc analysis of the PUNCH CD2 study that found treatment with RBX2660 was durable in both the randomized and open-label trials.

After a median follow-up of 8.3 months (range, 1.6-14.9 months), 95.8% of patients remained CDI-free, and the median time to a new CDI episode was 135 days (range 61-259 days) after treatment with RBX2660.

Long-term follow-up is ongoing, they noted. – by Adam Leitenberger

References:

Orenstein R, et al. Abstract LB08. Presented at: United European Gastroenterology Week; Oct. 15-19, 2016; Vienna.

Ray A, et al. Abstract P109. Presented at: American College of Gastroenterology Annual Scientific Meeting; Oct. 17-19, 2016; Las Vegas, NV.

Khanna S, et al. Abstract P872. Presented at: American College of Gastroenterology Annual Scientific Meeting; Oct. 17-19, 2016; Las Vegas, NV.

Ramesh MS, et al. Abstract P1633. Presented at: American College of Gastroenterology Annual Scientific Meeting; Oct. 17-19, 2016; Las Vegas, NV.

Disclosures: Many of the researchers report financial relationships with Rebiotix.