P0129 - CP101 Engraftment Drives Efficacy: Results From a Randomized, Placebo-Controlled Trial Evaluating CP101, an Investigational Orally Administered Microbiome Therapeutic for Prevention of Recurrent C. difficile Infection

Jessica R. Allegretti, MD, MPH, FACG¹, Colleen R. Kelly, MD, FACG², Thomas Louie, MD³, Monika Fisher, MD, MSc⁴, Susy Hota, MD, MSc⁵, Bharat Misra, MD⁶, Nicholas W. Van Hise, PharmD⁷, Eugene F. Yen, MD, MBA, FACG⁸, Jeff S. Bullock, MD⁹, John Pullman, MD¹⁰, Richard Nathan, DO¹¹, Michael Silverman, MD¹², Ian Davis, MD¹³, Sarah McGill, MD, MS¹⁴, Ylaine Gerardin, PhD¹⁵, Josh Silva, BS¹⁵, Sahil Khanna, MBBS, MS¹⁶, Darrell Pardi, MD, MS¹⁶, Robert Orenstein, DO¹⁷, Ari Grinspan, MD¹⁸, Najwa El-Nachef, MD¹⁹, Colleen S. Kraft, MD, MSc²⁰, Shrish Budree, MD¹⁵, Thomas J. Borody, MD, PhD, DSc, FRACP, FACG²¹, Zain Kassam, MD, MPH^15
1Brigham & Women’s Hospital, Harvard Medical School, Boston, MA; ²Warren Alpert Medical School of Brown University and Lifespan Physician Group Gastroenterology, East Providence, RI; ³University of Calgary, Calgary, AB, Canada; ⁴Indiana University, Indianapolis, IN; ⁵University of Toronto and University Health Network, Toronto, ON, Canada; ⁶Borland Groover Clinic, Jacksonville, FL; ⁷Metro Infectious Disease Consultants, Burr Ridge, IL; ⁸NorthShore University HealthSystem, Evanston, IL; ⁹Southern Star Research Institute, San Antonio, TX; ¹⁰Mercury Street Medical, Butte, MT; ¹¹Snake River Research, Idaho Falls, ID; ¹²St. Joseph's Health Care and Western University, London, ON, Canada; ¹³Dalhousie University, Halifax, NS, Canada; ¹⁴University of North Carolina Hospitals, Chapel Hill, NC; ¹⁵Finch Therapeutics, Somerville, MA; ¹⁶Mayo Clinic, Rochester, MN; ¹⁷Mayo Clinic, Phoenix, AZ; ¹⁸Mount Sinai Hospital, New York, NY; ¹⁹University of California San Francisco, San Francisco, CA; ²⁰Emory University Hospital, Atlanta, GA; ²¹Centre for Digestive Diseases, Five Dock, New South Wales, Australia

Introduction: Disruption of the microbiome is key to the pathogenesis of recurrent Clostridioides difficile infection (CDI). CP101 is an investigational orally administered microbiome therapeutic designed to restore microbiome diversity and enable early intervention in the management of recurrent CDI. Engraftment, the presence of administered microbes that colonize the gastrointestinal tract, is a key pharmacokinetic marker of microbiome therapeutics; however, there is a paucity of data on the impact of engraftment on clinical efficacy in recurrent CDI.

Methods: We conducted a double-blind, randomized, placebo-controlled trial (PRISM3) enrolling adults who received standard-of-care antibiotics for recurrent CDI. Patients with first CDI recurrence at high-risk for further recurrence (≥65 years), or those with two or more recurrences were eligible. The qualifying CDI episode was diagnosed prior to study entry by guideline recommended testing (PCR-based or toxin EIA-based). Following CDI antibiotics, participants completed a minimum 2-day washout period to limit the impact of residual antibiotics on CP101. Eligible participants were randomized 1:1 to receive one-time oral administration of CP101 or placebo without bowel preparation. The primary efficacy endpoint was sustained clinical cure, defined as an absence of CDI recurrence through Week 8 following dosing. Engraftment of CP101 was measured using 16S rRNA gene amplicon sequencing.

Results: Among the 198 enrolled participants analyzed, the CP101 arm demonstrated a statistically significant and clinically meaningful improvement in sustained clinical cure compared to placebo through Week 8 (74.5% [76/102] vs 61.5% [59/96], p=0.0488). Participants treated with CP101 had significantly higher engraftment of CP101-associated taxa compared to placebo (Fig. 1a), and engraftment was both rapid and sustained over time (p< 0.0001 at Week 1, p< 0.0001 at Week 8). Clinically, CP101 engraftment was strongly associated with efficacy in recurrent CDI. Among participants with successful engraftment at Week 1 following CP101, 96.0% achieved a sustained clinical cure, while unsuccessful engraftment resulted in a 54.2% sustained clinical cure rate, similar to placebo following CDI antibiotics (p< 0.001) (Fig. 1b-c).

Discussion: These data suggest that successful CP101 engraftment drives high rates of sustained clinical cure in recurrent CDI. Future trials will deploy strategies to optimize engraftment by further minimizing the effect of residual CDI antibiotics.



Disclosures:


Jessica R. Allegretti, MD, MPH, FACG¹, Colleen R. Kelly, MD, FACG², Thomas Louie, MD³, Monika Fisher, MD, MSc⁴, Susy Hota, MD, MSc⁵, Bharat Misra, MD⁶, Nicholas W. Van Hise, PharmD⁷, Eugene F. Yen, MD, MBA, FACG⁸, Jeff S. Bullock, MD⁹, John Pullman, MD¹⁰, Richard Nathan, DO¹¹, Michael Silverman, MD¹², Ian Davis, MD¹³, Sarah McGill, MD, MS¹⁴, Ylaine Gerardin, PhD¹⁵, Josh Silva, BS¹⁵, Sahil Khanna, MBBS, MS¹⁶, Darrell Pardi, MD, MS¹⁶, Robert Orenstein, DO¹⁷, Ari Grinspan, MD¹⁸, Najwa El-Nachef, MD¹⁹, Colleen S. Kraft, MD, MSc²⁰, Shrish Budree, MD¹⁵, Thomas J. Borody, MD, PhD, DSc, FRACP, FACG²¹, Zain Kassam, MD, MPH¹⁵. P0129 - CP101 Engraftment Drives Efficacy: Results From a Randomized, Placebo-Controlled Trial Evaluating CP101, an Investigational Orally Administered Microbiome Therapeutic for Prevention of Recurrent C. difficile Infection, ACG 2021 Annual Scientific Meeting Abstracts. Las Vegas, Nevada: American College of Gastroenterology.