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Selection and preclinical development of a bacteria-targeting, non-antibiotic lead candidate to improve cancer chemotherapy outcomes

Award Information
Agency: Department of Health and Human Services
Branch: National Institutes of Health
Contract: 4R44CA233157-02
Agency Tracking Number: R44CA233157
Amount: $1,987,050.00
Phase: Phase II
Program: SBIR
Solicitation Topic Code: 102
Solicitation Number: PA17-302
Solicitation Year: 2017
Award Year: 2019
Award Start Date (Proposal Award Date): 2019-09-01
Award End Date (Contract End Date): 2021-07-31
Small Business Information
Durham, NC 27703-5420
United States
DUNS: 078519208
HUBZone Owned: No
Woman Owned: No
Socially and Economically Disadvantaged: No
Principal Investigator
 (919) 522-1906
Business Contact
Phone: (919) 522-1906
Research Institution

The long-term objective of this project is a therapeutic adjunct to prevent chemotherapy-induced diarrhea (CID)
based on a completely new mechanism of action targeting enteric bacteria. This Fast-Track SBIR proposal
outlines the strategy for selecting a lead development candidate to be evaluated in investigational new drug
(IND)-enabling studies to support a first-in-human trial. The focus of this project is prevention of diarrhea
associated with irinotecan (IRI), an important drug used to treat advanced colorectal and pancreatic cancer
patients. Intense, delayed diarrhea is the major reason for reducing, postponing or stopping IRI chemotherapy.
The cancer-killing, active agent of IRI is SN38, a potent topoisomerase I inhibitor. As part of its elimination from
the body, SN38 is detoxified primarily by the liver to an inactive glucuronide (SN38-G) that is subsequently
shuttled to the lower gastrointestinal tract. The β-glucuronidase enzyme (GUS) expressed in a subset of gut
bacteria metabolizes SN38-G back into SN38, which is highly toxic to enterocytes. This reactivation of SN38 by
bacterial GUS in the gut microbiome is a key triggering event leading ultimately to serious, delayed diarrhea.
A selective, non-proprietary bacterial GUS inhibitor (SBX-1) was previously shown to alleviate IRI-induced
diarrhea in rodents. Phase 1 of this project discloses five proprietary analogs of SBX-1 and outlines the
efficacy/tolerability studies to enable selection of the two most promising analogs to advance into Phase 2
SBIR studies. The lead candidate will be selected in the first aim of Phase 2. The remaining Phase 2 activities
include chemistry/manufacturing/control (CMC)-related work and regulatory/safety preclinical studies that will
transition this project from drug discovery to preclinical development.
Aim 1 (Phase 1): Profile novel SBX-1 analogs in vitro for their off-target pharmacology, cytotoxicity,
metabolism liability and stability in plasma. Aim 2 (Phase 1): Identify the two most promising SBX-1 analogs
based on their therapeutic window and candidacy for formal preclinical studies. Aim 3 (Phase 2): Select lead
candidate. Generate CMC and additional non-GLP preclinical data to support a pre-IND meeting with the FDA.
Aim 4 (Phase 2): Conduct CMC-related activities to enable formal evaluations of the formulated lead
candidate in GLP toxicology and safety pharmacology studies. A key deliverable in the proposed Phase 2 work
is a preclinical data package that will adequately qualify the lead candidate for further evaluation in an acute-administration,
first-in-human clinical trial in advanced colorectal and/or pancreatic cancer patients undergoing
irinotecan-containing chemotherapy.Symberix is pioneering a new class of medicines that works by eliminating harmful bacterial activity in the gut
microbiome without killing its vast populations of beneficial bacteria. This project aims to discover and develop
a microbiome-targeted therapeutic that selectively blocks the activity of a bacterial enzyme responsible for
triggering the debilitating and sometime deadly diarrhea that can occur in cancer patients using irinotecan, an
important chemotherapeutic agent. This project also sets the stage for potentially expanding this unique
microbiome-targeted approach to other anti-cancer drugs to enhance the quality of life and survival outcomes
for cancer patients at risk of suffering or dying from chemotherapy-induced diarrhea.

* Information listed above is at the time of submission. *

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