Leveraging the Gut to Effectively Treat Disease

The gut is a critical system that plays a central role in many diseases by signaling to other organs how to respond to a variety of factors such as a meal, the microbiome or even pathogens.

OUR PLATFORM


UNDERSTANDING THE GUT

Our understanding of the gut or gastrointestinal (GI) tract is evolving on an almost daily basis, and the emerging view is that it is a critical and active sentinel organ that transmits signals to other organs throughout the body on how to respond to a meal, the microbiome or even pathogens.

We have created a unique discovery and design platform that integrates two critical concepts: (i) our proprietary chemistry capabilities that enable us to design and optimize gut-restricted compounds, which can provide a higher margin of safety than systemically absorbed compounds, and (ii) our stem cell-based translational technology called the Ardelyx Primary Enterocyte and Colonocyte Culture System, or APECCS, that enables us, at the lab bench, to discover the many targets the GI tract uses to control health and disease processes. Through this system, we are able to understand the biology that our targets control and thereby the mechanisms by which our compounds work to affect the physiological benefits we see in patients. Our platform can be applied across the entire GI tract, allowing for the broadest evaluation of disease targets to develop the best medicines for specific diseases.

 

The predictive ability of our platform enables us to better assess, at a very early stage, the potential for a small molecule compound to treat a disease.

HOW OUR PLATFORM WORKS

Gut-restriction Chemistry

Why is this important? Gut-restriction chemistry is a body of proprietary techniques, technology and know-how that we have developed in order to restrict the mechanism of the drug to targets within the GI tract, reducing absorption, which we believe will provide a safety benefit.

Stem Cell Technology

The Ardelyx Primary Enterocyte and Colonocyte Culture System (APECCS) is an in-vitro capability, derived from human GI stem cells obtained from healthy and diseased patients, we’ve developed that mimics key aspects of the human GI system.

WHAT IS APECCS?

We have developed a unique cell-culture system that simulates the gut in-vitro (outside the body).

We call this component of our discovery platform Ardelyx Primary Enterocyte and Colonocyte Culture System, or APECCS. APECCS involves obtaining biopsies of various segments of the human gut from both healthy subjects and those with a disease of interest. We then grow those cells under proprietary conditions emulating the way that they would naturally grow in the body. We have developed this into a miniaturized format that allows us to utilize it for cell-based drug screening, target validation, and to understand at the cell and molecular level how our drugs work and how identified compounds may interact with specific gut tissues.

ARDELYX
PRIMARY
ENTEROCYTE
COLONOCYTE
CULTURE
SYSTEM

Harvest Stem Cells from Gut
Grow in Monolayer Format
Measure Drug Response

“Everyone here is excited about what we’re creating and what it could mean for patients.”

- Kelli, HR

OUR CULTURE

DISCOVERY

Our platform serves as a discovery engine and has allowed us to identify a number of therapeutic programs that support long-term pipeline development.

RDX013
Our RDX013 program is aimed at discovering and evaluating orally administered small molecule therapeutic candidates that modulate the secretion of potassium in the GI tract. Our agents are designed to enhance potassium secretion in the colon in order to decrease systemic potassium, thereby correcting hyperkalemia, a condition caused by an excess of potassium in patients with chronic kidney disease (CKD) and/or congestive heart failure. For people with CKD or heart failure, and particularly those who are also taking highly beneficial renin-angiotensin-aldosterone system inhibitors (RAASi), there is a greater risk of developing hyperkalemia due to the side effects of those drugs and the kidney’s limited ability to keep potassium in balance. We have demonstrated proof-of-concept with RDX013 showing potassium secretion in preclinical models of disease.
RDX009
The focus of our RDX009 program is on the discovery and development of minimally systemic TGR5 agonists that stimulate the production of critical metabolic hormones such as those involved in the maintenance of the body’s reaction to nutrients and the maintenance and care of the structural integrity of the gut. We are evaluating RDX009 program molecules for their potential effect in multiple indications including nonalcoholic steatohepatitis (NASH), motility disorders and other GI indications. Our lead compound in this program is RDX8940, which is being evaluated for its safety and ability to stimulate sufficient levels of critical metabolic hormones to treat disease. We are considering pursuing multiple GI indications for the development of RDX8940. Given pre-clinical data we’ve generated, we have a particular interest in developing RDX8940 for the treatment of patients with NASH, a serious and devastating condition affecting the liver.
RDX011
In our RDX011 program, we are leveraging our knowledge of NHE3 inhibitors and their effect on sodium and phosphate homeostasis as we explore other potential indications for this unique mechanism of action.
RDX023
The focus of our RDX023 program is on the discovery and development of gut-biased (where we minimize, without completely restricting, systemic absorption) farnesoid X receptor (FXR) agonists for the treatment of GI and inflammatory diseases. FXR is expressed at high levels in the intestine and liver and plays a central role in the regulation of bile acid and lipid homeostasis. Systemic FXR agonists appear to have limitations based on their potential to have undesirable and negative effects on multiple systems in the body. We are evaluating our differentiated gut-biased RDX023 program molecules in animal models of nonalcoholic steatohepatitis (NASH)/nonalcoholic fatty liver disease (NAFLD), irritable bowel disease (IBD), bile acid diarrhea and other indications.