XORTX Therapeutics Inc. is a biopharmaceutical company with three clinically advanced products in development – XRx-008 for Autosomal Dominant Polycystic Kidney Disease (ADPKD), XRx-101 for Coronavirus / COVID-19 infection and XRx-221, under a letter of intent to establish a co-development program with Teijin Pharma Limited, for Type 2 Diabetic Nephropathy (T2DN). The Company has strong intellectual property rights and established proof of concept through independent clinical studies. XORTX is working to advance its clinical development stage products that target xanthine oxidase to inhibit production of uric acid. At XORTX Therapeutics, we are dedicated to developing medications to improve the quality of life and future of patients.
Pipeline:
Coronavirus – COVID-19 Program
The Company is actively reviewing current studies characterizing the outbreak of COVID-19. These published reports clearly illustrate that acute kidney injury and acute pulmonary injury are key factors in the most serious cases of COVID-19 hospitalization and death.
XORTX believes that XRx-101 (a formulation of Oxypurinol) could be relevant and important for decreasing kidney and lung injury, as well as health consequences associated with Coronavirus infection. Indeed, xanthine oxidase inhibitors (XOI) have been reported to have a potent antiviral effect against influenza-A virus5 and herpes infections suggesting a potential therapeutic benefit for suppressing the Coronavirus infection.
XRx-101 as a Treatment for Coronavirus / COVID-19.
Oxypurinol (XORTX’s XRX-01) is a well studied drug that is known to be clinically safe and effective for inhibiting xanthine oxidase and decreasing production of uric acid. Owing to its advanced development status, Oxypurinol could be quickly developed to help treat those most severely affected by COVID-19. XORTX has filed new intellectual property rights for XRx-101 for the treatment of respiratory and kidney disease due to viral infection.
COVID-19 is a serious viral infection due to a coronavirus. Coronavirus infections such as SARS and MERS and specifically COVID-19 can be frequently accompanied by pneumonia, acute kidney injury, proteinuria and hematuria1,2. Acute kidney injury (“AKI”) has been identified as an independent risk factor for patients’ in-hospital mortality due to COVID-19 as well as other Coronavirus infections2. Early reports suggested a lower incidence (between 3% to 9%) of AKI in those with COVID-19 infection2,6,7. Recent reports, however, have shown a higher frequency of renal abnormalities. A study of 59 patients with COVID-19 found that 34% of patients developed massive albuminuria on the first day of admission and 63% developed proteinuria during their stay in hospital8
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Based on these recent studies, the Company believes that its Oxypurinol formulation, XRx-101, has the potential to be a front-line treatment for severe cases of Coronavirus and that this therapy has the ability to decrease morbidity and mortality in hospitalized patients. Management’s belief that XRx-101 is a possible treatment for COVID-19 is based upon its potential anti-viral properties, and historic animal and human data that show that acute tissue injury can lead to rapid accumulation of uric acid and uric acid crystals that aggregate in kidneys and induce acute kidney injury3,4. When acute kidney injury accompanies pneumonia, post-discharge outcomes are worse than either diagnosis alone.
Patients who survive a pneumonia hospitalization and develop acute kidney injury are at high risk for major adverse kidney events including death and should receive careful follow-up4. Perhaps more importantly, Oxypurinol has been previously studied for anti-viral properties9, a characteristic that may decrease morbidity and mortality of COVID-19. Importantly, Oxypurinol has in the past received an “Approval Letter” from the US FDA, potentially accelerating development for this purpose.
The triple action of XRx-101, as an anti-viral therapy, to decrease the production of uric acid and increase the aqueous solubility of uric acid thereby decreasing uric acid crystal formation associated with tumor lysis “like” syndrome due to Coronavirus infection. Decreasing uric acid with a xanthine oxidase inhibitor is associated with decreased inflammation, oxygen radical concentrations, cytokine concentration and tissue protection. Any agent that decreases the severity of primary or secondary pneumonia leading to acute kidney injury is potentially highly relevant.
The Virus:
The complete clinical picture with regard to COVID-19 is not fully known, but evolving rapidly as more is learned. Reported illnesses have ranged from very mild (including some with no reported symptoms) to severe, including illness resulting in death. While information so far suggests that most COVID-19 illness is mild, recent reports suggest serious illness occurs in 10-14% of cases. Older people and people of all ages with severe chronic medical conditions — like heart disease, lung disease and diabetes, for example seem to be at higher risk of developing serious COVID-19 illness. A CDC Morbidity & Mortality Weekly Report that looked at severity of disease among COVID-19 cases in the United States by age group found that 80% of deaths were among adults 65 years and older with the highest percentage of severe outcomes occurring in people 85 years and older.
Autosomal Dominant Polycystic Kidney Disease:
Autosomal Dominant Polycystic Kidney Disease (ADPKD) is one of the most common life-threatening genetic diseases, affecting many individuals in all parts of the world. ADPKD is a progressive kidney and cardiovascular disease. Cardiovascular disease is the leading cause of premature mortality in patients with ADPKD, with over 80% of deaths attributable to coronary artery diseases (1, 2). Patients at greatest risk are those who have high serum uric acid (hyperuricemia) and high blood pressure (hypertension).
Hyperuricemia and hypertension are frequently early events in the progression of ADPKD and accompany the development of kidney cyst growth and kidney volume expansion. Together these precede the development of reduce kidney function. Hypertension is present in about half of all patients ages 24-30, and in all patients who reach kidney failure (3). The high prevalence of hypertension is considered to contribute to the excess risk of cardiovascular disease in ADPKD patients (4-6). Experimental data from animal studies suggests that process such as inflammation, renin-angiotensin-aldosterone system, insulin resistance and endothelial dysfunction may be involved in the pathogenesis of the disease (7, 8). This combination of risk factors is not unlike those observed in models of hyperuricemia and may directly contribute to vascular pathology seen in these patients or may be pathway factors via which hypertension leads to kidney disease progression and cardiovascular disease (9-13). Recently, the causative effect of high serum uric acid on high blood pressure in new onset hypertension has been reported, in the peer reviewed journal, ‘Hypertension’, by Feig et al.
The goals of treatment of ADPKD are to slow the progression of kidney damage and control related complications. Varied therapeutic strategies targeting ADPKD have been explored such as tight blood pressure control (14) using various inhibitors of the renin angiotensin aldosterone system (RAAS) (15) as well as preventing the progressive decline of glomerular filtration rate (GFR) – HALT trial. None of these therapies so far appear to slow the progression of kidney disease due to ADPKD. Transplantation or dialysis my be the only options available once end-stage renal disease develops. Insulin resistance and diabetes are also serious concerns for patients with ADPKD.
Diabetic Nephropathy:
Diabetes is prevalent worldwide and represents and EPIDEMIC in the US:
According to the CDC, diabetes affected 11.3% (~25.6 Million) of the U.S. population age 20 or older in 2010, with about 1.9 million people being newly diagnosed each year (2).
In 2005–2008, based on fasting glucose or hemoglobin A1C levels, 35% of U.S. adults aged 20 years or older had pre-diabetes (metabolic syndrome) (2).
Progressive kidney disease – Diabetic Nephropathy is responsible for nearly half of all kidney disease:
Diabetic nephropathy is the most common cause of chronic kidney failure and end-stage kidney disease in the United States and worldwide. In the U.S., diabetic nephropathy accounts for about 45% of new cases of ESRD(3).
About 30% of patients with type I or type II diabetes develop evidence of nephropathy (3).
XORTX’s Solution:
XORTX’s business model is built upon strong basic science, and recent clinical science successes, including:
Animal and epidemiological studies that have demonstrated an association between increased serum uric acid and hypertension (4,5).
Two recently completed Phase 2 Trials have demonstrated uric acid lowering agents are effective at reducing blood pressure in new onset adolescent hypertension (6,7).
Animal and epidemiological studies have demonstrated a statistically significant association between serum uric acid greater than the upper limit of normal and insulin resistance (8, 9), thus strongly suggesting that XOIs may be a potent option to treat pre-diabetics and diabetes.
Recent evidence has emerged in the last decade to suggest uric acid has several reported effects by which it may cause diabetic nephropathy (10).
Three observational studies in patients with diabetes have generated a substantial body of evidence that serum uric acid levels are strong determinants of the development of diabetic nephropathy and the loss of kidney function among individuals with diabetes, both Type 1 and Type 2 (11,12,13).
Two randomized controlled trials in patients with CKD and/or diabetic nephropathy demonstrated that xanthine oxidase inhibition can decrease uric acid and concentration and significantly improve kidney function (14, 15).
XORTX entered into a LOI to establish a co-development agreement with Teijin Pharma Limited in 2019 for TMX-049, XORTX’s XRx-221.
The Disease:
Diabetic nephropathy (DN) is a progressive kidney disease caused by thickening of the capillaries in the kidney glomeruli. People with both types I and type II diabetes are at risk. The risk is higher if blood-glucose levels are poorly controlled. Furthermore, once nephropathy develops, the greatest rate of progression is seen in patients with poor control of their blood pressure.
Diabetic nephropathy is the most common cause of chronic kidney failure and end-stage kidney disease in the United States and worldwide (1,2). In the U.S., diabetic nephropathy accounts for about 40% of new cases of ESRD (3). About 20–30% of patients with type I or type II diabetes develop evidence of nephropathy, but in type II diabetes, a considerably smaller fraction of these progresses to ESRD. However, because of the much greater prevalence of type II diabetes, such patients constitute over half of those diabetic patients currently starting on dialysis.
The goals of treatment of diabetic nephropathy are to slow the progression of kidney damage and control related complications. Different therapeutic strategies targeting diabetic nephropathy have been explored such as tight glycemic control (4), tight blood pressure control (5), and various inhibitors of the renin angiotensin aldosterone system (RAAS) (6-8). While these therapies appear to slow the progression of kidney disease due to diabetes, none of them are curative. Dialysis may be necessary once end-stage renal disease develops. At this stage, a kidney transplant must be considered. Another option for type 1 diabetes patients is a combined kidney-pancreas transplant.
Recent evidence has emerged in the last decade to suggest uric acid has several reported effects by which it may cause diabetic nephropathy; including endothelial dysfunction, increased activity of the renin-angiotensin system, induction of inflammatory cascades, and pro-fibrososis cytokine activation, all of which have been demonstrated to contribute to progression of micro-vascular disease and thereby renal injury in diabetic nephropathy (9). Evidence from three observational studies in patients with diabetes have generated a substantial body of evidence that serum uric acid levels are strong determinants of the development of diabetic nephropathy and the loss of kidney function among individuals with diabetes, both Type 1 and Type 2 (10,11,12). In addition, two randomized controlled trials in patients with CKD and/or diabetic nephropathy demonstrated allopurinol significantly improved kidney function (13, 14).
As the total number of people with type I and II diabetes is predicted to rise dramatically the prevalence of diabetic nephropathy is also expected to increase dramatically. Current treatments appear to slow the progression of kidney disease due to diabetes, none of them are curative. Pharmacologic therapy focused on treatment of hyperuricemia may provide a new and effective approach for the treatment of DN.
Strategic partnerships are an integral part of our corporate strategy. XORTX Therapeutics is working with a number of development and commercialization partners with proven competence in garnering new approvals, successfully launching products and are committed to developing novel products that meet the needs of both patients and physicians.
XORTX is developing two products to treat progressive kidney disease in patients with autosomal dominant polycystic kidney disease (ADPKD) or diabetic nephropathy (DN). The Company’s ADPKD program is a fast track approach to reposition a new formulation of Oxypurinol in this rare disease. Oxypurinol is a drug that has been extensively studied and characterized as safe and effective for decreasing uric acid in a patient’s blood. Recent clinical trials have shown that uric acid concentration in the blood is a risk factor for these patients and that decreasing uric acid has the potential to lower this risk factor and potentially slow the deterioration of kidney function. XORTX’s XRx-008 program, uses Oxypurinol, a drug with a well characterized clinical safety and effectiveness history in a patent pending formulation for this purpose. XORTX is also evaluating several drug candidates for use in treating diabetic nephropathy under the XRx-221 program and in preparation for Phase 2 clinical trials.
Pilot clinical studies published in recent years, suggests that blood concentrations of uric acid may be a causative in hypertension, inflammation, metabolic syndrome, diabetes and health consequences of diabetes such as diabetic nephropathy/kidney injury. The Company’s patent portfolio, and similarly this therapeutic approach, continues to be validated in a number of independent studies that show that by decreasing serum uric acid (SUA) can reduce markers of inflammation, progression of kidney injury including protienuria, glomerular filtration rate, hypertension, insulin resistance, and chronic kidney disease, in a clinically meaningful way. XORTX is dedicated to growing its patent portfolio to strengthen and broaden the Company’s position in this field.
Autosomal Dominant Polycystic Kidney Disease (ADPKD):
ADPKD is an orphan indication disease affecting perhaps 1:500-1:2000 individuals and a leading cause of end stage kidney renal disease. It is a disease representing up to 5% of all patients who have kidney failure before the age of 60 years and is amongst the fastest progressing forms or kidney disease.
Evidence from a variety of recent studies has accumulated, supporting the concept that serum uric acid (SUA), when increased above the upper limit of normal is a “causative” mediator of hypertension, with strong secondary basic evidence suggesting a role of hyperuricemia (elevated serum uric acid) in the development of insulin resistance, diabetes and diabetic nephropathy.
Diabetic Nephropathy- A Health Consequence of Diabetes:
DIABETES is prevalent worldwide and represents and EPIDEMIC in the US: According to the CDC, diabetes affected 11.3% (~25.6 Million) of the U.S. population age 20 or older in 2010, with about 1.9 million people being newly diagnosed each year (2). In 2005–2008, based on fasting glucose or hemoglobin A1C levels, 35% of U.S. adults aged 20 years or older had pre-diabetes (metabolic syndrome) (2).
Progressive kidney disease – DIABETIC NEPHROPATHY is responsible for nearly half of all kidney disease:
Diabetic nephropathy is the most common cause of chronic kidney failure and end-stage kidney disease in the United States and worldwide.
In the U.S., diabetic nephropathy accounts for about 45% of new cases of ESRD(3). About 30% of patients with type I or type II diabetes develop evidence of nephropathy (3).
A NOVEL SOLUTION:
XORTX’s business model is built upon strong basic science, and recent clinical science successes, including:
Animal and epidemiological studies that have demonstrated an association between increased serum uric acid and hypertension (4,5).
Two recently completed Phase 2 Trials have demonstrated uric acid lowering agents are effective at reducing blood pressure in new onset adolescent hypertension (6,7).
Animal and epidemiological studies have demonstrated a statistically significant association between serum uric acid greater than the upper limit of normal and insulin resistance (8, 9), thus strongly suggesting that XOIs may be a potent option to treat pre-diabetes and diabetes.
Recent evidence has emerged in the last decade to suggest uric acid has several reported effects by which it may cause diabetic nephropathy (10).
Three observational studies in patients with diabetes have generated a substantial body of evidence that serum uric acid levels are strong determinants of the development of diabetic nephropathy and the loss of kidney function among individuals with diabetes, both Type 1 and Type 2 (11,12,13). Two randomized controlled trials in patients with CKD and/or diabetic nephropathy demonstrated xanthine oxidase inhibition can decrease uric acid concentration and significantly improved kidney function (14, 15).
Given the wealth of data on currently approved XOIs and novel mechanism of action, the introduction of these agents for the treatment and prevention of hypertension, diabetes and diabetic nephropathy represents a highly de-risked opportunity for developing new medical therapies in areas of large unmet medical need.
For more information please contact XORTX Therapeutics Inc.
XORTX Therapeutics Inc. is a publicly traded company listed on the OTCQB under the ticker symbol XRTXF . This is not investment advice. Please view the disclaimer found on this website.
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