There are limited therapeutic options for people living with autosomal dominant polycystic kidney disease (ADPKD); currently, the only real standards-of-care include dialysis and kidney transplantation. When discussing the therapeutic landscape, Dr. Allen Davidoff, PhD, explains:
Only one drug has been approved for the treatment of polycystic kidney disease. However, its side effect profile means it is only used in about 5% of the ADPKD patient population.
That is why Dr. Davidoff, and the rest of his team at XORTX Therapeutics (“XORTX”) are working to develop novel solutions for those living with ADPKD. The goal is not just to expand the treatment landscape, but to genuinely contribute to patients’ wellbeing.
In a recent interview with Patient Worthy, Dr. Davidoff discussed what ADPKD is, its symptoms, the process of developing a new therapy, and how XRx-008 has the potential to confer significant health benefits.
About Dr. Allen Davidoff, PhD
Dr. Allen Davidoff received his PhD in Integrative Cardiovascular Physiology and Biophysics – studying Congestive Heart Failure at the University of Calgary. His academic background also includes transplant immunology of kidneys and heart.
In the early 2000s, Dr. Davidoff began his early career in Cardiome Pharma in Vancouver developing oxypurinol for gout and congestive heart failure, as well as an antiarrhythmic now marketed and sold in Europe. Prior to forming XORTX Therapeutics, Dr. Davidoff co-founded Stem Cell Therapeutics and worked for eight years as the Chief Scientific Officer, and Vice President of Product Development.
Now, Dr. Davidoff is the Founder and CEO of XORTX Therapeutics, which its website describes as:
a drug-based biotechnology company primarily focused on orphan disease indications which have aberrant purine metabolism and frequently high serum uric acid imbalance.
Dr. Davidoff explains:
A colleague and I founded XORTX based on a number of discoveries that showed that chronically high uric acid levels in a number of diseases were associated with weight gain, high blood pressure, insulin resistance, and diabetes, as well as the health consequences of diabetes. We confirmed many of these observations in new animal models, and the opportunity to aggregate patents based on these discoveries allowed the Company to consider developing oxypurinol, a drug which received an FDA-approvable letter, but was never advanced beyond that point of development and never marketed anywhere in the world.
Learn more about Dr. Davidoff and the team at XORTX Therapeutics.
Developing a Therapeutic Option for ADPKD
Currently, XORTX is planning to develop therapeutics that improve the quality-of-life (QOL) for individuals living with progressive kidney disease. The company is developing a product—XRx-008—that inhibits an enzyme called xanthine oxidase. In health the xanthine oxidase enzyme breaks down purines for the excretion as uric acid. However, increasing evidence suggest that this enzyme can act to accelerate disease progression, therefore the company believes that reducing uric acid levels could slow or reduce ADPKD progression.
To get to this point, Dr. Davidoff explains, meant:
During the inception of XORTX our understanding was that uric acid was associated with a disease axis and then as more evidence accumulated more broadly, it became clear that a number of disease areas existed where xanthine oxidase inhibition might prove successful. Through our contacts with specialists in chronic kidney disease and diabetic nephropathy, we saw growing evidence that inhibition of xanthine oxidase may provide a therapeutic benefit.
So we began developing xanthine oxidase. We’ve made developments over time to improve the bioavailability of oxypurinol and we are poised to start a Phase 3 trial treating with XORLOTM our proprietary oxypurinol formulation. That places the Company ready to initiate a registration clinical trial and marketing of this drug, and that’s a source of pride.
This process has included creating a high-quality, pure drug and characterizing its impurities to create a tablet; manufacturing these drugs for the Phase 3 trial; working with the regulatory team to refine the protocol, de-risking for clarity, and visiting the FDA for a protocol discussion; tailoring the protocol; and working with clinical research organizations on the protocol and site identification.
Although this process takes time, Dr. Davidoff hopes that the trial can begin enrolling patients by mid-2023 and that the drug can gain accelerated approval by 2026.
An Overview of XRx-008
So what actually is XRx-008? Dr. Davidoff shares:
The concept for this drug is based on an understanding that the xanthine oxidase enzyme is critical in our healthy life for breaking down purines into uric acid and excreting them. In a variety of kidney diseases, we have observed and very recently described that when you look at PKD models, you can see increased xanthine oxidase expression in the kidney. This suggests that xanthine oxidase plays a role in pathology and is associated with other markers of kidney injury. Prior research has also shown that uric acid increases drives kidney expansion. We have an ideal therapy to inhibit that enzyme and so its pathological role and supress the pathology we’re observing in animal models.
Independently conducted studies have suggested that the results seen in animal models are replicable in human models. So the goal of XORTX with XRx-008 is to take a proprietary formulation of oxypurinol for increased bioavailability, deliver it across the therapeutic range, inhibit disease progression, and stabilize ADPKD.
Learn more about XRx-008.
What is Autosomal Dominant Polycystic Kidney Disease (ADPKD)?
Autosomal dominant polycystic kidney disease is the most common form of polycystic kidney disease (PKD), a genetic disorder which causes cysts to grow in the kidneys. Dr. Davidoff explains:
ADPKD is initiated by a variety of genetic mutations that change the way that fluid is transported in and out of the kidneys. Individuals usually see a diagnosis in their early 20s when cysts are identified. These grow in number and size, and are associated with kidney function decrease. By mid-life, these individuals have kidneys that, rather than being fist-sized, are half a liter or more in size. When people reach their 40s and 50s, the kidneys are greater than a liter in size and not functioning. 50% of people with ADPKD lose a kidney by their mid-50s.
PKD1 and PKD2 gene mutations have been associated with ADPKD. These mutations, as the name suggests, are inherited in an autosomal dominant pattern. This means that someone must inherit just one mutated copy of a gene to have ADPKD. Symptoms and characteristics of ADPKD can include:
- Kidney cysts (often asymptomatic when they are smaller)
- Liver and pancreatic cysts
- Headaches
- High blood pressure
- Hematuria (blood in the urine)
- Fatigue
- “Fluttering” in the chest
- Urinary tract infections
- Pain in the back, sides, and between the ribs and hips
- Kidney stones
- Kidney failure
Many treatments focus on managing symptoms; these include surgery, blood pressure and pain medications, and dialysis. As Dr. Davidoff says:
This is a serious disease with very few therapeutic options. That is why XORTX is developing XRx-008.
Patient-Centricity: A Key Part of the XORTX Mission
One of the central parts of the XORTX mission is patient-centricity and ensuring that the needs of patients are met. To achieve this goal, XORTX frequently works with the PKD Foundation, a nonprofit organization that funds research into polycystic kidney disease. Says Dr. Davidoff:
In the future, we hope to conduct a survey of the individuals enrolled in the patient registry and work more closely with the PKD Foundation will help alert these patients of upcoming clinical trials. There are opportunities to use the substantial tools that they have built, like the Patient Outcomes database, to better understand the individuals eligible for recruitment and understand more clearly how their disease progresses. Those are key elements of how one addresses a variety of questions in clinical trial design.”
Ultimately, the XORTX team wants to slow the progression of ADPKD — but they also want to ensure that those affected are given the best help and resources possible. From reducing pain and stopping the need for dialysis, XORTX wants to keep individuals off of dialysis. Dr. Davidoff shares:
That’s our ultimate goal. We want to relieve these symptoms and these gnawing day-to-day concerns. If we can help patients, we’re doing what we were motivated to do.
