The slow pace of kidney disease drug development has highlighted the need for improved trial designs to produce more practical guidance that may offer earlier interventions, Duke nephrologists say.
Specialists have expressed growing concern about the lack of progress in identifying new therapies. In the United States, 37 million people have been diagnosed with kidney disease; globally, the total is approximately 700 million.
Cost of care is also a growing concern. The Centers for Medicare and Medicaid Services spend $84 billion annually in the U.S. on kidney disease treatment; approximately $36 billion is spent on end stage renal disease (ESRD).
“We have experienced a relatively stagnant period of kidney disease research,” says Daniel Edmonston, MD, a Duke nephrologist and researcher who has studied trial outcomes related to kidney disease. “The most significant burden is the substantial morbidity experienced by our patients with kidney disease. We have certainly made advances, but in all categories of kidney disease and kidney replacement, our patients experience higher rates of death.”
After demonstration of the benefits of angiotensin receptor blockers (ARBs) and angiotensin converting enzyme (ACE) inhibitors for treatment of diabetic kidney disease in the early 2000s, progress largely stalled for nearly two decades in the treatment of chronic kidney disease. Two recent clinical trials now demonstrate clear benefit of a new drug class to treat kidney disease: sodium glucose cotransporter-2 (SGLT2) inhibitors.
- In 2019, the CREDENCE trial demonstrated that the use of canagliflozin in patients with diabetes and kidney disease significantly improved kidney and cardiovascular outcomes.
- Presented During the European Society of Cardiology Congress in September 2020, Dapa-CKD, identified similar results with the use of dapagliflozin in patients with diabetic kidney disease but confirmed that this benefit extends even to patients without diabetes.
Many hurdles limit drug development
While these latest results are encouraging, Edmonston says, many hurdles continue to limit drug development. One major limitation is that the relatively slow progression of kidney disease presents a challenge in identifying results during traditional clinical trials periods.
“Among our patients, a relatively small percentage progress to ESRD [end-stage renal disease], and they do so over a period of many years.” Edmonston recommends incorporating new trial designs with an objective to reduce the number of patients and follow-up duration required to detect improvements in kidney disease.
Future trials must have multi-pronged approaches designed to detect outcomes that are clinically significant and meaningful to patients, Edmonston says. The use of “surrogate outcomes” in future trials could facilitate adaptive trial designs with early, interim analyses which gauges the potential success of a therapy earlier than traditional trial designs.
“Let’s focus on specific, short-term goals can be established to benefit clinical practice rather than solely focus on the assessment of long-term outcomes,” he says.
In addition to reducing the number of patients required for definitive clinical trials in chronic kidney disease, investigators can apply select trial designs to further improve the efficiency and feasibility of the clinical trial. Pragmatic trials are conducted within the context of clinical care with liberal eligibility criteria, real-world data collection, and typically a lower cost per study participant. One of the best recent models of a pragmatic trial is the ADAPTABLE study, a patient-centered trial that examines aspirin dosing and involves large numbers of participants monitored over longer periods of time. Duke cardiologists and patients participated in the ongoing trial. A notable example in nephrology is the HiLo trial of phosphate target in ESRD. This HiLo research is led by Myles Wolf, MD, chief of the Duke Nephrology Division; the project is coordinated by the Duke Clinical Research Institute.