Results from phase III clinical trials for diabetic nephropathy (DN), also known as diabetic kidney disease, are eagerly anticipated by the health care community. DN patients face increased risk of progression to end-stage renal disease (ESRD) and a high prevalence of cardiovascular (CV) disease – two major causes of morbidity and mortality. Any therapy able to effectively slow or halt the progressive nephropathy would provide significant clinical and economic benefits to patients and the healthcare systems that treat them. Three therapies are in Phase III testing: AbbVie’s atrasentan (an endothelin-receptor antagonist), Bayer’s finerenone (a mineralocorticoid receptor antagonist), and Janssen/Johnson & Johnson’s canagliflozin (a sodium glucose transporter-2 inhibitor), which is currently FDA approved for the treatment of type 2 diabetes mellitus (T2DM).
In Decision Resources Group’s Unmet Need: Diabetic Nephropathy, U.S. and European endocrinologist and nephrologists were surveyed on treatment drivers and goals for DN, how current therapies perform against these parameters, and the extent of the unmet need in DN. A key finding was that therapies offering CV benefits among DN patients are strongly preferred by surveyed endocrinologists and nephrologists in the United States and Europe. Utilizing an adaptive choice-based conjoint (ACBD) analysis, physicians reported which trade-offs across key attributes they are willing to make when considering which treatment to prescribe for DN. Several target product profiles (TPPs) were compared, with estimates of physician preference and likelihood to prescribe for each TPP determined by the ACBC analyses. In one scenario from the report, a TPP with a strong CV safety profile (i.e., 15% reduction in CV events) performed better than TPPs offering greater renal protection (see Table 1 and Figure 1). More than half of providers preferred TPP 6 over TPP 5 and TPP 4, despite TPP 6 offering much less nephroprotection. In addition, a greater percentage of the surveyed physicians indicate a likelihood to prescribe TPP 6 to their DN patients than TTP 4 or 5.
Figure 1. Preference Share
Table 1. Target Product Profiles
Only two of the three emerging therapies include a CV endpoint in their large Phase III trials – canagliflozin and finerenone. Canagliflozin’s Phase III CREDENCE trial (clinicaltrials.gov: NCT02065791; accessed May 19, 2017) analyzes the drug among patients with T2DM and eGFR between 90 – 30 mL/min/1.73m2. The study’s primary endpoint measures time to first occurrence of ESRD, doubling of serum creatinine, renal or CV death over 66 months. Canagliflozin is also analyzing its CV benefits among T2DM patients in the CANVAS outcomes trial (clinicaltrials.gov: NCT01032629; accessed May 19, 2017); publication of the results is pending. In all likelihood, physicians will draw conclusions on the CV benefits the drug offers based on both CREDENCE and CANVAS trials.
Finerenone is the other therapy that includes a CV measure in its Phase III clinical trials in DN patients. Unlike canagliflozin, finerenone is conducting two Phase III trials in DN populations. The primary endpoint in FIDELIO-DKD (clinicaltrials.gov: NCT02540993; accessed May 19, 2017) measures a composite renal endpoint while the primary endpoint in FIGARO-DKD (clinicaltrials.gov: NCT02545049; accessed May 19, 2017) measures a composite CV endpoint. This CV primary endpoint in FIGARO-DKD assesses time to first occurrence of composite endpoint of CV death and nonfatal CV events (e.g., stroke, hospitalization for heart failure, myocardial infarction); thus, it provides more robust results than canagliflozin’s CREDENCE study for physicians to evaluate CV impacts. However, finerenone’s primary endpoint is only measured over 36 months, significantly less than canagliflozin’s 66 month primary endpoint. With two large Phase III studies measuring unique primary endpoints of expressed value to physicians treating DN patients, finerenone is well positioned to capitalize on positive results from either (or both) studies, provided that the studies are of sufficient duration to demonstrate clinically meaningful CV benefits.
The third emerging therapy, atrasentan, does not analyze CV benefit in its Phase III trial SONAR, except as a secondary endpoint measured over 48 months (clinicaltrials.gov: NCT01858532; accessed May 30, 2017). Instead, SONAR’s primary endpoint measures a composite renal endpoint. The focus on a renal endpoint alone may hamper patient uptake and payer coverage, should the magnitude of nephroprotection relative to RAAS inhibitors underwhelm physicians and payers. However, with atrasentan anticipated to reach the U.S. market first, it may be able to gain its foothold in the DN market through creative outcomes-based contract agreements.
DN patients face an increased risk of CV events, and physicians signal that therapies offering CV protection would be a significant asset. Therapies that fail to include endpoints measuring CV outcomes are more likely to see slow uptake, reduced patient share, and possibly less preferential formulary coverage. Physicians and payers will likely look for real-world evidence demonstrating renal and CV protection – as these outcomes can take years to materialize and often remain insufficiently analyzed among the tightly controlled randomized clinical trial populations. Additionally, use of outcomes-based contracts may help secure these therapies a spot on formulary – regardless of Phase III endpoints. Overall, demonstration of morbidity/mortality benefits will spur increased use of emerging therapies among DN patients.
Complete results from DRG’s analysis on unmet need in diabetic nephropathy (U.S. and EU3) 2017 can be found here. To read more about outcomes-based contracting in the United States, Europe, and the rest of the world click here and here.
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