Atrasentan (AbbVie) is a selective antagonist for the endothelin type A (ETA) receptor, also known as the endothelin 1 (ET-1) receptor. ET-1 is a peptide that can act at either the ETA or endothelin B (ETB) receptor. The ETA receptor likely mediates several pathological effects of ET-1, including vasoconstriction, fibrosis, cell proliferation, and podocyte damage. The ETB receptor has some opposing actions, but is mainly involved in the regulation of fluid transport. The inhibition of ETA receptors decreases the binding affinity of ET-1 to the ETA receptor without affecting receptor density.
Atrasentan is currently in Phase III development in the US, Japan, and EU for the treatment of diabetic nephropathy (ClinicalTrials.gov identifier: NCT01858532).
The drug has a reasonably good chance of showing a benefit in its Phase III trial, although there is still uncertainty as to whether changes in the Phase II surrogate urinary albumin-to-creatinine ratio biomarker predict pivotal trial outcomes. Concerns about fluid retention could hinder the drug until physicians gain more experience, even if the Phase III trial shows this to be manageable. Atrasentan's Phase III trial is unique in including an enrichment period to select responders and those who tolerate the drug for randomization. This should improve the chances for a positive trial and yield a relatively higher efficacy number, although efficacy in non-responders is also likely to be on the label and physicians in busy practices may not want to spend the time involved in a personalized approach if there are other options. Additionally, atrasentan may also be hampered commercially by limited data on cardiovascular outcomes.
atrasentan: Diabetic nephropathy
List of Figures
Figure 1: Atrasentan for diabetic nephropathy - SWOT analysis
Figure 2: Drug assessment summary for atrasentan in diabetic nephropathy
Figure 3: Drug assessment summary for atrasentan in diabetic nephropathy
List of Tables
Table 1: Atrasentan drug profile
Table 2: Atrasentan Phase III trial in diabetic nephropathy
Table 3: Atrasentan Phase IIb pooled results of 12-week studies in diabetic nephropathy