Learning from Failure: New Therapy for Diabetic Nephropathy and Beyond?

It took only about 5 years after the discovery of the endothelin (ET) peptide to develop potent and selective endothelin receptor antagonists (ETRAs) (7). This was about 20 years ago, and there are now two antagonists currently approved for use in pulmonary hypertension. Other targets have demonstrated tremendous promise in preclinical studies, but patent expirations and failures in several clinical studies have discouraged most of the big pharmaceutical companies from further investigation of these drugs as therapies. The failures include a wide range of disorders, including heart failure, prostate cancer, and even resistant hypertension. The latter target remains a strong possibility, but unlikely because of financial reasons.

Endothelin-1 functions through ETA receptors primarily located on vascular smooth muscle to produce the well-known vasoconstrictor effects, but perhaps more importantly as a promoter of cell growth and inflammation. In healthy conditions, these effects are held in check by ETB-dependent vasodilation and anti-inflammatory effects. Many investigators believe that the loss of ETB receptor function is as important in generating these effects as is excess ET-1 synthesis, if not more so. Physiologically, ET-1 functions as a critical regulator of sodium and water homeostasis, but not in the same manner as the renin-angiotensin system (RAS). Rather, it functions as a pronatriuretic factor mediated by both hemodynamic and renal tubular actions (2).

Since the early days of endothelin research, a wide range of animal studies have revealed that chronic kidney disease (CKD) is associated with overproduction of ET-1 (3). These models include ischemia, chemotoxins, reduced mass, immune injury, and others. More important, the administration of selective ETA or combined ETA/ETB receptor antagonists can attenuate the severity of injury and disease in these models. Nonetheless, initial drug development focused on pulmonary hypertension, heart failure, and even prostate cancer.

Little attention was paid to the promising preclinical work on endothelin in the renal field until a small biotech company, Speedel, conducted several phase 2 and phase 3 studies exploring the potential therapeutic utility in patients with stage 3 and 4 CKD with diabetic nephropathy (4). Using avosentan, a relatively little known antagonist with marginal preference for the ETA receptor over the ETB receptor, they were able to observe remarkable reductions in proteinuria on the order of 40 to 50 percent, even while more than 90 percent of those studied were already taking RAS inhibitors, diuretics, and an average of nearly five medications.

Speedel’s phase 3 trial (ASCEND) had to be terminated early because of adverse events associated with drug-induced fluid retention, including congestive heart failure (5). The cause of edema is not known but is most likely mechanism-based, given that other ETRAs can also produce edema—an effect that can be reproduced in mice. The higher rate of edema in patients with CKD suggests that the kidney is involved. Another unfortunate aspect of this study is that the edema was predicted from the phase 2 trial. During that study, maximal reductions in proteinuria were observed even at the lowest dose over a dosage range of 5 to 50 mg/ day avosentan; yet fluid retention was dose dependent. For reasons that are not clear, the subsequent phase 3 trial moved forward with 25-mg and 50-mg dosing, thus maximizing the risk of fluid retention. Some anecdotal reports mentioned that the fluid issues could be managed with diuretic treatment, but adjustments in diuretic therapy were not part of the trial design, so accommodations could not be made.

So the use of ETRAs in CKD again looked like a lost cause until Abbott Laboratories (now AbbVie) recently decided to conduct a phase 2A trial with its highly selective ETA antagonist, atrasentan, in patients with diabetic nephropathy (6). They chose much lower doses (0.25 to 1.75 mg/day avosentan) and included careful management of fluids with diuretic treatment. Once again, the patients were already being treated with RAS inhibitors and a range of other standard drug therapies. Edema occurred at a much lower rate for most doses in such a manner that the 0.75-mg dose produced maximal efficacy in terms of reducing albuminuria; still, edema occurred at an identical rate as with placebo.

These promising findings led Abb-Vie to pursue a larger phase 2B trial (RADAR) using 0.75 and 1.25 mg/day, which showed a reduction of approximately 35 to 40 percent in albuminuria in patients with diabetic nephropathy, with no serious adverse events associated with drug-induced fluid retention (7). Currently, a phase 3 trial (SONAR), examining the effect of 0.75 mg/day atrasentan on hard renal outcomes with a planned enrollment of more than 4000 patients with diabetic nephropathy is ongoing.

One of the big lessons in the saga of ETRAs in CKD (as well as other drug development programs) is that basic pharmacology and physiologic mechanisms must remain front and center when trials are designed. A similar story developed with the use of ETRAs in resistant hypertension. Despite a large phase 3 trial and significant reductions in ambulatory blood pressure in patients taking an average of five antihypertensive drugs, a large decline in clinical blood pressure during the final week of the trial in the placebo group rendered the primary endpoint, clinical blood pressure, statistically insignificant (8). Although the vast majority of hypertension specialists insist that ambulatory blood pressure is the gold standard, this has yet to be used as a clinical endpoint by the U.S. Food and Drug Administration. In the final analysis, despite the significant problems encountered with studies involving ETRAs, there remain compelling reasons to study these agents in a variety of diseases, including CKD.

Notes

[1] David M. Pollock, PhD, is affiliated with the Section of Experimental Medicine in the Department of Medicine at Georgia Regents University in Augusta. He is president-elect of the American Physiological Society .

References

1. Opgenorth TJ. Endothelin receptor antagonism. Adv Pharmacol 1995; 33:1–65.

2. Kohan DE, et al. Physiology of endothelin and the kidney. Compr Physiol 2011; 1:883–919.

3. Dhaun N, Goddard J, Webb DJ. The endothelin system and its antagonism in chronic kidney disease. J Am Soc Nephrol 2006; 17:943–955.

4. Wenzel RR, et al. Avosentan reduces albumin excretion in diabetics with macroalbuminuria. J Am Soc Nephrol 2009; 20:655–664.

5. Mann JF, et al. Avosentan for overt diabetic nephropathy. J Am Soc Nephrol 2010; 21:527–535.

6. Kohan DE, et al. Addition of atrasentan to renin-angiotensin system blockade reduces albuminuria in diabetic nephropathy. J Am Soc Nephrol 2011; 22:763–772.

7. J Am Soc Nephrol, in press.

8. Bakris GL, et al. Divergent results using clinic and ambulatory blood pressures: report of a darusentan-resistant hypertension trial. Hypertension 2010; 56:824–830.


January 2014 (Vol. 6, Number 1)