Abstract: TH-PO500

Phase I Evaluation of AZD9977, a First in Class Mineralocorticoid Receptor (MR) Modulator

Session Information

Category: Chronic Kidney Disease (Non-Dialysis)

  • 305 CKD: Clinical Trials and Tubulointerstitial Disorders

Authors

  • Erlandsson, Fredrik, AstraZeneca R&D, Gothenburg, Sweden
  • Kjaer, Magnus B, AstraZeneca R&D, Gothenburg, Sweden
  • Hartleib-Geschwindner, Judith, AstraZeneca R&D, Gothenburg, Sweden
  • Albayaty, Muna, PAREXEL International, Berlin, Germany
  • Chialda, Ligia E, PAREXEL International, Berlin, Germany
  • Ericsson, Hans Ingemar, AstraZeneca R&D, Gothenburg, Sweden
  • Amilon, Carl, AstraZeneca R&D, Gothenburg, Sweden
  • Nelander, Karin, AstraZeneca R&D, Gothenburg, Sweden
  • Bamberg, Krister, AstraZeneca R&D, Gothenburg, Sweden
  • Jansson-Lofmark, Rasmus, AstraZeneca R&D, Gothenburg, Sweden
  • Wernevik, Linda Christina, AstraZeneca R&D, Gothenburg, Sweden
Background

MR antagonists may improve outcomes in patients with chronic kidney disease, but are associated with hyperkalemia. Pre-clinical data indicate AZD9977 could be a first in class MR modulator with similar organ protection as eplerenone, but associated with minimal urinary electrolyte effects.

Methods

Phase I development began with a single dose escalation trial from 5mg to 1200mg, followed by a randomized placebo controlled cross-over four period clinical trial in 23 healthy volunteers. The treatments administered were fludrocortisone (A), 200mg AZD9977 + fludrocortisone (B), 100mg eplerenone + fludrocortisone (C), and 200mg AZD9977 + 100mg eplerenone + fludrocortisone (D). Treatment D was administered to assess if AZD9977 could attenuate the natriuresis induced by eplerenone as observed in rodent studies. A baseline session without treatment was performed. Food and fluid intake was controlled and urine collected in 2h intervals. The primary endpoint was log[Na]/[K] in urine collected from 2 to 8h.

Results

In the single dose escalation trial all doses were well tolerated. Pharmacokinetic and safety results were compatible with further development.

In the cross-over trial 200mg AZD9977 (B) exhibited similar effects on diuresis and urinary electrolytes as 100mg eplerenone (C), and the combination (D) had an additive effect on urinary electrolytes. Fludrocortisone exposure was similar across treatments, and there was no significant pharmacokinetic interaction between eplerenone and AZD9977.

Conclusion

The results in man contradict the results in rodent models driven by aldosterone, in which AZD9977 had minimal electrolyte effects, but aligned with studies in rodent models driven by fludrocortisone. The effect of MR modulators on electrolyte excretion may depend on the MR agonist. Clinical studies of how AZD9977 or other MR modulators affect urinary electrolytes in the presence of aldosterone are needed.

Cross-over trial results
EndpointBaselineABCD
Log [Na]/[K] 2-8h2.4-4.1-0.69-0.540.69
Diuresis 2-8h (ml)782668749766774
U-Na 2-8h (mmol)4711252838
U-K 2-8h (mmol)2036313230

Funding

  • Commercial Support