ACTION (AT1R and CCR2 TARGETS FOR INFLAMMATORY NEPHROSIS) PHASE 2a TRIAL FOR FOCAL SEGMENTAL GLOMERULUSCLEROSIS

S ROGER1, D PACKHAM2,3, R SHEPHARD2, D POWER4
1Gosford Hospital, Gosford, Australia, 2Dimerix Limited, Melbourne, Australia, 3Melbourne Renal Research Group, Reservoir, Australia, 4Austin Health, Heildelberg, Australia

Aim: To test the hypothesis that simultaneous antagonism of AT1R and CCR2 is beneficial in patients with primary FSGS.
Background: Focal segmental glomerulosclerosis (FSGS) is a disease of podocytes. The angiotensin II receptor type 1 (AT1R) and chemokine receptor 2 (CCR2) are G protein coupled receptors that form functional heteromers and are co-expressed in podocytes. Simultaneous antagonism of these receptors has a beneficial effect on proteinuria and podocyte viability in the sub-total nephrectomy rat model. Further, a Phase 2a study of 27 patients with proteinuric chronic kidney disease showed that simultaneous antagonism of AT1R with irbesartan and CCR2 with propagermanium, an antagonist registered in Japan for the treatment for hepatitis B, was safe and well tolerated with 25% of patients achieving a greater than 50% reduction in proteinuria.
Methods: A multi-centre, randomised, placebo-controlled, two-way crossover study in 10 primary FSGS patients receiving irbesartan is underway to explore safety events and reduction of proteinuria. Patients will be randomised to receive propagermanium or placebo for 16-weeks, followed by a 6-week washout, and then reversed treatment with placebo or propagermanium for a further 16-weeks. At the end of treatment, investigators may apply for access to propagermanium as part of a special access scheme. Patients must be aged 18-80 with a diagnosis of primary FSGS confirmed by renal biopsy, any immunosuppressive therapy regime must be stable, and must be receiving irbesartan 300 mg/day for at least 3-months prior to and throughout the study. Screening urine protein/creatine values must be ≥ 150 mg/mmol and eGFR ≥ 25 ml/min/1.73m2.
Conclusions: This study will determine the benefit of simultaneous AT1R and CCR2 inhibition in FSGS patients who have only limited therapeutic options.


Biography:
Simon Roger underwent advanced training in Nephrology at Westmead Hospital, followed by two years of clinical and laboratory research in London. In 1993, Dr Roger was appointed as a nephrologist to Royal North Shore Hospital, and that year, took over as Medical Head of the Division of Medicine at Gosford Hospital. He is a past Chairman of the Gosford Hospital Medical Staff Council. In 2000 he was appointed Clinical Associate Professor at the University of Newcastle and in 2012 he was selected as the inaugural Conjoint Professor of Medicine within his Local Hospital District and the University.

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