Dr David Fuller1, Alisha Smith1, Dr Carl White1, Dr Robert Shepherd1
1Dimerix Ltd, Fitzroy, Australia
Biography:
Dr Fuller is a pharmaceutical physician and pharmacist who has worked in clinical development and medical affairs for over 30 years for companies including Pfizer, Genzyme and Dimerix. David was part of the team who developed sevelamer (Renagel) as a phosphate binder and now works for Dimerix leading the clinical development of DMX-200: a CCR2 inhibitor for focal segmental glomerulosclerosis (FSGS). DMX-200 is currently in Phase III trials.
Aim:
To develop DMX-200 for the treatment of FSGS.
Background:
FSGS is a progressive glomerular disease typically presenting with proteinuria and subsequently progressing to kidney failure. CCR2 signalling is implicated in the pathology of FSGS and enhances inflammatory signalling that leads to podocyte damage. Separately, the angiotensin II receptor type1 (AT1R) is implicated in the initiation and progression of renal fibrosis. In vitro CCR2 and AT1R form functional complexes and the combination of DMX-200 and blockade of AT1R results in a greater reduction in proteinuria, macrophage infiltration and podocyte loss compared with either antagonist alone in pre-clinical FSGS models. These data provide the rationale for clinical development of DMX-200 for FSGS.
Methods:
DMX-200 combined with stable AT1R blockade (irbesartan) has been assessed in 3 phase II studies: A dose finding study in proteinuric kidney disease (n=27) and 2 placebo-controlled trials 1) a pilot study in patients with FSGS (n=8) and 2) a 45 patient study in diabetic kidney disease.
Results:
A dose of 120mg DMX-200 (b.i.d.) was identified and used in 2 subsequent placebo-controlled trials. Reductions in proteinuria were observed across all 3 studies with good tolerability. Similar adverse events rates were seen in the DMX-200 and placebo arms and reflected underlying comorbidities. Based on these results a pivotal Phase III trial to investigate the efficacy and safety of DMX-200 in FSGS (NCT05183646/ACTION3) was initiated. The ACTION3 trial is currently enrolling 286 adults with biopsy-confirmed FSGS, proteinuria >1.5g/day, and eGFR >25mL/min/1.73 m².
Conclusion:
Clear biological plausibility, pre-clinical evidence, and encouraging Phase II results suggest that DMX-200 may represent a novel therapeutic approach for patients with FSGS. The ongoing ACTION3 pivotal trial will test this hypothesis.