Kidney Week

Abstract: SA-PO672

ACTION3 Phase 3 Clinical Trial Assessing the Efficacy and Safety of DMX-200 (Repagermanium): Mid-trial Safety Assessment and Pharmacometric Model-Informed Pediatric Dose Selection

Session Information

• Pediatric Nephrology - 2
  October 26, 2024 | Location: Exhibit Hall, Convention Center
  Abstract Time: 10:00 AM - 12:00 PM

Category: Pediatric Nephrology

• 1900 Pediatric Nephrology

Authors

• Fuller, David E., Dimerix Bioscience Pty Ltd, Melbourne, Victoria, Australia

David E. Fuller, PharmD, MBBS

• van Schaick, Erno, Calvagone, Amsterdam, Netherlands

Erno van Schaick, PhD

• Smith, Alisha J., Dimerix Bioscience Pty Ltd, Melbourne, Victoria, Australia

Alisha J. Smith

• Shepherd, Robert, Dimerix Bioscience Pty Ltd, Melbourne, Victoria, Australia

Robert Shepherd, PhD, MBA

• White, Carl, Dimerix Bioscience Pty Ltd, Melbourne, Victoria, Australia

Carl White, PhD

Background

DMX-200 (repagermanium) is a C-C chemokine receptor type 2 (CCR2) inhibitor which when administered with an angiotensin II receptor blocker (ARB) inhibits CCR2/AT1R complex function. This modulates the aberrant response to inflammation, blocking attraction of inflammatory cells into the kidneys and reducing both proteinuria and podocyte loss.
Following encouraging Phase 2 data, Dimerix have commenced a Phase 3 randomized double-blind placebo-controlled study (ACTION3) investigating the efficacy and safety of DMX-200 (120 mg BID) compared with placebo in patients with FSGS on a stable ARB dose. In March 2024 the study passed an interim futility assessment, and following safety review, PK assessment and pharmacometric modelling, will now include adolescent patients aged 12-17 years.

Methods

An interim safety analysis covered the first n=91 patients randomised in ACTION3.
PK data from n=46 DMX-200 evaluable patients was assessed in a population PK model (popPK) built on previous data from Phase 1 and 2.

Results

Median duration of exposure to DMX-200 or placebo was 9.1 months (range 0.5-17.3) with median total exposure of 65.76 g (range 3.6-124.56 g).
277 individual adverse events (AEs) were reported by 72/91 (79%) patients. 80% of AEs were rated as “mild” and reflected the underlying disease (FSGS) and associated comorbidities.
DMX-200 has a half-life (t_1/2) of 3.6 hrs and is not metabolised. PK data were variable with a wide exposure range due to the short t_1/2 of DMX-200 but were comparable with prior data and supported the use of the popPK model to predict adolescent exposure. Simulations of exposure in renally impaired adolescent patients (AP) showed that AP will generally have similar drug exposures to adults. APs with a combination of very low body weight and poor renal function may experience higher exposure that is likely covered by the observed exposures in adults.

Conclusion

No safety signal that would preclude paediatric dosing was identified. Based on this comprehensive review of safety, PK data and PopPK modelling of predicted exposure, a dose of 120mg BID will be used for adolescents (12-17 years) who are now being recruited into the ACTION3 study.

Funding

• Commercial Support – Dimerix Biosciences Pty Ltd