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Abstract: PO1142

Pharmacokinetics, Pharmacodynamics (PK-PD), and Exposure-Efficacy Evaluation from CaLIPSO, a Phase 2B Study to Assess the Effect of SNF472 on Progression of Cardiovascular Calcification in Patients on Hemodialysis

Session Information

Category: Dialysis

  • 701 Dialysis: Hemodialysis and Frequent Dialysis

Authors

  • Perelló, Joan, Sanifit Therapeutics, Palma, Balearic Islands, Spain
  • Alberti, Joan J., Admetra Consulting, Palma, Balearic Islands, Spain
  • Torres Martin, Juan Vicente, Syntax for Science SL, Palma, Balearic Islands, Spain
  • Perez, Maria del mar, Sanifit Therapeutics, Palma, Balearic Islands, Spain
  • Ferrer, Miquel D., Sanifit Therapeutics, Palma, Balearic Islands, Spain
  • Bassissi, Firas, Sanifit Therapeutics, Palma, Balearic Islands, Spain
  • Salcedo, Carolina, Sanifit Therapeutics, Palma, Balearic Islands, Spain
Background

Cardiovascular calcification (CVC) is a major contributor to increased morbidity and mortality in end stage kidney disease (ESKD) patients on dialysis. SNF472, a selective calcification inhibitor that interferes in the formation and growth of ectopic hydroxyapatite (HAP), has showed a significant reduction in CVC progression in CaLIPSO, a randomized, double-blind, placebo-controlled phase 2b trial. The drug is also currently in Phase 3 trial for the treatment of calciphylaxis. Our aim was to perform PK-PD and exposure-response analyses from the CaLIPSO trial.

Methods

PK and PD were assessed at weeks 1, 10, 22 and 52, following intravenous administration thrice weekly over 52 weeks. Efficacy was assessed as % change in coronary artery calcification score by volume (CACv) over 52 weeks. The relationship between PK (Cmax) - PD (ex-vivo inhibition of HAP crystallization in plasma), PK-efficacy and PD-efficacy was evaluated using linear and Emax models.

Results

The analyses included data from 56 patients. Cmax values and PD responses per group were similar over the 52 weeks of treatment, indicating no accumulation of SNF472. Mean plasma Cmax, mean PD effect and % change in CACs over 52 weeks per group are shown in the table. An Emax model described well the relationship between PK-PD (E0=8.8%, Emax=75.9%, EC50=5.5 μM); and PK-efficacy (E0=16.9%, Emax=-14.5%, EC50=12.2 μM). The PD-efficacy relationship was better described by a linear model.

Conclusion

SNF472’s PK showed no accumulation and PD remained constant over 52 weeks of treatment. Emax models showed a robust relationship between SNF472’s Cmax and both the ex-vivo inhibition of HAP crystallization and clinical efficacy measured by % change in CACv over 52 weeks. Higher SNF472 exposure and inhibition of HAP crystallization correlated with a reduction in CVC progression in ESKD patients on dialysis.

ParameterGroup
Placebo300 mg600 mg
PK (Cmax, μM)Undetectable (<0.76)1545
PD effect (%)176075
% change CACv149-2

CACv: Coronary artery calcification score by volume

Funding

  • Commercial Support