PyROphosPHate Supplementation to Fight ECtopIc Calcification in PseudoXanthoma Elasticum
Status:
Not yet recruiting
Trial end date:
2024-09-01
Target enrollment:
Participant gender:
Summary
Pseudoxanthoma elasticum (PXE) is a rare inherited metabolic disorder (OMIM 264800, frequency
1/25000) characterized by progressive ectopic calcification of connective tissues.
PXE mainly affects the skin (unsighting skin folds and papules), the retina (central
blindness), the vasculature (peripheral arterial occlusive disease and stroke) and the renal
system (renal lithiasis) in adulthood. Although rarely, early lethal forms have been
reported.
This chronic and highly disabling condition results from a loss of function of the gene
encoding for the ABCC6 membrane transporter primarily expressed in the hepatocytes and renal
tubular cells. Recently, it has been reported that PXE was characterized by a 50-60% decrease
in the plasma level of inorganic pyrophosphate (PPi), a major physiological anti-calcifying
factor. PXE is an incurable disease although encouraging advances with animals PXE models and
human patients were obtained with the use of etidronate (Eti), a stable, non-hydrolysable
analog of PPi.
However, this proof-of-concept study was statistically underpowered, mitigating the overall
results, notably with respect to the effect on vascular calcification and ocular lesions.
Renal lithiasis was also not investigated in the study.
Furthermore, the long term use of Eti maybe a concern because of its side-effects
(spontaneous fracture and mandibular necrosis) and the fact that non-hydrolysable
bisphosphonate lead to stable and irreversible calcification.
Recent studies in animals and healthy volunteers have shown that, contrary to what was
initially reported and thought, the oral administration of PPi salts resulted in increased
PPi plasma levels, opening up new therapeutic perspectives in PXE by using PPi in place of
Eti.
Therefore,the investigators propose to perform the first Phase II randomized controlled trial
(RCT) to evaluate the safety and efficacy of a daily and oral administration of PPi salts
against safety and efficacy of treatment with Eti (reference treatment) in PXE patients.