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Phosphate serves as a structural component of nucleic acids, cell membranes and bones,
and is important for enzymatic interactions, ATP synthesis and plays a critical role
in cellular signalling through phosphorylation reactions. Therefore, the maintenance
of phosphate balance is essential for life being tightly regulated by a sophisticated
system in humans, involving intestinal uptake of dietary inorganic phosphate (Pi),
storage in bone and excretion of excess Pi in the kidney. However, due to the dependence
of phosphate elimination on urinary excretion by the kidneys, patients with decreased
kidney function are likely to be in a positive phosphate balance. The resulting hyperphosphatemia
has been well recognized as a crucial factor in the pathogenesis of mineral and bone
disorders associated with chronic kidney disease, being also associated with increased
risks of death and cardiovascular complications.
1
,
2
Regular monitoring and prevention of hyperphosphatemia is therefore universally recommended
in clinical guidelines,
3
although normalization of serum phosphate with phosphate binders with concurrent dietary
measures in dialysis patients remains challenging. Furthermore, the use of phosphate
binders is also frequently accompanied by gastrointestinal side effects and poor patient
compliance, which limits their use and underscores the need for additional therapeutic
options.
3
Although phosphate binders are the mainstay of pharmacological therapy, lowering phosphate
levels by targeting the intestinal phosphate absorption seems an interesting approach.
Drugs that actively target gastrointestinal phosphate transport combined with phosphate-binder
therapy could optimize the therapeutic effects of both treatments and enhance the
effectiveness of dietary phosphate restriction. The discovery nearly two decades ago
of the sodium-dependent phosphate co-transporter type 2b (NaPi-IIb) which mediates
active phosphate absorption in the small intestine
4
opened the road of studying different molecules oriented toward NaPi-IIb inhibition
as a target for hyperphosphatemia treatment.
In the latest number of Kidney Int. Reports, Maruyama S. et al. presents the results
of a 2-part, randomized, placebo- and active-controlled, single- and repeated-dose,
phase 1b study evaluating the safety and efficacy of DS-2330, for the treatment of
hyperphosphatemia in haemodialysis patients.
5
DS-2330b is an oral NaPi-IIb inhibitor that inhibits the uptake of phosphate via NaPi-IIb
in the small intestine in animal and ex vivo studies, resulting in reduced intestinal
phosphate absorption.
In their comprehensive study, Maruyama S. et al demonstrated that DS-2330, either
alone or in combination with sevelamer was generally well tolerated with no concerning
safety signals. However, DS-2330b produced only a small decrease in serum phosphate
either as a single agent or in combination with sevelamer therefore raising concerns
about efficacy of this molecule in controlling hyperphosphatemia in patients on haemodialysis.
The lower plasma concentration of DS-2330 in patients concomitantly receiving sevelamer
compared to DS-2330b alone along with a higher reduction in serum phosphate among
sevelamer with placebo treatment group suggest a possible competing effect between
sevelamer DS-2330b for phosphate binding sites, causing a reduction in bioavailability
of DS-2330b.
Other clinical approaches with other oral inhibitors of active phosphate transport
modulating NaPi-IIb have also yielded disappointing results. Thus, a recent clinical
trial in end-stage renal disease patients revealed that another selective NaPi-IIb
inhibitor - ASP3325 neither inhibited intestinal phosphate absorption nor ameliorated
hyperphosphatemia or provide a reduction in phosphate metabolism biomarkers.
6
Nicotinamide, a metabolite of nicotinic acid (niacin, vitamin B3), is a marketed drug
with anti-inflammatory and cholesterol-lowering properties; in addition it may lower
phosphate levels by a mechanism involving negative transcriptional regulation of NaPi-IIb
in the intestine. Despite some promising result in some clinical studies,
7
,
8
a more recent randomized controlled trial found that nicotinamide and sevelamer were
equally effective in lowering serum phosphorus in chronic haemodialysis patients but
with the price of a more adverse events in the nicotinamide arm resulting in a higher
discontinuation rate.
9
Taken together, the results of these studies suggest a limited effect of NaPi-IIb
inhibitors for the treatment of hyperphosphatemia in CKD patients. This lack of effect
may be due to the decreased NaPi-IIb intestinal expression in advanced CKD as suggested
by a recent experimental study; this suggests that other alternative phosphate transporter
may predominate in the setting of advance kidney disease
10
Thus, low-affinity transporters, such as PiT-1 or PiT-2 gain importance for intestinal
phosphate absorption; inhibition of these transporters might represent a novel therapeutic
approach to ameliorate hyperphosphatemia in kidney diseases.
Phosphate is actively absorbed in the small intestine via the above described transporters
but also passively via the tight junctions between cells (i.e. paracellular).S1 The
later represents the target of tenapanor, a minimally absorbed inhibitor of gastrointestinal
sodium/hydrogen exchanger 3 (NHE3); it acts via a non– phosphate-binding mechanism,
reducing paracellular phosphate transport in the intestine. In a phase 3 randomized,
double-blind trial, tenapanor significantly reduced serum phosphate compared with
placebo at eight weeks in patients receiving hemodialysis. Tenapanor is a minimally
absorbed compound with detectable levels in serum only rarely being described, its
administration being also associated with a dramatic reduction in pill burden when
compared with commonly used doses of phosphate binders. Adverse effects were limited
to a modest increase in stool frequency, thought to be due an increase in stool water
content, which led to drug discontinuation in 8 percent of those treated.
Although the relative contribution of the active versus passive pathway remains unknown,
a pan-phosphate transporter inhibitor would therefore represent a better alternative
to control hyperphosphatemia in CKD patients. In this regard, a novel inhibitor, EOS789,
that interacts with several sodium-dependent phosphate transporters (NaPi-IIb, PiT-1,
and PiT-2) markedly decreasing the serum phosphate, fibroblast growth factor-23, and
intact parathyroid hormone in rats.S2 Thus, this novel approach might provide a significant
benefit to patients who are ineffectively treated with phosphate binders. However,
extrapolating these results from rodents to humans remains an open question; studies
using human intestine are required to elucidate the expression levels of phosphate
transporters.
Disclosure
The authors declared no competing interests.