TRIENTINE DIHYDROCHLORIDE VS. TETRAHYDROCHLORIDE: A PHASE 1, SINGLE CENTER, RANDOMIZED, INTERVENTIONAL, SINGLE DOSE, OPEN-LABEL, CROSSOVER STUDY IN ADULT HEALTHY MALE AND FEMALE SUBJECTS TO EVALUATE THE PHARMACOKINETICS AND THE SAFETY, TOLERABILITY OF TWO DIFFERENT ORAL FORMULATIONS

Wilson*s disease (WD) is a life-threatening inborn error of copper metabolism
leading to an excessive copper accumulation, mainly in the liver or brain,
causing hepatic and neurologic severe symptoms (Gitlin 2003). The gene
responsible for WD, ATP7B, was identified on chromosome 13 (Tanzi 1993). The
gene ATP7B is highly expressed in the liver, kidney, and placenta. The product
of ATP7B is a copper-transporting P-type ATPase responsible for transporting
copper from intracellular chaperone proteins into the secretory pathway, both
for excretion into bile and for incorporation into apoceruloplasmin for the
synthesis of the functional plasma protein ceruloplasmin (Tao 2003). More than
500 distinct mutations have been described in the Wilson gene, from which 380
have a confirmed role in the pathogenesis of the disease (refer to the WD
mutation database).

Normal dietary consumption and absorption of copper, approximately 1 to 2 mg
per day , exceeds the metabolic need, approximately 0.75 mg daily, and
homeostasis of this element is maintained exclusively by the biliary excretion
of copper (Ala 2007).
The most common presentations are with liver disease or neuropsychiatric
disturbances.
In about 40% of WD patients, hepatic symptoms are highly variable, from
asymptomatic, with only biochemical abnormalities, to overt cirrhosis with all
its complications, or acute hepatic failure sometimes associated with
Coombs-negative hemolytic anemia, acute renal failure or chronic hepatic
disease. Indeed, WD accounts for 6-12% of all patients with acute liver failure
who are referred for emergency transplantation.
About one-third of all WD patients initially present with psychiatric
abnormalities, like declining school performance, personality changes,
impulsiveness, labile mood, sexual exhibitionism, inappropriate behavior,
paranoia, schizophrenia or depression.
The neurological abnormalities, which usually present in the third decade of
life, are the initial symptoms of WD in approximately 40-50 % of patients
(Yarze 1992). Those neurologic disturbances can be classified as akinetic-rigid
syndrome similar to Parkinson*s disease, pseudosclerosis dominated by tremor,
ataxia, and dystonic syndrome.
The main ophthalmologic changes are Kayser-ayseres o rings, caused by
deposition of copper in Descemets membrane of the cornea, present in 95% of
patients with neurologic symptoms and somewhat over half of those without
neurologic symptoms. Other ophthalmologic changes are rare and include
sunflower cataracts, which are caused by deposits of copper in the center of
the lens.

Less common presentations include gigantism, lunulae, renal abnormalities
including aminoaciduria and nephrolithiasis, hypercalciuria and
nephrocalcinosis, cardiomyopathy, myopathy, chondrocalcinosis and
osteoarthritis, hypoparathyroidism, pancreatitis, infertility or repeated
miscarriages.

Untreated WD, or in case of a poor adherence to drug therapy (when a patient
starts skipping doses daily for months), is universally fatal, with most
patients dying from liver disease and a minority from complications of
progressive neurologic disease. WD is therefore chronically debilitating and
life threatening.

In general, prognosis for survival depends on the severity of liver and
neurological disease, and compliance with drug treatment, to avoid the
recurrence of symptoms and progression of the disease (Ala 2007)

Trientine, also referred to as triethylene tetramine, is an organic compound
with the formula [CH2NHCH2CH2NH2]2. This oily liquid is colorless but, like
many amines, assumes a yellowish color due to impurities resulting from
air-oxidation. It is soluble in polar solvents and exhibits the reactivity
typical for amines. In terms of activity, trientine exhibits chelating
properties.

The first trientine salt developed was a dihydrochloride (also referred to as
trientine hydrochloride). It is a registered drug in United Kingdom (marketing
authorization number PL 41626/0001 delivered on 8 August 1985, renewed on 16
April 1996), authorized in WD patients who are intolerant to D-penicillamine.

GMP-orphan has formulated a different already known trientine salt, trientine
tetrahydrochloride (TETA•4HCl) for the treatment of WD. TETA•4HCl has largely
been used over more than two decade in France through a named-patient program
for WD patients intolerant to D-penicillamine, and has been therefore
integrated in the French guidelines for the management of WD patients (refer to
Haute Autorite* de Sante* (or French National Authority for Health), French
guidelines in WD.

Trientine is a chelating agent with a polyamine structure chemically, distinct
from D-penicillamine, which chelates copper by the formation of stable
complexes with the four constituent nitrogens in a planar ring (Ala 2007,
Boiocchi 2005). Like D-penicillamine, trientine promotes urinary copper
excretion.

The rationale for developing this tetrahydrochloride salt is that, unlike the
dihydrochloride, TETA•4HCl is stable at room temperature, has been developed as
a convenient pharmaceutical formulation for adults as well as children, and
will improve WD patients* access throughout EU.

The principal aim of this study is to evaluate the PK parameters of both oral
formulations in adult healthy volunteers in order to propose for
Marketing Authorization Application an adequate strength for TETA•4HCl (i.e. a
strength providing a PK profile similar to TETA•2HCl)

This is a single center, randomized, interventional, single dose, cross-over
study to explore the safety, tolerability and PK of both oral formulations
(capsules of TETA•2HCl and tablets of TETA•4HCl) in adult healthy male and
female subjects.

Single dose of 900 mg of TETA•2HCl (i.e. 3 capsules of 300 mg containing each
225 mg of trientine base) or 1200 mg TETA•4HCl (i.e. 4 tablets of 300 mg
containing each 150 mg of trientine base) will be given (crossover design)

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