Conservative iron chelation as a disease-modifying strategy in Parkinson*s disease

Background and overall aim
The problem: Parkinson*s disease (PD) is a common, chronic, fast-progressing,
non-communicable disease. As the second most frequent neurodegenerative
disorder worldwide, PD affects millions of people - about 1% of the over-60s
and up to 4% of people in the oldest age groups. It is estimated that the
prevalence will at least double by 2030. None of the currently available drugs
can slow down the dramatic progression of the motor handicap (e.g. falls) and
non-motor handicap (dementia), which generally lead to institutionalization and
death. At present, only symptomatic treatments are available (i.e., drugs that
partially and transiently reduce the patient*s level of handicap). None of the
treatments has demonstrated the ability to decrease the long-term progression
of handicap. Today, most patients with PD irremediably progress to a severe
state of dependence. In Europe, the cost of PD was estimated to be at least
¤13.9 billion in 2010. The huge and increasing socio-economic impact of PD and
the immense emotional burden placed on patients and their caregivers represent
a great challenge to society. There is an urgent need for a *game-changer*
strategy, with the development of disease-modifier treatments with
neuroprotective and/or neurorestoration effects that can help to avoid this
dramatic situation in PD and, more generally, in other neurodegenerative
diseases with common physiopathological mechanisms. For many years, the excess
oxidative stress related to mitochondriopathy has been considered as one of the
main mechanisms involved in cell death (Schapira and Patel, 2014). Oxidative
stress is exacerbated by free iron. Chelation of this free iron is known to
dramatically increase cell survival. Indeed, iron deposition and oxidation are
two major pathways involved in the physiopathology of PD and have been
extensively studied (for a review, see Cabantchik et al. 2013). There is a
large body of evidence that shows that iron chelation-based antioxidants
greatly enhance cell survival in PD cell models and that iron chelators have
therapeutic potential in mouse models of PD. However, we reasoned that to
develop this therapeutic approach in humans, chelation strategies that target
local and regional iron overload (i.e. siderosis) in the brain will necessarily
need to avoid systemic iron depletion via the redistribution of iron to
endogenous acceptors (i.e. in order to prevent harmful systemic metal loss):
this is the new concept of *conservative iron chelation*. We recently
demonstrated (for the first time) the feasibility, efficacy and acceptability
of the conservative iron chelation approach in pilot translational studies in
PD with a prototype drug: deferiprone (1,2-dimethyl-3-hydroxypyridin-4-one,
DFP) (in the FAIR-PARK-I project led by the applicant and funded by French
Ministry of Health). The only available blood-brain-barrier-permeable iron
chelator DFP is approved for treating systemic iron overload in transfused
patients with thalassemia. DFP has been on the EU market since 1999, with a
favourable risk/benefit balance at dose of 75 to 100 mg/kg/day. We shall adopt
a repositioning strategy by using DFP at a lower dose of 30 mg/kg/day in this
new indication for local iron overload in PD. DFP will be the first-in-class
drug for this novel therapeutic strategy. On the basis of our preclinical and
clinical data from FAIR-PARK-I, the present FAIR-PARK-II project should
constitute a model for future cytoprotection strategies in neurodegenerative
diseases; if DFP treatment is associated with significant slower disease
progression, it would be the first non-dopaminergic drug to have a proven
disease-modifying effect in PD.
Conservative iron chelation was assessed in cell-based models, corroborated in
an animal model of regional siderosis and then translated into a clinical
setting (Devos et al., 2014). These preclinical, translational and pilot
clinical studies (Devos et al., 2014; details of our results are specified
elsewhere in this application): have demonstrated that iron chelation with DFP:
(i) induced greater neuroprotection in cell models (dopaminergic neurons:
LHUMES model, patients* lymphocytes) than deferoxamine (used as a reference
iron chelator) through a powerful antioxidant effect.
(ii) reduced regional siderosis of the brain and the motor handicap in the
1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) neurotoxin mouse model.
(iii) reduced regional siderosis of the brain in PD patients
(iv) reduced motor handicap of PD patients (possibly through central and
peripheral inhibition of catechol-O-methyl transferase (ICOMT) in a
double-blind, placebo-controlled study in 40 patients.
(v) slowed the progression of motor handicap in a pilot study in early-stage
PD patients (thus suggesting a disease-modifying effect) in a double-blind,
placebo-controlled study in 40 patients with a delayed start paradigm.
(vi) had a good safety profile, although weekly blood counts are required
during the first six months to detect the (reversible) neutropenia that
typically occurs in 2-3% of treated patients.
Thus, DFP appears to have disease-modifying potential and also inhibits
dopamine metabolism through ICOMT (Waldmeier et al. 1993; Devos et al., 2014;
Dexter et al., 2014). The latter associates a more direct symptomatic benefit
for the patients, together with the expectation of slower disease progression.
The ICOMT activity could be also of high value because there is a lack of
well-tolerated drugs with central ICOMT. Entacapone has only peripheral ICOMT
activity (and thus a lower efficacy). Although tolcapone has both central and
peripheral ICOMT activity, its prescription is restricted indicated by a high
risk of hepatitis.
Interestingly, these clinical results were recently confirmed by another
independent pilot study on 18 PD patients, which showed a reduction in brain
iron overload and a better clinical effect for DFP at 30 mg/kg/day than for
placebo and DFP at 20 mg/kg/day (Dexter et al., 2014). Thus, the two pilot
studies have been used to calculate the required sample size to lead our
project based upon a large randomized clinical trial to demonstrate this new
therapeutic concept
Moreover, by taking advantage of collaborations and involvement in other
European studies, we shall assess DFP's impact and the prognostic value of
biomarkers obtained from large-scale, on-going studies. This will increase the
scientific impact and dissemination of our study (i.e. publications) and limit
the risk of failure and negative results.
Finally, the health economics and societal impacts will be monitored because it
is increasingly acknowledged that conclusions based on conventional clinical
trials may not be useful for making decisions on management in a "real-life"
clinical setting. If DFP is associated with significant slowing of disease
progression in FAIR-PARK-II, it would be the first non-dopaminergic drug to
have a proven disease-modifying effect. As such, DFP would also have a huge
socio-economic impact. In order to move towards an assessment of DFP's
potential real-world benefits data, we shall concomitantly analyse the drug's
impact on health economics aspects and the PD patients' and caregivers' quality
of life via questionnaires and the continuous quantitative monitoring of
PD-associated handicaps in the home environment (i.e., bradykinesia, gait and
balance, tremor, sleep) using the SENSE PARK device (developed in the frame of
FP7).
At present, no neuroprotective drugs are available. If our academic
proof-of-concept study demonstrates a disease modifying effect, this new
therapeutic strategy could be offered to the population of patients with PD as
a whole. This would represent a considerable market and would have a huge
socio-economic impact.

Objectives
The main objective of the FAIR-PARK II trial is to demonstrate an effect of DFP
on the course of PD (including both disease-modifying and symptomatic effects).
The trial's overall objective can be summarized as follows: to demonstrate for
the first time in a large phase III II, multicentre, parallel-group,
placebo-controlled, randomized clinical trial (RCT) that conservative iron
chelation, with the prototype drug, DFP, will slow down the progression of
handicap in PD patients and will not be associated with a negative clinically
benefit/risk ratio. A putative slow-down in the progression of handicap will be
monitored in a multicentre, placebo-controlled RCT with 372 patients with de
novo PD (169 patients per arm) (the best population for assess a
disease-modifying effect without the bias caused by the effects of dopaminergic
treatment).

Objective 1: To successfully manage the demonstration of the Investigating DFP
efficacy as a treatment for PD in a large placebo-controlled study and thus
demonstrate (for the first time in a neurodegenerative disease) the concept of
conservative iron chelation as a disease modifier treatment. We aim to
demonstrate a lower progression of motor and non-motor handicap at week 36 in
PD receiving DFP as compared with placebo.
Objective 2: To demonstrate the feasibility of a multi-site European clinical
trial of a potential PD treatment with a demonstrated safety profile, with a
specific monitoring.
Objective 3: To fund the larger scale investigation of DFP in PD patients,
which the existing preclinical and clinical data strongly mandate and to
promote a European clinical trial network of PD clinicians and researchers.
Objective 4: To investigate clinical, radiological, biological and genetic
biomarkers of PD progression in response to DFP.
Objective 5: To bring the first data of DFP's potential real-world benefits
based upon the drug's impact on health economics aspects and the continuous
monitoring of motor and non-motor handicap at home.
Objective 6: To expedite the availability of disease-modifying treatments to PD
patients. Based upon our demonstration of efficacy and safety of conservative
iron chelation with the only available and prototype drug, DFP, we aim to
promote and support the clinical development of iron chelators as a new
treatment modality in PD. The following clinical development with large phase
III II studies and registration of DFP, the first in class, by ApoPharma could
be done within 7 years. We also aim to promote the clinical development (from
phase I) of future other iron chelators (i.e. hydroxypyridinones) for PD and
other neurodegenerative diseases (i.e. Alzheimer, ALS, multisystem atrophy,
etc.).
Objective 7: To evaluate the effect of DFP on the disease progression, taking
into account the drop out rate with a combined criterion of disease progression
measured by the total score of the MDS-UPDRS and the dropout because of disease
worsening

A multicentre, parallel-group, randomized, placebo-controlled trial of DFP 15
mg/kg BID. A 9-month treatment period (period 1) will be followed by a 1-month
post-treatment monitoring period (period 2), in order to assess the
disease-modifying effect in the absence of a symptomatic effect (i.e. an effect
of inhibition of catechol-O-methyl transferase (COMT) activity (ICOMT) on
dopamine metabolism) of DFP (versus placebo). Considering the short half-life
of DFP, one month will be enough to assess the level of handicap of patients in
the absence of ICOMT due to DFP treatment.

Pharmacotherapeutic group: iron chelator.
The active substance is 3-hydroxy-1,2-dimethylpyridine-4-one (DFP, FERRIPROX®),
a bidentate ligand that binds to iron in a 3:1 molar ratio. DFP decreases
excessive iron and ferritin levels. Its low molecular weight and liposolubility
enable it to cross the blood-brain barrier. Clinical haematology studies have
demonstrated that DFP is effective in promoting iron excretion and that a dose
of 25 mg/kg three times per day can prevent the progression of iron
accumulation (as assessed by serum ferritin levels) in patients with
transfusion-dependent thalassemia. However, chelation therapy may not
necessarily protect against iron-induced organ damage. DFP (provided by
ApoPharma) is unique among available iron chelators in that it readily
penetrates the CNS and has been shown to function as an iron redeployment
agent. The drug has been approved for many years in the indication of
haemosiderosis in thalassemia major patients undergoing chronic blood
transfusion. We intend to reposition DFP, with a disease-modifying effect in PD.
Patients will receive placebo or 30 mg/kg per day DFP divided into two doses
(at 08.00 and 20.00). An initial DFP dose escalation will be applied every
third day during a period of 15 days
We shall check on tolerability (assessed by interviews and examinations) and
compliance (assessed by interviews and tablets counts) every 3 months.
Interviews of patients and caregivers will be performed by the investigators.
In the event of poor tolerance, we shall delay the titration phase by 1 week.
The dose can be temporarily reduced to 20 mg/kg per day (suspicious of adverse
event or variation of blood ANC toward neutropenia). However, we shall ask to
the centers to maintain the patients at the dose of 30 mg/kg per day.

Expected benefits:
We expect to observe a significantly lower handicap in the DFP group and thus a
lower disease progression.
It appears to have no loss of opportunity for the patients under placebo since
there is still no validated neuroprotective treatment. Rasagiline has shown a
weak disease modifying effect, for which a pure symptomatic effect remains
subject of debate. Moreover, it has been specified in the exclusion criteria
that *Subjects with a handicap likely to require symptomatic dopaminergic
treatment in the coming nine months* in order to avoid patients having a
handicap requiring symptomatic effect.
Possible risks:
- Risk of neutropenia (< 3%)
- No anemia expected
- Adverse effect of DFP (see products characteristics).