A Proof-of-Concept Study to Explore the Potential Efficacy of Deferiprone in Patients With
Pelizaeus-Merzbacher disease (PMD)

Pelizaeus-Merzbacher disease (PMD) is a devastating brain white matter
disorder, caused by mutations in the gene encoding proteolipid protein 1
(PLP1). It is an X-linked disorder, carrier mothers may become symptomatic
later in life. In the classic form of the disease, motor handicap is severe:
patients are not able to sit without support.

There are more severe and milder forms, depending on the PLP1 mutation.
Typically, affected boys develop a pendular nystagmus at the age of several
weeks, similar to infants with congenital nystagmus. Shortly thereafter,
delayed psychomotor development becomes apparent. These infants show axial
hypotonia with difficult head control, titubation, exaggerated tendon reflexes
and a combination of ataxia and extrapyramidal features. Nystagmus may improve
or even disappear over time. Optic atrophy is common. In classic PMD, patients
are unable to walk, and usually unable to sit without support. If they develop
active speech, it is difficult to understand because of dysarthria and scanning
speech. Learning problems or mental retardation is common, although motor
impairment tends to be more pronounced than cognitive disability. In connatal
PMD, symptoms are evident shortly after birth and often include congenital
stridor, feeding difficulties and profound hypotonia. Development is more
impaired than in the classic form, and connatal PMD patients do not learn to
talk or sit without support and make very little developmental progress.
Microcephaly is common. Transitional PMD is intermediate in severity to the
connatal and classic variants. Clinical course in PMD is chronic. Until late
childhood or early adolescence, patients may improve and make definite, albeit
slow, developmental progress. From this age, however, slow deterioration
begins, with insidious progression of neurologic symptoms and slow cognitive
decline. Optic atrophy, if not yet present, develops. While difficult to
predict for individual patients, life expectancy is reduced, and depends on
severity of neurologic deficits and additional complications. Connatal PMD
patients often die within the first decade of life, classic PMD patients in the
second or third decade. There is currently no treatment for PMD other than
symptomatic treatment. Symptomatic treatment aims at preventing contractures,
ensure adequate nutrition (a gastrostomy often becomes necessary) and treating
spasticity, among other measures to stabilize general health.

MRI in PMD shows hypomyelination, indicated by diffusely elevated signal white
matter signal on T2. There is a severe myelin deficit. Still, when imaged
sequentially, PMD patients do show some, albeit a minor progress of
myelination, certainly in the first years of life. This progress is greater in
children with milder PMD forms. Myelination is then arrested and fails to
progress on repeated scans. In older patients, atrophy becomes more prominent.

Located on Xq22.2, PLP1 encodes the proteolipid 1 protein, which constitutes
roughly half of all myelin protein. There are different genetic defects
affecting PLP1 in PMD patients. Most commonly, the PLP1 gene is duplicated.
Missense mutations are less frequent and, depending on the mutation, may lead
to even more severe disease. Genotype-phenotype correlations have been
established for most PLP1 variants, although some clinical heterogeneity among
patients with common genetic alterations makes definitive characterization
difficult. Symptoms do not correlate with duplication size, but high copy
number (PLP1 triplication) predicts increased clinical severity. Missense
mutations are associated with the full spectrum of PLP1-associated disorders.
All genetic defects lead to failure of oligodendrocyte lineage maturation,
defective myelination and subsequently axonal damage.

There are several mouse models for PMD, among these Jimpy mice, harbouring a
severe point mutation in intron 4, causing a putative truncation of Plp1
protein, and animal death by P28. This model is a good representation of human
disease, reflecting severe myelin deficit due to early oligodendrocyte death.
There is also a mouse model for PLP1 duplication. These mouse models are well
characterised.

Recently it has been shown that iron overload may contribute to PMD
pathogenesis. This was studied using patient-derived induced pluripotent stem
cells (iPSCs) and gene-corrected isogenic cells. PLP1-mutant, iPSC-derived
oligodendrocyte precursors (OPCs) developed to the pre-myelinating stage
normally, but subsequently underwent apoptosis. Unexpectedly, UPR and ER stress
pathways were not activated, and the mutant protein was transported to the cell
membrane. Rather, mutant OPCs demonstrated severe lipid oxidative stress,
abnormal iron metabolism and sensitivity to extracellular iron. Gene-corrected
OPCs, on the other hand, were insensitive to iron. Remarkably, pharmacological
iron chelation treatment with iron chelation rescued mutant OPCs in vitro.
Systemic administration of deferiprone, a blood-brain-barrier permeable iron
chelator reduced jimpy mouse lethality at P28 and levels of oligodendrocyte
apoptosis in the corpus callosum.

Deferiprone (3-hydroxy-1,2-dimethyl-4(1H)-pyridone) is registered in the United
States and Europe for the treatment of iron overload in patients > 6 years with
thalassaemia major when current chelation therapy is contraindicated or
inadequate. Deferiprone in combination with another chelator is indicated in
patients with thalassaemia major when monotherapy with any iron chelator is
ineffective, or when prevention or treatment of life-threatening consequences
of iron overload (mainly cardiac overload) justifies rapid or intensive
correction. Deferiprone has been used in patients (children and adults) with
different neurological disorders in treatment studies.

This study has been transitioned to CTIS with ID 2024-511968-81-00 check the CTIS register for the current data.

Studying the effect of deferiprone on the motor function of patients with
Pelizaeus-Merzbacher disease.

This is an open-label, non-randomized explorative study with historical control
group to evaluate (1) efficacy on motor function in patients with PMD, (2)
potential major beneficial effects of deferiprone on quantitative MRI
parameters relevant to brain white matter integrity and VEP/AEP and (3) the
relationship between deferiprone and possibly efficacy-related biomarkers in an
exploratory analysis.

Patients with genetically proven PMD and a brain MRI compatible with the
diagnosis will be eligible for participation in the study if they have connatal
or classic PMD and are between age 6 months and 7 years at screening. For a
more detailed comparison, historical controls will be matched as much as
possible to the study population based on age at disease onset, duration of
disease at study entry, and disease severity category on the basis of the
patient*s genotype.

The study will consist of a screening period of 1 to 3 days, followed by an
open-label, non-randomized treatment period of 1 year. After this period,
deferiprone will be prescribed off-label to those patients wishing to continue
the study until all patients have completed at least 1 year of deferiprone.
A target of 5(-10) patients are planned to receive deferiprone treatment at a
dose of 25 mg/kg/day. Deferiprone will be administered as an oral solution in 2
daily doses (in the morning and in the evening) and in addition to the usual
standard of care.
The total study duration will depend on the time needed to recruit the planned
number of patients. This is expected to be 1 year.

The study will be conducted in a multicentre setting (locations VUmc and AMC of
Amsterdam UMC) in Amsterdam, The Netherlands).

oral administration of deferiprone oral solution 25 mg/kg/d in 2 single doses

Based on (1) the effect of deferiprone on PMD oligodendrocytes in vitro and (2)
results of previous studies using deferiprone in a mutant mouse model that is
representative of human PMD, deferiprone may ameliorate PMD in patients.
As all classic and connatal PMD patients have an infantile disease onset, the
present study cannot be conducted without participation of patients belonging
to this group. The strongest beneficial effects of deferiprone on the
neurological phenotype are expected to occur in children with severe disease,
early in the disease course, when neurons and axons are still relatively intact.
In addition to the twice daily intake of deferiprone, the burden of study
participation includes:
• Regular (every 3 months) control visits to the site (VU University Medical
Center; VUmc) for physical and neurological examinations, motor function
assessment, temperature, blood pressure and heart rate measurements, and blood
sampling (full blood count, iron parameters, zinc).
• Assessment of motor function by physiotherapist at day -10 to 0, 180 and 365
including video documentation.
• EEG registration at day -10 to 0, 180 and 365.
• Brain MRI scans (at day 0 and day 365). The MRI procedures will take place
under superficial anaesthesia aiming at spontaneous respiration. At VUmc,
annual / biannual MRI scans under superficial anaesthesia are routine practice
for patients with a leukodystrophy, including PMD.
• Weekly capillary blood sampling for full blood count. Capillary blood
sampling is also necessary when children have fever > 38 degree C.
• CSF and blood sampling for biomarker analysis when the child is under
anaesthesia for MRI.
• Skin biopsy (2mm diameter) for fibroblast cultures when the child is under
anaesthesia for his first MRI (if fibroblasts are not yet available).
• Bi-annual assessments (by standard questionnaires and scales) of quality of
life and disability.

In summary, given the severity of the disease with (1) poor quality of life and
severe disability of PMD patients, (2) the absence of effective treatment
options, (3) non-clinical evidence indicating that deferiprone may ameliorate
PMD, (4) its proven safety in children including infants, and adults with
hematological conditions, and (5) the absence of risks related to determination
of the study parameters versus standard procedures, the potential value of this
study for future PMD patients outweighs the risks and burden for participating
PMD patients.

Main risk of deferiprone is leukopenia. This can lead to serious infections.
Weekly monitoring of full blood count is an established method to prevent
severe neutropenia and its complications. This monitoring will be performed
using capillary blood sampling (as for glucose testing in patients with
diabetes), close to home or at home, minimising burden of this intervention for
the patients.