Effects and health economic aspects of enzyme therapy in children and adults with Pompe disease. Long-term follow-up of patients receiving commercially available Myozyme

Pompe disease (glycogen storage disease type II) is a genetic, lysosomal
storage disorder with a frequency of 1 in 40.000 newborns. The disease is
caused by deficiency of alpha-glucosidase, a lysosomal hydrolase involved in
the degradation of glycogen. This deficiency causes accumulation of glycogen in
many tissues, like cardiac and skeletal muscle and liver tissue. Patients with
the classic infantile form of Pompe disease have severe cardiorespiratory
problems and motor developmental delay. These children usually die within the
first year of life. Patients with the non-classic form of the disease can
present at any age and there is a spectrum in severity of disease.

Until recently, no therapy was available for patients with Pompe disease. In
2006 treatment with Myozyme (alglucosidase alfa; enzyme therapy) was registered
for long term treatment of all patients with Pompe disease (both children and
adults). However, information about the effect of enzyme therapy is limited,
especially in older children and adults. Further research is essential,
especially to determine the long-term effects of enzyme therapy.

Therapy for the classic infantile form of Pompe's disease is most effective if
started as soon as possible after diagnosis. Currently, the average diagnostic
delay is 5,3 months. Early diagnosis is essential for better outcome in
survival, respiratory, cardiac and muscle function. An obvious way to reduce
this diagnostic delay in Pompe's disease would be early detection with
universal newborn screening. Alternative treatment regimens, for example a
different dose or the use of immunomodulation, may also further improve
treatment outcomes in this patient group is.

Exercise training possibly further improves muscle strength and muscle
function. Exercise training programs improve oxidative capacity and muscle
function in other myopathies. Existing studies on exercise training programs in
patients with Pompe disease are not performed systematically or are performed
in small groups of patients. Therefore exercise training is not a standardized
treatment for patients with Pompe disease. A recent inventarisation in 51 adult
patients showed that there patients would like to combine a standardized
exercise trainings program and/or physical therapy program with their enzyme
replacement therapy.
As previously shown, exercise therapy improves endurance, muscle strength,
muscle function and core stability. However, little is known about the long
term effects of exercise therapy in Pompe patients. We would like to know
whether patients benefit from exercise therapy in the long term, thus whether
their physical functioning and fitness is better with exercise in addition to
enzyme therapy.

Patient with Pompe disease might have an increased aortic stiffness due to
accumulation of glycogen in the vessel wall. This could be an independent risk
factor of cardiovascular accidents.

Since the start of treatment with enzyme replacement therapy muscle strenght
and pulmonary function in sitting position stabilize or improve. The effects on
pulmonary function in supine position are less pronounced; in 1/3 of the
patients this parameter decreases despite treatment. The decrease in pulmonary
function in supine position is possibly due to weakness of the diaphragm. With
MRI in combination with spirometry we want to obtain insight into the function
and strength of the diaphragm and pulmonary abnormalities. Moreover we want to
investigate the effects of enzyme replacement therapy on the diaphragm.

In non-classic Pompe disease, which may present at any age, muscular weakness
is the predominant symptom. However, the clinical phenotype is very variable.
In a substantial number of these patients features of Pompe disease which are
less familiair to clinicians are present, such as bulbar weakness, scapular
winging or ptosis. In Facioscapulohumeral dystrophy (FSHD), scapular winging
and facial weakness are the key symptoms. Recently, a second gene related to
FSHD has been identified as:SMCHD1(FSHD2) . Recent family studies show that
SMCHD1 can co-segregate in patients with FSHD1 but also in patients with other
hereditary muscular dystrophies with similar phenotype. SMCHD1 might therefore
play a role as an epigenetic regulator in muscular dystrophies.

During long-term treatment with enzyme replacement therapy we notice that new
features emerge in Pompe disease. We found hampering of
cognitive development or even neurological deterioration in treated patients
with classic infantile Pompe disease. Also we noticed the development of distal
weakness in both classic infantile and late onset Pompe disease. Both can be
driven by the involvement of the central and peripheral nervous system.

Previous research showed increased aortic stiffness and blood pressure in adult
Pompe patients compared to controls. These are independent risk factors for
cardiovascular disease and may lead to more cardiovascular morbidity in Pompe
patients.

This study has been transitioned to CTIS with ID 2024-518269-92-00 check the CTIS register for the current data.

The objective of the study is to gather more information about the long-term
effect of enzyme therapy in patients with Pompe disease with a different
severity of disease. The goal is also to set guideline for start and stop of
treatment and to evaluate health economic aspects. Furthermore, it is important
to find an optimal dosing regimen.
We will study whether newborn screening for Pompe disease in The Netherlands is
possible and desirable/ advisable.
Furthermore, the effectiveness and safety of a standardized exercise trainings
program next to enzyme replacement will be studied.
The frequency and characterization of pain in adult patients with Pompe disease
will be studied.
Aortic stiffness in adult patients with Pompe disease will be studied.
Study the function and strength of the diaphragm and effects of enzyme
replacement therapy.
Modifying factors in Pompe disease will be investigated.
To characterize the occurrence and the extent of clinical and radiological
features of CNS involvement in ERT-­*treated classic infantile Pompe patients
in different age groups, and to investigate its course over time. To
investigate whether impaired functioning of anterior horn cells, peripheral
nerves, or neuromuscular junction contribute to the development of distal
muscle weakness of the limbs.
To investigate the prevalence of cardiovascular morbidity and cardiovascular
risk factors in adult Pompe patients.

This study is a therapeutic intervention study with a registered product.
Patients are followed for at least 3 years by general/neurological examination,
combined with examination of muscle strength and function, pulmonary function,
cardiac function and hearing.
For the substudy on newborn screening, the bloodspots of patients with Pompe's
disease, parents of patients with Pompe's disease and anonymous Guthrie cards
from the RIVM (National Institute for Public Health and the Environment) will
be analysed with a fluorimetric method and tandem mass spectometry. Health
damage at diagnosis will be evaluated using information from medical files and
questionnaires. Semi-structured interviews will assess the attitude of health
care workers towards the possible implementation of Pompe disease to the
national newborn screening project.
For the substudy on exercise training patient will be placed randomized in two
groups. Group 1 will start with the exercise trainings program and will train
for 3 months. The last 3 months of the study they will not train in order to
study the effects of "detraining". Group 2 will not train for the first 3
months and therefore serve as controls for group 1. They will train the last 3
months of this substudy. Patients are followed by muscle strength, muscle
function and muscle architecture, body composition, endurance and quality of
life.
The substudy for pain in Pompe dsiease is a cross-sectional, observational
study. Patients 18 years and older will be asked to complete once a subset of
questionnaires on pain.
The substudy for aortic stiffness in Pompe disease is a case control study.
Ultrasound is a non-invasive way to measure pulse wave velocity and
distensibility of the a. carotis and a. femoralis. It's the golden standard for
measuring the aortic stiffness.
The substudy on the function of the diaphragm is a case control study. MRI in
combination with spirometry is a non-invasive way to measure this function and
the strength of the diaphragm. To investigate changes over time, we will repeat
the MRI scan after one year. Secondly we aim to make an ultrasound of the
diaphragm to investigate whether this correlates with MRI-findings and lung
function.
The substudy on modifying factors in Pompe disease is a cross-sectional study.
Three tubes of blood will be taken just before start of treatment with enzyme
replacement therapie, so patients don't need an extra vena punction.
The international study on treatment regimens is a retrospective study on data
available in the patient files.
The study on the emerging new features in Pompe disease is a prospectively
observational study in which patients will be followed up by neuropsychological
tests, MRI's of the brain and nerve and muscle ultrasounds. A muscle biopsy,
EMG, SSEP, VEP, ORG and OCT and a MRI of the myelum and lower extremities will
be performed once. The muscle MRI of the lower extremities and a one time MRI
of the brain will be conducted at the LUMC.
The substudy on cardiovascular morbidity is a case-control study. Length,
weight, hip circumference and waist circumference will be measured.
Participants will be asked to fill in a questionnaire regarding cardiovascular
risk factors. 30-minute blood pressure measurement, blood analysis and
urinalysis and an EKG will be performed.
The substudy on long term effects of exercise therapy is a cross-sectional
study. Patients included in the previous exercise study
will be included again. Patients who didn*t follow the exercise program at the
time will be included as controls. They will be matched by gender, age and also
disease progression at the time of the previous exercise therapy. Data of the
standard outpatient clinic assessments will be collected. These assessments
contain vital parameters, height, weight, standard blood and urine tests,
pulmonary function, six minutes walking test, muscle strength measured manually
and by HHD (hand held dynamometry), muscle function measured with GMFM (gross
motor function measure) and timed tests. Patients will be asked to visit the
outpatient clinic for an extra day. This is necessary to perform endurance
tests by cycle ergometer, to fill in questionnaires about fitness and fatigue
and to measure bone density and body composition using a dexa-scan.

All patients who participate in the study will receive Myozyme. Myozyme is a
registered (orphan)drug for treatment of all patients with Pompe disease.
Patients will come once every 2 weeks to the Erasmus MC for their infusions.
Patients participating in the substudy on exercise training will follow a
standardized exercise trainings program for 3 months.
Patients participating in the substudy on aortic stiffness will get a
non-invasive measurement wih ultrasound of the a. carotis and a. femoralis.
Patients participating in the substudy on function of the diaphragm will get an
MRI in combination with spirometry and an ultrasound of the diaphragm.
Of patients participating in the substudy on modifying factors 3 tubes of blood
will be taken just before start of treatment with enzyme replacement therapie,
so patients don't need an extra vena punction.
Patients participating in the substudy on emerging new features will be studied
by the above mentioned examinations.
Patients participating in the substudy on cardiovascular morbidity will be
studied by the above mentioned examinations.
Patients participating in the substudy on long term effects of exercise therapy
will be studied by the above mentioned mostly standard outpatient clinic
examinations.

During the study, blood will be drawn and in some patients a skin and muscle
biopsy will be performed. All other study evaluations like general/neurological
evaluation, pulmonary function, cardiac function and hearing are considered
without risk. Patients will come once every 2 weeks to the hospital for their
infusion. All other examinations will be combined with this infusion visit.
For the substudy on newborn screening, blood will be drawn once from the
parents of patients with Pompe's disease to prepare blood spots in which enzyme
activity will be measured.
Patients participating in the substudy on exercise training have to visit the
hospital for additional assessments. Exercise training possibly further damages
muscle tissue. Earlier studies on exercise training in patients with Pompe
disease have not found any further damage. Furthermore we will monitor muscle
damage by biweekly analysis of blood samples (0.5 ml) taken before the start of
the enzyme replacement therapy.
There will be no risks for the patients and controls participating in the
substudy on aortic stiffness. The ultrasound will take place during a visit
when the patients and controls are already at the Erasmus MC.
For the substudy on the function of the diaphragm patients do not have to visit
the hospital an extra time. The MRI will be scheduled during one of the regular
visits or on the day the patient receives his infusion in the Erasmuc MC. There
aren't major risks for the patients. They only could get short-winded during
the investigation.
For the substudy on modifying factors patients do not have to visit the
hospital an extra time. Three tubes of blood will be taken just before start of
treatment with enzyme replacement therapie, so patients don't need an extra
vena punction. There aren't additional risks for the patients. Only the already
existing risk of the vena punction for administration of ERT.
All patients will have a muscle biopsy and a nerve conduction and needle
myography. Children under the age of 7 years will be anesthesized to enable
these procedures and the MRI's.
For the sub study on cardiovascular morbidity all investigations will take
place during the patient*s regular assessment day. One extra tube of blood will
be drawn from patients, there will be no additional venipuncture for patients.
Controls will undergo a venipuncture once, three tubes of blood will be drawn.
Patients participating in the substudy on long term effects of exercise therapy
will be asked to visit the outpatient clinic one extra day for approximately 6
hours to perform the afore mentioned examinations. This will be asked just
once.