A Global, Multicenter, Single-arm, Matched External Control Study of Intrathecal SHP611 in Subjects with Late Infantile Metachromatic Leukodystrophy

Deficiency of the lysosomal enzyme arylsulfatase A in MLD leads to the
accumulation of sulfated glycosphingolipids, known collectively as sulfatides.
These accumulate in, and are toxic to, the cells which maintain the myelin
insulation sheath of axons both centrally and peripherally. It is hypothesized
that IT administration of recombinant human arylsulfatase A (SHP611) would be
sufficient to hydrolyze accumulated sulfatides in cells of the nervous system
and could slow or prevent further accumulation, which should translate into
motor system benefits. There are currently no approved therapies for MLD.
Administration of SHP611 via an implanted intrathecal drug delivery device
(IDDD) was well tolerated in Phase 1/2 studies in pediatric subjects with MLD
and the device appeared to have an acceptable safety profile. In these studies,
the higher dose appeared to show a signal of stabilized motor function in 4 of
12 subjects who received the 100 mg every-other-week (EOW) dose. This Phase 2b
study will investigate the potential of IT SHP611 at a higher dose of 150 mg
once weekly to stabilize or slow progression of motor dysfunction in pediatric
subjects with late infantile MLD. The extension period of the study will
evaluate long-term safety and efficacy outcomes of treatment with IT SHP611 in
subjects who have participated in the study through Week 106.

The primary objective of this study is to evaluate the effects of intrathecal
(IT) administration of SHP611 (also known as TAK-611) on the time to loss of
locomotion, as indicated by category 5 or higher in the Gross Motor Function
Classification in Metachromatic Leukodystrophy (GMFC-MLD) compared with matched
external control group data in children with late infantile MLD.

The key secondary objective of this study is to evaluate the effects of IT
administration of SHP611 on gross motor function, using the Gross Motor
Function Measure 88 (GMFM-88) total score compared with matched historical
control data in children with MLD.

If suitable controls cannot be matched despite the sponsor's best efforts,
change form baseline results of GMFC-MLD at week 106 will be compared with a
prespecified objective threshold to evaluate primary efficacy for this study.

SHP611-201 is an a single-arm, matched external control, global, multicenter,
Phase 2 trial. The study was planned to enroll up to 42 subjects with late
infantile MLD who have an initial onset of neurological symptoms documented
prior to 30 months of age (Groups A, B, C, and F), or who are minimally
symptomatic and >=6 to <18 months of age (Group D), or who are early symptomatic
and >=12 to <18 months of age (Group E). Minimally symptomatic is defined as
being without clear symptoms of late infantile MLD or only showing mild
symptoms (such as weakness) that do not meet the criteria for a GMFC-MLD
category of >0. The rate and severity of disease progression is well documented
in late infantile MLD. A distinguishing feature of the definition of late
infantile MLD is the early age at disease symptom onset with a majority of
patients with late infantile MLD showing first motor dysfunction before the age
of 18 months. Six subject groups are defined for this study based on age and
motor dysfunction at screening:
• Group A (GMFC-MLD category 1 or 2): 18 to 48 months of age with a GMFC-MLD
category of 1 or 2
• Group B (GMFC-MLD category 3): 18 to 72 months of age with a GMFC-MLD
category of 3
• Group C (GMFC-MLD category 4): 18 to 72 months of age with a GMFC-MLD
category of 4
• Group D (minimally symptomatic): >=6 to <18 months of age, with the same ASA
allelic constitution as an older sibling with confirmed late infantile or
juvenile onset MLD
• Group E (GMFC-MLD category 1 or 2 ): >=12 to <18 months of age, with
documented diagnosis of MLD per inclusion criteria 1 and 2 with a history of
achieving stable walking (defined as at least 1 month of independent walking)
and a GMFC MLD category of 1 or 2
• Group F (GMFC-MLD category 5 or 6): 18 to 72 months of age with a GMFC-MLD
category of 5 or 6
Subjects weighing >=7 kg (15.4 lbs) will receive 150 mg IT SHP611 weekly. It is
anticipated that the majority of subjects will receive 150 mg IT weekly for a
total treatment duration of 105 weeks; however, subjects weighing >=5 kg (11.0
lbs) to <7 kg (15.4 lbs) will receive 100 mg IT SHP611 weekly until they weigh
>>=7 kg, at which time they will begin dosing with 150 mg IT SHP611 weekly.
The study will evaluate safety and efficacy of the treatment regimen on gross
motor function using the GMFC MLD and GMFM-88 total score to measure disease
progression (Groups A, B, C, E, and F). Subjects in Group D will be assessed
with the Alberta Infant Motor Scale (AIMS) and the GMFM-88 until they are
ambulating or 18 months of age, whichever comes first. Once the AIMS is no
longer being used, the GMFC-MLD and GMFM-88 will be used to measure motor
function in this group.
The primary efficacy endpoint is time to loss of locomotion, measured by
progression to GMFC-MLD category 5 or higher, or death, whichever occurs first,
up to Week 106, evaluated on subjects in Group A. A secondary efficacy endpoint
is response in Group A, defined as maintenance of gross motor function at Week
106, evaluated as subjects who do not experience any event within Week 106,
where event is defined as a decline in GMFC-MLD to category 5 or higher, or
death.

The efficacy of SHP611 will be evaluated by comparison of SHP611-201 enrolled
subjects in Group A with a matched external control group. The data from these
untreated MLD subjects (ie, subjects who have received no investigational
product or therapy) will come from the ongoing Global Leukodystrophy Initiative
(GLIA MLD) natural history study.

The matched external control group must have data for at least baseline gross
motor function evaluation. The filtering criteria for these external control
subjects will be very similar to the inclusion/exclusion criteria for enrolled
subjects in Group A of this present study.
Subjects will be implanted with the SOPH-A-PORT Mini S IDDD. Procedures for
implantation are detailed in the device*s Instructions for Use (IFU) manual.
Standard hospital procedures for surgery will be followed and the subject may
be under anesthesia for this procedure. Prior to implantation, individual
neurosurgeons may order additional imaging to estimate the canal size and
spinal cord conus location in younger patients. After implantation, a leak test
is performed by the neurosurgeon to ensure a sealed system is in place. X-rays
may be performed as needed, particularly for younger subjects, throughout the
study to confirm placement of the device and/or evaluate a nonworking catheter.
In order to facilitate healing, subjects should remain under observation in the
hospital setting until deemed clinically stable by the investigator and should
limit activity for 24 hours after IDDD implantation. To allow for healing, a
waiting period of 3 to 5 days after device implantation must be observed before
the first administration of SHP611 may occur. If the device becomes
nonfunctional at any time during the study, it may be removed, replaced, or
revised as appropriate. After IDDD replacement or revision, a waiting period of
3-5 days must be observed before IT SHP611 dosing may resume. Examination of
both the port and catheter track will be performed before each IT injection,
which includes aspiration of CSF via the port.

During the treatment period, subjects will undergo assessments of gross motor
function, brain imaging, and health-related quality of life. Initial assessment
of gross motor function using the GMFC-MLD scale will be conducted by local,
trained healthcare professionals and video-recorded. Videos of GMFC-MLD
assessments will be evaluated by central video reviewers for primary scoring of
gross motor function on the instrument.

Safety will be assessed by collection of adverse events, physical examinations,
vital signs, concomitant medications, ECG, clinical laboratory testing, and
monitoring of anti-SHP611 antibodies. Periodic assessments will be performed
before and after SHP611 administration at specific study visits (eg, serum/CSF
PK sampling and CSF, serum, and urine biomarkers sampling and testing).
The study will consist of a screening period of up to 28 days. Implantation of
the SOPH-A-PORT Mini S IDDD may occur during a period of up to 10 days prior to
the first administration of IT SHP611 to 28 days after the first administration
of IT SHP611.IT SHP611 administrations that occur prior to implantation of the
IDDD will be administered via LP.
Subjects will be assessed according to the following schedule:
• Screening (-28 to -1 days)
• Surgical implantation of IDDD (-10 to 28 days)
• Primary treatment period (Week 0 [baseline assessments prior to dosing]
through Week 105)
• End of primary treatment period (Week 106)
• Extension treatment period (from Week 106 administration of SHP611)
• End of treatment (EOT) (last administration of SHP611)
• End of study (EOS) (1 week after EOT)
• Safety follow-up (2 weeks after EOS)
After the primary treatment period is completed at Week 106, subjects may
participate in the extension period of the study where they may continue to
receive treatment with SHP611 for an extended duration of time.
Subjects will receive weekly treatment until they or their parents/guardians
decide to discontinue treatment; the sponsor discontinues the study; the
subject is discontinued from the study due to medical or safety concerns; or
the product becomes commercially available in the subject*s country of
residence, whichever comes first. During the extension period, main site
assessments will be scheduled every 6 months. These assessments may be skipped
for a visit at the discretion of the investigator and upon discussion of the
investigator with the Medical Monitor if it is determined that the subject is
unable to perform the assessments. At the EOT visit, subjects will receive
their last administration of SHP611 and comprehensive assessments will be
completed at the EOS visit.
If a subject discontinues from the study earlier than EOS, every effort should
be made to complete assessments for the EOS and the safety follow-up visits.
Subjects are to have the IDDD removed when they discontinue from the study,
unless the subject is continuing to receive treatment with SHP611 through
another mechanism (eg, commercially available) or the investigator determines
that the IDDD should not be removed from the subject based upon a safety
assessment and the IDDD (full or partial) should remain in the subject.

SHP611 (formerly designated as HGT-1110), recombinant human arylsulfatase A
(rhASA).
Subjects weighing >=7 kg (15.4 lbs) will receive 150 mg IT SHP611 weekly for 105
weeks. Subjects weighing >=5 kg (11.0 lbs) to <7 kg will receive 100 mg IT
SHP611 weekly; however, when the subjects weigh more than 7 kg they will begin
dosing with 150 mg IT SHP611 weekly for the remainder of the study.
SHP611 administration will be via an implanted SOPH-A-PORT Mini S IDDD. If the
device becomes nonfunctional at any time during the study, it will be removed
and may be replaced or revised as appropriate. If use of the IDDD is not
possible a lumbar puncture (LP) may be utilized to obtain CSF samples and/or to
deliver investigational drug product. It is anticipated that LP may have to be
performed with anesthesia support at the discretion of the investigator. After
12 consecutive LPs, the feasibility of further use of LPs for that subject will
be determined at the discretion of the investigator and the Shire medical
monitor and documented in a note to file.

This study requires that the patient will visit hospital 213 times over a
period of 215 weeks. A visit will take 3 to about 4 hours. The patient will go
through screening assessments. The child will receive the SOPH-A-PORT Mini S
intrathecal drug delivery system (IDDD) via surgical implantation.
The child will receive once weekly injections of the study drug at 150 mg or
100mg depending on the weight of the patient, along with additional assessments
conducted at each of the visits as written below :
- Physical examination - every visit
- Heart tracing (ECG) - at one visit
- Blood draws- a total of 15 times for testing purposes. The volume of blood
that will be taken each time will vary from 1 mL to 16.5 mL. The total amount
of blood drawn in this study will be about 162.5 mL.
- Questionnaires about about the child*s symptoms and well-being
- Anesthesia, as determined by the study doctor
- Vital signs (blood pressure, breathing rate, temperature, and heart rate) -
every visit
- Height, weight and head circumference
- Hearing and vision
- The child*s overall motor functions,
- Urine sample
- Cerebrospinal fluid sample- every visit
- MRS (Magnetic Resonance Spectroscopy) and MRI (Magnetic Resonance Imaging)

Risks associated with the study drug
Pain and headache during or after the injection of study drug are possible. The
injection procedure may be done incorrectly, including injecting study drug
into the surrounding tissue, or using the wrong type of needle or improper
technique while injecting medicine.
Injection of study drug, as with any protein, carries with it the risk of an
infusion-related reaction. It is possible that the child will develop an
allergic reaction or antibodies against the injected study drug.
Possible reactions to study drug may include a change in mental status or level
of consciousness that are not caused by anesthesia or sedation medicine and may
either occur immediately or develop post-injection over time, sudden behavior
changes, seizure, rash, pruitis (itching), fever, feeling of warmth,
respiratory (breathing) problems, change in blood pressure and heart rate,
pain, stiffness and possible death. Other risks include headache, vomiting,
nausea, dry mouth, loss of smell, and metallic taste. The child may also have a
tingling or painful sensation to the lower legs.

Risks with Sedation or General Anesthesia
Serious side effects of anesthesia are uncommon but include: breathing
problems, swallowing problems, an irregular heartbeat, increases or decreases
in blood pressure, difficulty putting in or taking out a breathing tube, rapid
changes in body temperature, allergic reactions, heart attack or stroke, a
reaction to a medicine used in the anesthesia, or death from complications
including changes in heartbeat, blood pressure, body temperature, or breathing.

Risks with the implanted study device
Implantation of the device involves risks similar to other procedures that
involve direct access to the CSF in the spinal canal area. The risks associated
with the insertion and use of the implanted device (the port and tube) includes
the following.

The component parts of the device may be mishandled before, during or after
implantation of the device. During surgery, the access port may be placed or
positioned incorrectly. The catheter (tube) may be positioned incorrectly.
Potential complications from the surgery include infection, bleeding or
bruising. Spinal cord or nerve damage resulting in nerve pain, inflammation of
the tissues around the spinal cord, or paralysis may also occur during surgery.

After surgery, the port may break, fracture, invert (flip over) or rotate. The
tube or port may become clogged or blocked, making injection of the study drug
difficult or impossible. The tube may become kinked, disconnect from the port,
or break. The port or tube may poke through the skin and scar tissue may form
around the device. The child*s body may not respond well and may reject the
implanted device. If these complications happen, the device will need to be
repaired or replaced with surgery. The wound may not heal properly and may open
along the suture line. The skin where the port is placed may become infected.
Infection may also occur under the skin around the port site and/or along the
catheter (tube). An infection may require treatment with medication and
hospitalization. Fluid or blood collection or bruising around the port or
catheter or at the incision sites may occur after surgery.
The device is made of artificial materials that contain various chemicals. For
instance, the catheter contains Barium, which is a chemical that helps the
doctor to see the catheter on X-rays. When the catheter comes into contact with
fluids like cerebrospinal fluid, saline solution or study drug solution, it is
possible that some of these chemicals may seep out of the catheter and into the
fluids, which may then come into contact with the spinal canal, spinal cord and
brain. At the moment, it is not completely known to what extent that happens,
what chemicals might leach out of the device, and what might be the
consequences. The potential risks associated with chemicals and materials
used in the production of the device are not known

There are additional risks associated with direct access (directly into the
spinal fluid), including spinal fluid leaks or spinal fluid collection beneath
the skin. In clinical trials to date, patients have experienced spinal fluid
effusions or leakage. Although CSF leakage/effusions are often mild, not
requiring surgical intervention, there are cases where additional surgery
including repair or replacement the device and anesthesia is required.
Infection in the nervous system including meningitis (infection of the
membranes covering the brain and spinal cord) or encephalitis (infection of the
brain) may occur and could lead to brain injury or death.

If the surgeon experiences difficulty in implanting the catheter in the usual
way via a hollow needle inserted between two vertebrae (bones of the spine), it
may be necessary to remove a small piece of the bone of the vertebrae. This
procedure is called a laminotomy (or laminectomy, if the entire back part of
the vertebra is removed). If such a procedure is necessary, the surgery will
take longer than foreseen, and a longer hospital stay may be needed to allow
for adequate pain control. Additional or increased risks include:
• Spinal instability and/or curvature of the spine
• Nerve damage - Damage can cause numbness, weakness, problems with urination
or bowel movements, or persistent pain
• Spinal fluid leak
• Bleeding
• Infection

During and after the surgery to put in the device, the child will be properly
monitored to make sure the risks are reduced as much as possible.
The device might fail to work properly at some point during the study. This
would require additional surgery under general anesthesia, similar to what was
done at the time of the initial device implantation. Depending on the nature of
the problem with the device, the surgery may be limited to the port implant
site (under the skin on the side of your child*s chest) or be a repeat of the
entire implant procedure (implant of the port and catheter under the skin and
reinsertion of the catheter in the spinal canal). The risks of surgery and
general anesthesia at the time of device replacement are the same as those at
the time of the initial implantation. In some patients, more than one revision
will take place during the course of the study.

If the study doctor determines that the study device should not be removed from
the subject based upon a safety assessment and the study device (full or
partial) remains in the subject, then the subject will continue in the study
under the safety follow-up period upon completion of their last study treatment
period visit.The risks of partial removal (leaving a complete or a portion of
the catheter in the spinal canal) include catheter migration and infection.

Risks of lumbar puncture
Lumbar puncture can cause a mild to severe headache which may last for several
days. Other risks associated with the lumbar puncture include pain at the site
where the needle entered the spinal canal, meningitis (an infection of the
nervous system), bleeding, spinal fluid leakage, nerve damage and paralysis. It
is also possible that an attempt to collect fluid will not yield any fluid. In
order to decrease the risk of headache associated with lumbar punctures, the
child will be asked to lie flat in a bed for about two hours after the
procedure is completed and drink plenty of liquids. Medication may be used as
well.

Risks of blood collection
The child may experience pain and discomfort at the site where the needle
enters the skin. There is a slight risk of fainting, bruising, or swelling. On
rare occasions, an infection may develop at the site where the needle enters
the skin.

Risk of Magnetic Resonance Imaging (MRI)and Magnetic Resonance Spectroscopy
(MRS)
For some people lying still inside this tube can bring out a fear of closed
spaces. The MRI/MRS is also noisy. In order to limit movements and get a good
picture, the child will be placed under general anesthesia.

Risk of X-rays
Once the intrathecal device has been surgically implanted, x-rays will be taken
to make sure that device has been placed properly. X-rays expose the body to a
small amount of radiation. X-rays may be performed as needed throughout the
study to check if the device is still placed correctly and that the catheter is
working as expected.

Risk of Electrocardiograms (ECG)
The sticky pads may cause a temporary skin reaction or skin irritation. In
addition, these pads may cause some discomfort when they are removed, similar
to the pulling sensation associated with the removal of a Band-Aid.

Risks associated with genetic testing
If your child*s genetic research data are shared with unauthorized users, your
child may be at risk of loss of the privacy of his/her health data. This risk
is minimized by protections described in the section below on protection of
personal information.


Other Risks
The procedures in this study may have risks that are not known at this time.
*