Prospective, Retrospective, Multicenter, Observational Study of Disease Progression in Adults with Inherited Forms of Spastic Paraplegia

Progressive weakness and spasticity of the legs are characteristics of numerous
disorders and conditions, including those that are inherited neurological
disorders. Adrenomyeloneuropathy (AMN) is an example of an inherited form of
spastic paraplegia.
Adrenoleukodystrophy (ALD) is a progressive neurodegenerative disorder caused
by a mutation in the ABCD1 gene localized to the X-chromosome (Xq28). The ABCD1
gene encodes a peroxisomal adenosine triphosphate (ATP) binding cassette
transporter responsible for transport of very long chain fatty acids (VLCFA)
from the cytosol into the peroxisome for degradation. A mutation in ABCD1
results in reduction in the degradation of the VLCFA by peroxisomal β-
oxidation, and saturated VLCFA, in particular C26:0, accumulate in tissues and
body fluids (i.e., brain, nervous system, adrenal glands). One of the key
clinical symptoms during aging of ALD patients is a slowly progressive
axonopathy affecting sensory ascending and motor descending spinal cord tracts
with 100% penetrance in men, an ALD phenotype knows as AMN. There are no
treatment options available, which leaves AMN patients with a progressive
disorder that leads to lifelong physical disability. The progressive dying-back
axonopathy represents the core clinical feature of AMN, with onset usually
between 20 and 30 years of age in male participants. The initial symptoms
include progressive stiffness and weakness of the legs, impaired vibration and
position senses in the lower limbs, falls, sphincter disturbances and
impotence, as well as scarce scalp hair (alopecia). About 66% of male AMN
patients have adrenocortical insufficiency (Addison disease). Abnormal magnetic
resonance imaging (MRI) signals of white matter in the centrum ovale, pyramidal
tracts in the brainstem and internal capsules have frequently been observed in
AMN, but no gadolinium enhancement is present, indicating an intact blood-brain
barrier and the absence of an acute inflammatory process.

SwanBio Therapeutics is developing SBT101, a recombinant adeno-associated virus
9 (AAV9) encoding the functional ABCD1 gene, for treatment of AMN to correct
underlying gene defects in the central nervous system (CNS). Development of
SBT101 has the potential to address a significant clinical need for AMN
patients for whom there are no curative treatment options available.

The course of AMN-related disabilities over time is poorly or incompletely
understood due to a limited number of patients and lack of treatments. This
study will help obtain a better understanding of the progression of disease
with AMN and facilitate efficient clinical development

Study Objectives:
• To characterize disease progression (clinical and rehabilitation) in adults
diagnosed with AMN
• To characterize the change in Quality of Life (QoL) parameters
• To characterize the change in electrophysiological (EP) parameters
• To estimate variability of outcome measures
• To support the definition of a minimal clinically important difference (MCID)
for the AMN population
• To evaluate the medical-economic impact of AMN

This is an observational study to determine the natural history of AMN in adult
male participants (aged >=18 years) with a confirmed diagnosis of ALD. All
participants will have clinical evidence of spinal cord involvement with
minimum Expanded Disability Status Scale (EDSS) score of one, and will be able
to walk with <=2 walking aids for about 20 meters (EDSS = 6.5) at the Baseline
Visit. Participants with evidence of active or history of cerebral inflammatory
disease (with Gadolinium-enhancing lesion) will be excluded. Participants with
pathologic brain lesion(s) (e.g., ischemic, neoplastic, demyelinating, etc.)
other than the typical lesion of AMN will also be excluded. Typical AMN brain
lesion is defined as Gadolinium non-enhancing lesion affecting corticospinal
tracts.
A minimum of 80 participants will be enrolled in the study. In addition to the
prospective data collection over 24 months, relevant retrospective information
about clinical manifestations, gait, balance and strength assessments,
laboratory values, and imaging will be extracted from the historical medical
records of the participants and documented in the electronic Case Report Form
(eCRF).
Participants will be asked to wear the CentrePoint Insight Watch that will
collect overall activity and sleep data. Participants will undergo assessments
at the clinic at the Baseline, Month 12, Month 24, Months 36, Month 48, and
Month 60 visits and complete a Telemedicine Visit every 3 months (Month 3, 6,
9, 15, 18, and 21) and then every 6 months until Month 60 (Months 30, 42, and
54). The assessments performed at each visit will be as predefined by the
Schedule of Assessments and include clinical, physical, and neurological
examinations, assessments of gait, balance, and strength, as well as
patient-reported QoL questionnaires.
The total study duration for a participant from enrollment to the last visit in
this study is expected to be approximately 60 months (±8 weeks). Patients will
be asked to opt-in to long-term follow-up to Month 60 at the Month 24 visit.

Sub-study
There will be an optional Electrophysiology Sub-study in addition to the main
study. The trial site and participant will need to opt in before any data is
collected. Participation in the Electrophysiology Sub-study will not impact
enrollment in the main study.
For this, an EP assessment will be conducted to assess the function of
peripheral nerve, dorsal root ganglia, and spinal roots. The EP assessment
should be performed at the Baseline, Month 12, Month 24, Month 36, Month 48 and
Month 60 visit.

Participating patients will undergo additional assessments during their
standard of care annual visit to the clinic. At the first (baseline) visit
questionnaires will be completed as well. These questionnaires can be completed
prior to the clinic visit in year 1, 2, 3, 4, and year 5.

In between the annual clinic visit there will be a video-call visit
(telemedicine visit) once per quarter and once per 6 months after 2 years,
during which the patient need to undergo a number of movement assessments.

During the clinic visit the following activities will take pace: Physical
examination, collection of demographic data, discussion of medical history,
checking eligibility criteria, discussion adverse events, discussion of
concomitant medication. Thensubject will complete several questionnaires (only
during baseline) and several tests related to movement capabilities will be
performed.
An activity tracker, a movement sensor kit to be used for the assessments
during the video call visit (Opal mobility lab), and a mobile device for
completion of the questionnaires will be provided to the patient. Extensive
instructions will be provided for all.

A visit to the clinic will take approximately 2 days. If needed accommodation
for the subject will be provided.

The video-call visit (telemedicine visits) will take approximately 1 hour

Completion of the questionnaires will take about 1 hour.