A Phase 1/2 Randomized, Blinded, Dose-escalation Study to Evaluate the Safety and Efficacy of Intrathecal Administration of AAV9-ABCD1 Gene Therapy (SBT101) in Adult Patients with Adrenomyeloneuropathy

Adrenoleukodystrophy (ALD) is an inherited progressive neurodegenerative
disorder caused by a mutation in the adenosine triphosphate (ATP)-binding
cassette transporter subfamily D member 1 (ABCD1) gene. This gene is localized
to the X chromosome and encodes a peroxisomal ATP-binding cassette
half-transporter responsible for transporting very long chain fatty acids
(VLCFAs) from the cytosol into the peroxisome for degradation. A mutation in
the ABCD1 gene results in reduced degradation and accumulation of saturated
VLCFAs in tissues and body fluids (i.e., brain, nervous system, adrenal
glands), which in turn leads to demyelination, central nervous system (CNS)
deterioration, and neurologic defects. The accumulation of VLCFAs -
particularly C26:0 - is acknowledged to be the biochemical hallmark of ALD and
serves as a diagnostic marker.

The principal phenotypes observed in males with ALD are adrenomyeloneuropathy
(AMN), the cerebral demyelinating form of ALD (cerebral ALD), and adrenal
insufficiency (Addison*s disease). There are marked differences in the clinical
presentations of these phenotypes, including the age of onset, pathology, and
progression of disease, indicating that AMN, cerebral ALD, and adrenal
insufficiency are etiologically related but distinct disease states that
necessitate different treatment strategies. Among these disease states, AMN is
the most common.
It is characterized by a slowly progressive axonopathy affecting sensory
ascending and motor descending spinal cord tracts that manifests in aging
patients, with 100% penetrance in men.

In AMN, the largest and longest axons in the spinal cord sustain the greatest
degree of damage and a dying back pattern of axonal degeneration has been
reported in the dorsal columns (gracile fasciculus, and the cuneate fasciculus)
and corticospinal tracts; the large myelinated fibers appear to be the most
susceptible.

Onset typically occurs between the ages of 20 and 30 years in male patients;
the initial symptoms include poor balance and falls, progressive stiffness and
weakness of the legs, impaired vibration and position senses, sphincter
disturbances, sexual dysfunction, scarce scalp hair (alopecia), and impaired
adrenocortical function. Patients with AMN typically start to use walking aids
13 to 16 years after onset of AMN symptoms.

Approximately half of patients with AMN show some degree of brain involvement
on magnetic resonance imaging (MRI) or clinical examination. Abnormal MRI
signals of white matter have been observed, but no gadolinium enhancement is
present, indicating an intact blood brain barrier and the absence of an acute
inflammatory process. In 20 to 60% of patients with AMN, brain involvement
becomes severely progressive and leads to serious cognitive and behavioral
disturbances that may progress to total disability and death. In two-thirds of
patients with AMN, neurological disability progresses slowly and, within 10 to
15 years, motor disability becomes severe and patients require the use of
walking aids.

Mutation in the ABCD1 gene affects adrenal glands, and primary adrenal
insufficiency is common in males with AMN. Adrenal insufficiency can be treated
using steroid (prednisone/prednisolone) replacement therapy. Undiagnosed or
inappropriately treated adrenal insufficiency or rapid change of steroid dose
can progress to adrenal crisis, which can lead to rapid deterioration and death
if left untreated.

There are no curative treatments available for AMN. Current therapeutic
strategies are aimed at eliminating or ameliorating symptoms that affect
functional abilities and/or impair quality of life. These include, among
others, monitoring of patients to prevent the development of secondary
impairment or disability, such as lumbar disc degeneration and chronic
immobility caused by gait disturbances; managing spasticity through
physiotherapy and the use of anti-spasticity medications; and reducing urinary
symptoms through physiotherapy, anticholinergic drugs, and long-term
catheterization. These therapies can somewhat improve the quality of life of
patients; however, without addressing the genetic root cause of AMN, patients
are left with a progressive disorder that leads to lifelong disability.

This study has been transitioned to CTIS with ID 2024-518451-39-00 check the CTIS register for the current data.

• To characterize the safety and tolerability of one-time IT administered
SBT101 in adults diagnosed with AMN.
• To characterize the efficacy of IT administered SBT101 in adults diagnosed
with AMN.
• To assess the change in quality of life, patient abilities, and daily living
activities from Baseline to Month 12 and Month 24.
• To evaluate the safety of the catheter used to infuse SBT101 intrathecally in
Europe (European only objective)

This is a Phase 1/2 randomized, blinded, dose-escalation study to evaluate the
safety and efficacy of intrathecal (IT) administration of SBT101, a recombinant
adeno-associated virus serotype 9 (AAV9) containing a functional copy of the
human adenosine triphosphate (ATP)-binding cassette transporter subfamily D
member 1 (ABCD1; hABCD1) gene, in adult patients with adrenomyeloneuropathy
(AMN) aged 18-65 years. The core study consists of a parallel design with a
control crossover in Part 2. During dose escalation, Dose Level 1 and Dose
Level 2 patients will receive open-label SBT101 to establish safety and the
maximum tolerated dose (MTD). After confirmation of safety, the MTD will be
selected for the randomized, blinded Cohort 3 dose expansion phase. Patients
will receive a single dose of SBT101 via IT route and will be followed for
safety and efficacy for 5 years.
The study consists of two parts after infusion of SBT101:
• Part 1: A 24 month core study period to evaluate the safety and potential
impact of SBT101 on disease progression. Part 1 will consist of 2 phases:
o Dose Escalation Phase (open-label): Two (2) doses of SBT101 will be evaluated
to establish the maximum tolerated dose (MTD).
• Dose Level 1 Cohort - 1.0E14 vector genomes (vg)
• Dose Level 2 Cohort - 3.0E14 vg
o Dose Expansion Phase (randomized, blinded): Additional patients will be
enrolled to receive SBT101 at the MTD
• Part 2: An unblinded 3-year long-term safety follow-up period with annual
follow-up visits to evaluate the safety of SBT101 and disease progression.
Informed consent will be obtained from all patients at the Screening Visit
(Visit 1) prior to conducting any screening procedures to assess study
eligibility. The duration of the study for patients receiving SBT101 will be up
to 66 months, including up to 4 months for Screening, the 24-month core study
period (i.e., Part 1), and 36 (±2) months for long-term safety follow-up (i.e.,
Part 2). The duration of the study for patients randomized to the control arm
who choose to receive SBT101 after the cohort primary analysis will be a
maximum of 90 months, including up to 4 months for Screening, the 24-month core
study period, another 24 months for follow-up post-administration of open-label
SBT101, and 36 (±2) months for long-term safety follow-up.
In Part 1, a minimum of 16 patients will be enrolled in 2 phases: Dose
Escalation Phase and Dose Expansion Phase. The Dose Escalation Phase aims to
establish the MTD. In the Dose Escalation Phase, a minimum of 8 patients will
be enrolled, with a minimum of 4 patients enrolled to Dose Level (1.0E14 vg)
and a minimum of 4 patients enrolled to Dose Level 2 (3.0E14 vg). In the Dose
Expansion Phase, an additional 8 patients will be randomized to treatment on a
3:1 basis to receive SBT101 at MTD. The decision on dose escalation and
treatment of additional patients at each dose level during the Dose Escalation
Phase will be made after review of safety by the independent Data Safety
Monitoring Board (DSMB) and the Sponsor.
• An independent DSMB will be established; members will include at least 3
independent physicians with expertise in neurological diseases or gene therapy,
and an independent statistician.
• The Sponsor*s Medical Monitor will review the safety data after each
patient completes the Day 30 Visit before treatment of subsequent patients
within that Dose Level Cohort.
• The DSMB will review the available safety data after at least 2 patients
complete the Day 30 visit at each Dose Level prior to recommending treatment of
additional patients or initiation of dose escalation or expansion.
The Sponsor, in consultation with the DSMB, may:
• Decide to investigate an additional dose of SBT101 in the Dose Expansion
Cohort different than Dose Level 1 and Dose Level 2;
• Elect to increase or decrease the number of patients in a Dose Level Cohort
during the study.
All patients in the control arm will have the option to be treated with
open-label SBT101 after the last patient in the cohort has completed the Month
24 Visit. Patients who opt to be treated with open-label SBT101 must continue
to meet all exclusion and inclusion criteria (except for inclusion criterion
(#1 and #3) and exclusion criterion (#3)). If they choose to be treated with
open-label SBT101, they will restart all procedures at Day 1 and will be
followed for another 5 years.

The study consists of two parts after infusion of SBT101:

• Part 1: A 24 month core study period to evaluate the safety and potential
impact of SBT101 on disease progression. Part 1 will consist of 2 phases:
Phase 1: se Escalation Phase (open-label): Two (2) doses of SBT101 will be
evaluated to establish the maximum tolerated dose (MTD).
• Dose Level 1 Cohort - 1.0E14 vector genomes (vg)
• Dose Level 2 Cohort - 3.0E14 vg

Phase 2: Dose Expansion Phase (randomized, blinded): Additional patients will
be enrolled to receive SBT101 at the MTD


• Part 2: An unblinded 3-year long-term safety follow-up period with annual
follow-up visits to evaluate the safety of SBT101 and disease progression.

Potential risks with the SBT101 administration:

Elevated Transaminases
Elevation in liver enzymes is the most common side effect associated with this
type of gene therapy. This can be controlled by taking steroids. The patient
will be given these medications before and after the procedure, and the levels
of these liver enzymes will be closely monitored for at least 3 months after
procedure with SBT101.

Low Platelet Counts
This type of gene therapy, when given through an IV, has been shown to cause
decreased platelet counts. The risk of this event may be lower in this study
because The IMP is administered via Intrathecal infusion.

Cardiac Adverse Events
Elevation in cardiac enzyme, troponin, indicating a problem with the heart has
been reported with IV administration of AAV9 gene therapy. The risk of this
event may be lower in this study because the study drug is not administered
intraveneously.

Spine and Dorsal Root Ganglion Adverse Events
Adverse inflammatory responses in the spinal cord and/or structures (ganglions)
transmitting sensory nerves have been reported with IT AAV administration in
animal studies (Hordeaux et al., 2020; FDA, 2021). Etiology of the pathology is
unknown. Systemic corticosteroids and immunosuppressive will be administered
before and after the procedure and for at least 3 months, to prevent the
inflammatory response. Assessment of sensation and nerves carrying the sensory
information will be monitored for at least 3 months after procedure.

Shedding viral particles
Since SBT101 is a virus, treated patients may be able to shed the virus from
their body, for example in their bodily fluids. This type of virus is
non-replicating, meaning it cannot make more of itself, so that the risk of the
virus infecting other people is extremely low. Reliable barrier contraception
for 6 months post dose is mandatory.

Creation of new medical conditions
Viruses can insert their own DNA into the DNA of the animal they infect. If
this happens, there is a risk that new medical conditions could occur in the
animal, such as developing tumors, because the animal*s DNA has been changed.
The risk of this happening with the type of virus being used in this study is
considered low. This virus does not typically inert its DNA into the animal*s
DNA and there are no reports of this occurring in any of the previous clinical
trials which have used this type of virus.

Risks Related to methylprednisolone/prednisolone Use
Common side effects that can occur with short-term use include the following:
• Increased appetite
• Weight gain
• High blood pressure
• Elevated blood sugar
• Fluid retention (facial or limb swelling)
• Mood changes and depression
• Hyperactivity
• Difficulty sleeping
• Increased risk of infection

Common side effects that can occur with long-term use include the following:
• Peptic ulcer (a sore in the lining of your stomach)
• Gastrointestinal (GI) bleeding (black stools)
• Vision problem
• Suppressed adrenal gland hormone production.
• Loss of calcium from bones, which can lead to osteoporosis.
• Skin thinning and bruises.

Risk of Medical Evaluations

Blood Draws
Possible side effects of blood draws are tenderness, pain, bruising, bleeding
and/or infection where the needle goes into the skin, vein, and blood. Having
blood drawn may also cause nausea and light-headednes. Very rarely, the needle
may damage a nerve.

Electrocardiogram (ECG):
An ECG is a recording of the electrical activity the heart and is taken by
placing electrodes on the skin of chest, arms and legs. Sometimes there may be
some minor skin redness or itchiness from the tabs.

MRI:
There are no known risks of receiving an MRI.

Electrophysiology (EP):
Electrodiagnostic Testing is safe and electric stimulation is too weak and
short to cause an injury or permanent damage, but it can be an unpleasant
feeling.

Lumbar Puncture:
A lumbar puncture is a procedure where a needle is inserted into the spinal
canal between the lumbar bones in the spine. The skin will be treated with
lidocaine. this can sting and burn.
Sometimes pain occurs if a nerve is hit during the procedure. The pain is
usually sharp and quick and doesn*t persist.
There is a slight risk of infection because the needle breaks the skin's
surface.
There is an additional risk of infection from use of a catheter to infuse the
study drug.
It is also possible to have short-term numbness of the legs, or lower back pain
may be experienced.
More common is a severe headache which should resolve within a few days.
The risk of headache and the need for a blood patch may be increased as
compared to a standard lumbar puncture. The needle size and length of the
infusion may increase the risk of needing a blood patch.

Potential benefits

The study drug may improve gait and balance affected by AMN as well as improve
overall health and well-being, but there is no guarantee of any benefit. The
information from this study might help to develop better treatments in the
future for people with AMN or other similar diseases, considering teh there no
available therapies at present.