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

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Swanbio Therapeutics Limited

Participant type

Patients

Age range

18-64 years

Gender

Male

Therapeutic area

Diseases [C] - Nervous System Diseases [C10]

Trial duration

19 Sep 2023 → 15 Jul 2025

Decision date (initial)

2024-11-19

Transition trial

Yes

Low-intervention

No

Rare-disease indication

Yes

Vulnerable population

No

External identifiers

EU CT number

2024-518451-39-00

EudraCT number

2021-004410-19

ClinicalTrials.gov

NCT05394064

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Efficacy, Safety

To characterize the safety and tolerability of one-time IT administered
SBT101 in adults diagnosed with AMN

Secondary objectives 1

1. To characterize the efficacy of IT administered SBT101 in adults diagnosed with AMN

Conditions and MedDRA coding

Adrenomyeloneuropathy

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 6

1. Male adults aged ≥18 and ≤65 years
2. Diagnosed with X-linked adrenoleukodystrophy (ALD)), including proven mutation in the ABCD1 gene through confirmatory genetic testing, and supported by historically elevated VLCFA.
3. Clinical evidence of spinal cord involvement with EDSS score between 1 and 4.5 and a pyramidal function score of ≥1 in the Functional System Score of the EDSS. Signs of pyramidal tract dysfunction don't include hyperreflexia.
4. Must agree to use double-barrier contraception methods (e.g., condom and 1 other form of contraception for female sexual partners that are of childbearing potential, such as diaphragm, intrauterine device, spermicidal jelly, and/or hormonal contraceptive) and to not donate sperm for at least 6 months following the IMP procedure.
5. For patients who are receiving any other treatment for ALD, including off-label medications and/or supplements (e.g., antioxidants, Lorenzo's oil, statins, etc.) or physical rehabilitation support, such treatments must have been at a stable dose and/or frequency for ≥4 weeks prior to Screening and patients must agree to continue at the same dose and/or frequency through Part 1 of the study.
6. The patient provided written informed consent prior to any study procedures being performed

Exclusion criteria 18

1. Presence of inflammatory cerebral disease, established by radiographic review of brain MRI demonstrating a Loes score ≥0.5 on the 34-point scale, except for the abnormalities that can be observed in patients with AMN without inflammatory cerebral demyelination with Loes score ≤4.
2. Pathological changes identified on brain MRI including all lesions from previous diagnosis of inflammatory cerebral disease identified on brain MRI as contrast-enhancing (gadolinium-enhancing) lesion with Loes score ≥ 0.5 on the 34-point scale, except for the abnormalities that can be observed in patients with AMN without inflammatory cerebral demyelination with Loes score ≤4
3. 15 years or more have elapsed since the initial onset of myeloneuropathy manifestations, such as walking or running difficulties, bladder dysfunction, increased muscular tone, spasticity, weakness, balance problems, etc.
4. Contraindications for MRI procedure and/or contrast materials.
5. History of a brain or spinal cord disease that would interfere with lumbar puncture procedures, CSF circulation, and/or safety assessments.
6. Contraindication to steroids, sirolimus, tacrolimus, and/or anesthetic medications.
7. Contraindication to SBT101 and/or any of its ingredients.
8. Unstable adrenal function (e.g., untreated or inappropriately treated adrenal insufficiency). a. Adrenal function will be evaluated through laboratory assessments of cortisol, plasma adrenocorticotropic hormone (ACTH), plasma renin, aldosterone, sodium, and potassium levels at Screening. Monitoring of replacement therapy will be mainly clinical. Determination of inappropriately treated adrenal insufficiency will be made by the Investigator in consultation with the Medical Monitor. b. Patients who meet the following criteria will be considered to have adrenal insufficiency: (i) basal cortisol concentration <275 nmol (10 μg/dL) in the morning (i.e., 6 AM to 10 AM) and (ii) plasma ACTH >2 × upper limit of normal (ULN).
9. Positive for human immunodeficiency virus (HIV) type 1 or 2 (HIV-1, HIV-2), hepatitis B virus (HBV), or hepatitis C virus (HCV). a. Patients who have been vaccinated against HBV (e.g., HBV surface antibody-positive) who are negative for other markers of prior HBV infection (e.g., HBV core antibody-negative) are eligible. b. Patients who are positive for anti-HCV antibodies are eligible, as long as they have a negative HCV load as measured by quantitative polymerase chain reaction (qPCR).
10. Presence of clinically significant active bacterial, viral, fungal, parasitic, or prior - associated infection.
11. History of diabetes or abnormal fasting serum glucose (≥126 mg/dL) or hemoglobin A1C ≥6.5%.
12. Patients who have received a gene therapy.
13. Current use of medications that could potentially lead to changes in intracranial pressure (e.g., levothyroxine, vitamin A supplementation, oral contraceptives, tetracycline, acetazolamide [Diamox]).
14. Patients who are currently using strong CYP3A4 inducers or strong CYP3A4 inhibitors, and are unwilling or unable to stop prior to and during the immunosuppression regimen.
15. Patients who are currently receiving or have received an investigational drug or procedure within 3 months prior to Screening. The use of investigational drugs is prohibited throughout Part 1 of the study.
16. Patients with unstable, clinically significant neurologic (other than AMN), psychiatric, cardiovascular, ophthalmologic, pulmonary, hepatic, renal, metabolic, gastrointestinal, urologic, immunologic, hematopoietic, and/or endocrine disease (other than adrenal insufficiency) and/or other abnormality that may impact the ability to participate in the study or that may potentially confound the study results. It is the responsibility of the Investigator to assess clinical significance; however, consultation with the Sponsor's Medical Monitor may be warranted.
17. Patients who, in the opinion of the Investigator, have any other medical or psychological condition or social circumstance that would impair their ability to participate reliably in the assessments, or who may increase the risk to themselves or others by participating.
18. Patients who are an immediate family member, study site employee, or are in a dependent relationship with a study team member involved in the conduct of this study (e.g., spouse, parent, child, sibling).

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. Percentage of patients with at least 1 Grade III or Grade IV AE that is at least possibly related to SBT101 at Month 24, as reported by the patients or observed by the Investigator, after SBT101 treatment

Secondary endpoints 12

1. • Changes in the 6-minute Walk Test (6MWT) at Month 12 and Month 24 compared to controls, and compared to the reference changes determined by the prospective SBTNHX-CT901 study.
2. • Changes in the 2-minute Walk Test (2MWT) at Month 12 and Month 24 compared to controls, and compared to the reference changes determined by the prospective SBTNHX-CT901 study.
3. • Changes in the 5 times Sit-to-Stand Test (5XSST) at Month 12 and Month 24 compared to controls, and compared to the reference changes determined by the prospective SBTNHX-CT901 study.
4. • Changes in postural body sway amplitudes at Month 12 and Month 24 compared to controls, and compared to the reference changes determined by the prospective SBTNHX-CT901 study.
5. • Proportions of patients with Expanded Disability Status Score (EDSS) of ≥5.5 at Month 12 and Month 24 compared to controls, and compared to the reference changes determined by the prospective SBTNHX-CT901 study.
6. • Proportions of patients with increased anti-spasticity medication dose at Month 12 and Month 24 compared to controls, and compared to the reference changes determined by the prospective SBTNHX-CT901 study.
7. • Changes in Timed Up and Go (TUG) at Month 12 and Month 24 compared to controls, and compared to the changes observed in the prospective SBTNHX-CT901 study.
8. • Changes in Dual-task TUG (TUG-DT) at Month 12 and Month 24 compared to controls, and compared to the changes observed in the prospective SBTNHX-CT901 study.
9. • Changes in Balance Evaluation System Test (miniBESTest) at Month 12 and Month 24 compared to controls, and compared to the changes observed in the prospective SBTNHX-CT901 study.
10. • Changes in Clinical Global Impression (CGI; performed by a qualified professional) score at Month 12 and Month 24 compared to controls.
11. • Changes in Patient Global Impression of Severity (PGI-S), Patient Global Impression of Severity – Balance (PGI-S Balance), and Patient Global Impression of Change – Balance (PGI-C Balance) scores at Month 12 and Month 24 compared to controls, and compared to the changes observed in the prospective SBTNHX-CT901 study.
12. • Percentage of patients with at least 1 Grade III or Grade IV AE that is at least possibly related to SBT101 at Month 60, as reported by the patients or observed by the Investigator, after SBT101 treatment.

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 1

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Swanbio Therapeutics Limited

Sponsor organisation

Swanbio Therapeutics Limited

Address

2nd Floor, 8 Bloomsbury Street 8 Bloomsbury Street

City

London

Postcode

WC1B 3SR

Country

United Kingdom

Scientific contact point

Organisation

Swanbio Therapeutics Limited

Contact name

David Rifkin

Public contact point

Organisation

Swanbio Therapeutics Limited

Contact name

David Rifkin

Third parties 10

Locations

1 EU/EEA country · 1 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 5 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

5 submissions — initial application plus substantial / non-substantial modifications