ADX-629 Therapy for Sjogren-Larsson Syndrome

Study Overview
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Brief Summary
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This research study will determine whether orally administered ADX-629 is safe and has biochemical efficacy in patients with Sjögren-Larsson syndrome (SLS), a rare inherited disorder of fatty aldehyde metabolism The disease is caused by bi-allelic mutations in ALDH3A2, which results in deficient activity of fatty aldehyde dehydrogenase (FALDH) and leads to the build-up of harmful long-chain (C16-C20) aldehydes and alcohols. Accumulation of these lipids and their metabolic products in skin, brain and eyes is responsible for the symptoms, which persist lifelong. ADX-629 is an aldehyde trapping agent that is expected to eliminate fatty aldehydes and negate aldehyde toxicity, improve the biochemical abnormalities and have clinical efficacy for SLS. The primary objective of this clinical protocol is to determine whether ADX-629 is safe and tolerable for use in SLS subjects. The secondary objective is to determine the efficacy of ADX-629 in reversing the biochemical abnormalities in SLS. Exploratory objectives are to evaluate the short-term clinical effects of ADX-629 on neurologic, cutaneous and ophthalmologic disease in SLS. Patients will be treated with ADX-629 for 12 weeks and monitored for safety and biochemical efficacy.

Detailed Description
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Sjögren-Larsson syndrome (SLS) is a rare inherited disorder of fatty aldehyde metabolism characterized by congenital ichthyosis, spastic diplegia, intellectual disability, seizures and a distinctive retinopathy. The disease is caused by bi-allelic mutations in ALDH3A2, which results in deficient activity of fatty aldehyde dehydrogenase (FALDH) and leads to the build-up of harmful long-chain (C16-C20) aldehydes and alcohols. Accumulation of these lipids and their metabolic products in skin, brain and eyes is responsible for the symptoms, which persist lifelong. We hypothesize that elimination of fatty aldehydes using the oral pharmacologic aldehyde trapping agent ADX-629 will negate aldehyde toxicity, improve the biochemical abnormalities and have clinical efficacy for SLS patients. This study is an open label, Phase 1/2, single center investigation of ADX-629 in SLS. The primary objective is to determine whether ADX-629 is safe and tolerable for use in SLS subjects. The secondary objective is to determine the efficacy of ADX-629 in reversing the biochemical abnormalities in SLS. Exploratory objectives are to evaluate the short-term clinical effects of ADX-629 on neurologic, cutaneous and ophthalmologic disease in SLS. Up to 10 subjects with genetically confirmed SLS who meet eligibility criteria will be enrolled. All subjects will be studied at the University of Nebraska Medical Center/Children's Hospital & Medical Center in Omaha, Nebraska. Subjects will be treated with ADX-629 administered orally as 250 mg tablets for 12 weeks. Subjects will be monitored for safety of ADX-629 every 4 weeks by physical examination and biochemical safety tests. The effects of ADX-629 on SLS-specific biomarkers will be determined after 12 weeks of drug treatment. Clinical tests will monitor neurological, dermatological and ophthalmologic response to drug.

Official Title
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An Open-Label, Phase 1/2, Single-Site Study of the Safety, Biochemical Efficacy, and Exploratory Clinical Effects of Oral ADX-629 in Subjects With Sjögren-Larsson Syndrome

Conditions
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Sjogren-Larsson Syndrome

Intervention / Treatment
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* Drug: ADX-629


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Subject or subject's guardian is willing to provide written informed consent prior to the initiation of any study procedures. Assent will be solicited from subjects intellectually capable of providing assent. Subject is willing to comply with all study procedures and availability for the duration of the study Subject is male or female and 18-50-years of age at the time of enrollment. Subject body weight is at least 35 kg (35 kg). Subject has a genetically-confirmed diagnosis of SLS with two pathogenic sequence variants in ALDH3A2. Subject has active ichthyosis and neurologic symptoms of spasticity. Subject is able to swallow oral tablet medication and is willing to adhere to the study regimen. Subject is willing to suspend use of all topical creams 7 days before initial baseline evaluation and before the 12-week center visit. Subject has not been treated with any experimental drug for 1 month before baseline visit and during ADX-629 treatment. Subject who is sexually active agrees to use adequate contraception throughout the duration of the study, as follows: For females of child-bearing potential: Negative pregnancy test at Baseline and compliant with a medically approved contraceptive regimen during the study or documented to be surgically sterile or postmenopausal. For sexually-active men: Compliant with a barrier contraceptive regimen during the study. Exclusion Criteria: History of any malignancy within 5 years of screening except for basal cell or squamous cell in situ skin carcinomas or carcinoma in situ of the cervix that has been treated with no evidence of recurrence. Subject is known to be human immunodeficiency virus (HIV) positive or has other known immunodeficiency. Subject has evidence of an active systemic or skin infection, including severe acute respiratory syndrome (SARS-CoV-2). History of significant tachycardia, bradycardia, acute or chronic cardiovascular disease, or any clinically significant abnormalities in rhythm or conduction detected on electrocardiogram (ECG), or QT interval corrected for heart rate using Fridericia's formula (QTcF) of >440 ms or <340 ms during screening. History or presence of gastrointestinal, hepatic disease, moderate or severe hepatic impairment (defined as Child-Pugh Class B and Class C) or any other condition known to interfere with absorption, distribution, metabolism, or excretion of drug. Acute or chronic renal disease, moderate or severe renal impairment, history of renal disease, or estimated glomerular filtration rate (eGFR) <60 mL/min/1.73 m2 calculated by Chronic Kidney Disease Epidemiology (CKD-EPI) equation. Subject has a history of any other condition that, in the opinion of the Investigator, would compromise the subject's ability to comply with the protocol or that might compromise the subject's safety or the interpretation of the study results. Subject is currently receiving immunosuppressive therapy, including intermittent or low-dose corticosteroids and is not able or willing to suspend its use for a period from 2 weeks before and throughout the study. Subject is currently receiving and refuses to interrupt any systemic or topical medication that is excluded. Subject received an investigational systemic or topically administered prescription drug within 30 days before enrollment. Subject has received botulinum toxin (Botox) injections within 6 months of enrollment. Subject has a known allergic reaction to any ingredients of study drug formulation. Subject is currently participating in any other therapeutic clinical study. Subject is pregnant, intending to become pregnant, or breastfeeding.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 50 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Interventional Model Description: Open label
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: ADX-629 treatment<br>Open label treatment with ADX-629 | Drug: ADX-629<br>* Subjects will be administered ADX-629 250 mg tablets twice daily<br>* Other names: Open label;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of participants with treatment-related adverse events as assessed by CTCAE v4.0 | Participants are required to report any adverse events as they arise and will be contacted weekly for information regarding adverse events. Physical examinations with vital signs will be done monthly. | weekly for 12 weeks | 
| Number of participants with abnormal drug-related safety blood tests | Participants will have monthly medical tests to monitor safety of ADX-629 including Complete Blood Count, Comprehensive Chemistry Panel, vitamin A, vitamin B6 (pyridoxal phosphate), Homocysteine, and Urinalysis. | monthly for 12 weeks | 
| Compliance and tolerability of ADX-629 | A written drug log will be required for recording daily administration of ADX-629 tablets and any problems tolerating the drug. Unused tablets will be counted as a measure of compliance. | daily for 12 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Biochemical efficacy of ADX-629 as determined by reversal of abnormal biomarkers | Biochemical efficacy of ADX-629 in reversing disease-specific abnormalities in blood levels of fatty alcohols, alkylglycerol lipids, SLS metabolomic profile, SLS lipidomic profile, and oxidative stress markers. Skin elasticity and thickness, transepidermal water loss, stratum corneum fatty alcohols and alkylglycerol lipids will also be measured. | Tests will be done at week 1 and week 12. | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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ichthyosis, spasticity, intellectual disability, retinopathy, spastic diplegia