Clinical trial NCT05443685: ADX-629 Therapy for Sjogren-Larsson Syndrome
Official title: 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
Study type: INTERVENTIONAL
Overall status: ACTIVE_NOT_RECRUITING
Phase: PHASE1
PHASE2
Conditions: Sjogren-Larsson Syndrome
Keywords: ichthyosis
spasticity
intellectual disability
retinopathy
spastic diplegia
Lead sponsor: University of Nebraska
Sponsor class: OTHER
First posted: 2022-07-05
Enrollment: 8
Sex: ALL
Minimum age (years): 5
Maximum age (years): 50
Standard ages: CHILD
ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Intervention model description: Open label
Primary purpose: TREATMENT

Brief summary: This research study will determine whether orally administered ADX-629 is safe and has biochemical efficacy in participants 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. Participants will be treated with ADX-629 for 12 weeks and monitored for safety and biochemical efficacy.

Detailed description: 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. Investigators 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 participants. 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 paticipants with genetically confirmed SLS who meet eligibility criteria will be enrolled. All participantss will be studied at the University of Nebraska Medical Center/Children's Hospital \& Medical Center in Omaha, Nebraska. Participants will be treated with ADX-629 administered orally as 250 mg tablets for 12 weeks. Participants 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.

Eligibility criteria: Inclusion Criteria:

* Patricipant or participant's guardian is willing to provide written informed consent prior to the initiation of any study procedures. Assent will be solicited from participant intellectually capable of providing assent.
* Participant is willing to comply with all study procedures and availability for the duration of the study.
* Participant is 5-50 years of age at the time of enrollment.
* Participant has a genetically-confirmed diagnosis of SLS with two pathogenic sequence variants in ALDH3A2.
* Participant has active ichthyosis and neurologic symptoms of spasticity.
* Participant is able to swallow oral tablet medication and is willing to adhere to the study regimen.
* Participant is willing to suspend use of all topical creams 7 days before initial baseline evaluation and before the 12-week center visit.
* Participant has not been treated with any experimental drug for 1 month before baseline visit and during ADX-629 treatment.
* Participant 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.
* Participant is known to be human immunodeficiency virus (HIV) positive or has other known immunodeficiency.
* Participant 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.
* History of any other condition that, in the opinion of the Investigator, would compromise the participant's ability to comply with the protocol or that might compromise the participant's safety or the interpretation of the study results.
* Participant 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.
* Participant is currently receiving and refuses to interrupt any systemic or topical medication that is excluded.
* Participant received an investigational systemic or topically administered prescription drug within 30 days before enrollment.
* Participant has received botulinum toxin (Botox) injections within 6 months of enrollment.
* Participant has a known allergic reaction to any ingredients of study drug formulation.
* Participant is currently participating in any other therapeutic clinical study.
* Participant is pregnant, intending to become pregnant, or breastfeeding.

Primary outcomes:
measure: Number of Participants With Treatment-related Adverse Events as Assessed by CTCAE v4.0
timeFrame: weekly for 12 weeks
measure: Number of Participants With Abnormal Drug-related Safety Blood Tests
timeFrame: monthly for 12 weeks
measure: Compliance and Tolerability of ADX-629
timeFrame: daily for 12 weeks
Secondary outcomes:
measure: Biochemical Efficacy of ADX-629 as Determined by Reversal of Abnormal Biomarkers
timeFrame: Tests will be done at week 1 and week 12.
Other outcomes:
measure: Exploratory Clinical Outcomes to Determine Drug Dependent Changes in Abnormal Clinical Measures
timeFrame: Examinations and procedures will be done at week 1 and week 12.
Locations:
city: Omaha
country: United States
facility: University of Nebraska Medical Center
state: Nebraska
Study officials:
affiliation: University of Nebraska
name: William B Rizzo, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Rizzo WB. Sjogren-Larsson syndrome: molecular genetics and biochemical pathogenesis of fatty aldehyde dehydrogenase deficiency. Mol Genet Metab. 2007 Jan;90(1):1-9. doi: 10.1016/j.ymgme.2006.08.006. Epub 2006 Sep 22.
citation: Rizzo WB. Genetics and prospective therapeutic targets for Sjogren-Larsson Syndrome. Expert Opin Orphan Drugs. 2016 Apr;4(4):395-406. doi: 10.1517/21678707.2016.1154453. Epub 2016 Mar 10.
citation: Rizzo WB, S'aulis D, Dorwart E, Bailey Z. Sjogren-Larsson syndrome: A biochemical rationale for using aldehyde-reactive therapeutic agents. Mol Genet Metab Rep. 2021 Dec 23;30:100839. doi: 10.1016/j.ymgmr.2021.100839. eCollection 2022 Mar.