A Phase 1b Study of Adenylosuccinic Acid (ASA-001) for Adenylosuccinate Synthase 1 (ADSS1) Deficient Myopathy.

Phase 1Enrolling By InvitationNCT07412821

Cure ADSSL12 enrolled

Overview

The goal of this clinical trial is to evaluate the safety, tolerability and preliminary efficacy of ASA-001 in two adults diagnosed with ADSS1 deficient myopathy. The main questions it aims to answer are: * Whether ASA-001 can be safely administered to ADSS1 deficient myopathy patients; * Whether daily treatment with ASA-001 provides benefit or slows progression of disease. Participants will: * Take ASA-001 every day for 8 months; * Visit the clinic once every 2 weeks for check-ups and tests

Study Type

INTERVENTIONAL

Allocation

Purpose

TREATMENT

Masking

NONE

Enrollment

Conditions

Adenylosuccinate Synthase 1 Deficient Myopathy

Interventions

adenylosuccinic acid

ASA-001 will be administered as a sterile solution (500-2500 mg/day) by sub-cutaneous infusion pump.

Eligibility

Sex: ALLMin age: 18 Years

Medical Language ↔ Plain English

Inclusion criteria: * Male and females, age 18 years and above and weighing between 60 and 85 kg * Patient(s) diagnosed with ADSS1 deficient myopathy with homozygous or compound heterozygous mutations in the ADSS1 gene. * Able to understand and comply with all the study requirements * Is willing and legally able to provide written informed consent. * Willing to use highly effective contraception Exclusion criteria: * Any medical condition that could, in the Investigator's opinion, adversely affect the safety of the patient, make it unlikely that the course of treatment would be completed, or impair the assessment of study results. * Any patient who, in the Investigator's opinion, seems unable/unwilling to comply with the study procedures. * Women who are pregnant or breastfeeding, or planning to become pregnant * As judged by the investigator, clinical features are present at the time of screening / baseline assessments indicating that safe travel and completion of the study and its assessments are unlikely * Other severe systemic illness or disease * Participation in another treatment clinical study within thirty (30) days or 5 half-lives of the investigational product, whichever is longer, prior to signing and dating of Informed Consent Form for this study. * Known hypersensitivity to any of the components/excipients in ASA-001 * Serologic evidence of hepatitis B, C, or HIV * Ongoing/active infection (including current COVID-19 infection) * Presence of clinically significant liver or renal abnormalities * Clinical chemistry and hematology outside the limits acceptable for this patient population * History of anaphylaxis or severe allergic reaction to drug therapy or foods. * Concomitant medications to manage chronic condition(s) must not interfere with the mechanism of action for ASA-001 in the opinion of the Investigator and dose(s) must not alter for at least 4 weeks before screening through to dosing (Day 1).

Locations (1)

University of California Los Angeles (UCLA)

Los Angeles, California, United States

Outcomes

Primary Outcomes

Incidence and severity of all adverse events (AEs), treatment emergent adverse events (TAEs) and serious adverse events (SAEs).

AEs are classified as to seriousness, expectedness, and potential relationship to the investigational product. Seriousness (SAE) criteria: * Results in death * Is life-threatening * Requires in-patient hospitalization or prolongation of existing hospitalization * Results in persistent or significant disability/incapacity * Is a congenital anomaly/birth defect in the offspring of a participant. Severity criteria: * Mild: Awareness of signs or symptom, but easily tolerated * Moderate: Discomfort sufficient to cause interference with normal activities * Severe: Incapacitating, with inability to perform normal activities Expectedness criteria: * Unexpected: An AE for which the nature or severity is inconsistent with information in the protocol/consent form * Expected: An AE known to be associated with any of the study procedures Causality criteria: * Unrelated * Possibly related * Probably related

Time frame: Screening through to the last assessment at 10 months.

Observed and changes from baseline in vital signs.

Vital signs (including blood pressure (BP; mmHg), heart rate (HR; beats per minute), respiratory rate (RR; breaths per minute), and oral/tympanic/axillary temperature are measured at all visits. Height is measured at baseline only (cm); weight is measured at each visit (Kg).

Time frame: Screening through to the last assessment at 10 months.

Observed and changes from baseline in 12-lead electrocardiogram (ECG).

A standard 12-lead ECG will be recorded per Schedule of Events after 5 mins rest. The ECG has little or no risk. Skin may become red or itchy in the areas where the stickers with ECG electrodes are placed. The gel that is used may cause mild skin irritation/abrasion, along with the sticky pads used to attach the electrodes.

Time frame: Screening through to the last assessment at 10 months.

Observed and changes from baseline in physical examination.

A physical exam will be given at screening and per schedule of events to assess general appearance, HEENT (head, eyes, ear, nose and throat), cardiovascular, respiratory (chest), gastrointestinal (abdomen), dermatological, extremities, neurological (mental status, cranial nerves, motor examination, sensory examination, coordination, reflexes, gait), musculoskeletal and lymphatics.

Time frame: Screening through to the last assessment at 10 months.

Observed and changes from baseline in hematology, comprehensive metabolic panel (CMP), hepatic tests, renal function, and serology.

Laboratory analyte samples will be collected throughout the study per Schedule of Events. Hematology (complete blood count with auto-differential), comprehensive metabolic panel (CMP) including HbA1C, with hepatic tests (to include serum transaminases, , total bilirubin and alkaline phosphatase), renal function to include creatinine, Cystatin C, urinalysis, uric acid, INR, APTT; Serology will include HIV-1, hepatitis B and C at screening.

Time frame: Screening through to last assessment at 10 months.

Observed and changes from baseline in pulmonary function.

Forced Vital Capacity (FVC), Maximal Inspiratory Pressure (MIP) and Maximal Expiratory Pressure will be measured by spirometry to assess the strength of respiratory muscles, with MIP indicating the maximum pressure generated during a forceful inhalation against a closed airway, and MEP indicating the maximum pressure generated during a forceful exhalation against a closed airway monitor.

Time frame: Screening through to the last assessment at 10 months.

Observed and changes from baseline in cardiac function.

A standard trans-thoracic echocardiogram will be recorded and read at selected study visits per Schedule of Events. Assessments include standard assessments of the anatomy (veins and atria, atrioventricular segment, ventricles, conotruncus, great arteries) as well as left ventricular and valvular function (including measurements of the left ventricular ejection fraction (LVEF)).

Time frame: Screening through to the last assessment at 10 months.

Observed and changes from baseline in injection site monitoring.

Injection site(s) will be examined at each visit.

Time frame: Screening through to the last assessment at 10 months.

Secondary Outcomes

Plasma pharmacokinetic (PK) concentration of ASA-001.

Singles doses of ASA-001 will be administered on Day 1 and Day 14 and samples will be taken at baseline (time 0), 0.5, 1, 2, 4, 6, 8 h post dose. The results from Day 1 samples are required prior to dose escalation on Day 14. The multiple dose escalation phase will commence on Day 29 and conclude on Day 85 - plasma samples will be taken pre-dose (time 0) and at 1, 2 and 4 h post-dosing.

Time frame: Day 1 through to Day 85 (visit 8).

Observed and changes from baseline in serum creatinine concentration (preliminary efficacy).

Serum creatinine will be assessed within the clinical chemistry assessment, since prior clinical experience with ASA showed normalisation (from below normal range) of this measure.

Time frame: Screening through to the last assessment at 10 months.

Change from baseline in Ten meter walk/run time (10MWT) (preliminary efficacy).

The time required for the participant to run or walk (fastest way to cover the distance safely) 10 meters (on a safe walkway) from a standing position will be measured (sec or min)

Time frame: Screening through to the last assessment at 10 months.

Change from baseline in Timed Up-and-Go (TUG) (preliminary efficacy).

The time taken to stand from a chair, walk three metres, turn around and return and sit in the chair will be measured (sec or min).

Time frame: Screening through to the last assessment at 10 months.

Change from baseline in Jamar grip strength dynamometry (preliminary efficacy).

Squeeze and grip strength will be measured using a hand held dynamometer (Kg).

Time frame: Screening through to the last assessment at 10 months

Change from baseline in nerve conduction study with repetitive nerve stimulation test (preliminary efficacy).

The speed at which electrical signals travel through peripheral nerves will be assessed to identify nerve damage or dysfunction (meters/sec).

Data from ClinicalTrials.gov

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Time frame: Screening through to the last assessment at 10 months

Change from baseline in clinical muscle histopathology on core needle muscle biopsy (preliminary efficacy).

Muscle core needle biopsy will be sampled at baseline and at the end of treatment (day 239) and clinical histopathology scoring will measured to assess preliminary efficacy.

Time frame: Screening and at the end of treatment at Day 239.

Changes from baseline in muscle protein abundance and phosphorylation on core needle biopsy (preliminary efficacy).

Quantitative proteomics (including of phosphorylated proteins) will be used to measure muscle protein abundance and phosphorylation (preliminary efficacy).

Time frame: Screening and at the end of treatment at Day 239.

Change from baseline in Quality Of Life (QOL)/patient reported outcomes measure (preliminary efficacy).

Patient reported outcomes will be assessed using Neuro-QOL Item Bank v.10 - Upper Extremity Function (Fine Motor, ADL) - Short Form (PROMIS Health Organization, National Institute for Neurological Disorders and Stroke (NINDS), 2008-13).

Time frame: Screening through to the last assessment at 10 months

Changes from baseline in muscle metabolomics on core needle biopsy (preliminary efficacy).

Semi-quantitative metabolomics will be used to measure relative changes in muscle metabolite levels from baseline.

Time frame: Screening and at the end of treatment at Day 239.

Change from baseline in muscle transcriptomic signature on core needle biopsy (preliminary efficacy).

RNA sequencing will be used to assess the muscle transcriptomic signature in response to treatment.

Time frame: Screening and at the end of treatment at Day 239.