Adenylosuccinate Synthase 1 Deficient Myopathy
Conditions
Keywords
ADSS1 myopathy, adenylosuccinic acid, adenylosuccinate, ASA-001, Phase 1b clinical trial, ADSSL1 myopathy, Adenylosuccinate synthase-like 1 myopathy
Brief summary
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
Interventions
DRUGadenylosuccinic acid
ASA-001 will be administered as a sterile solution (500-2500 mg/day) by sub-cutaneous infusion pump.
Sponsors
Cure ADSSL1
University of California, Los Angeles
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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).
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Incidence and severity of all adverse events (AEs), treatment emergent adverse events (TAEs) and serious adverse events (SAEs). | Screening through to the last assessment at 10 months. | 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 |
| Observed and changes from baseline in vital signs. | Screening through to the last assessment at 10 months. | 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). |
| Observed and changes from baseline in 12-lead electrocardiogram (ECG). | Screening through to the last assessment at 10 months. | 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. |
| Observed and changes from baseline in physical examination. | Screening through to the last assessment at 10 months. | 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. |
| Observed and changes from baseline in hematology, comprehensive metabolic panel (CMP), hepatic tests, renal function, and serology. | Screening through to last assessment at 10 months. | 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. |
| Observed and changes from baseline in pulmonary function. | Screening through to the last assessment at 10 months. | 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. |
| Observed and changes from baseline in cardiac function. | Screening through to the last assessment at 10 months. | 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)). |
| Observed and changes from baseline in injection site monitoring. | Screening through to the last assessment at 10 months. | Injection site(s) will be examined at each visit. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Plasma pharmacokinetic (PK) concentration of ASA-001. | Day 1 through to Day 85 (visit 8). | 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. |
| Observed and changes from baseline in serum creatinine concentration (preliminary efficacy). | Screening through to the last assessment at 10 months. | 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. |
| Change from baseline in Ten meter walk/run time (10MWT) (preliminary efficacy). | Screening through to the last assessment at 10 months. | 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) |
| Change from baseline in Timed Up-and-Go (TUG) (preliminary efficacy). | Screening through to the last assessment at 10 months. | 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). |
| Change from baseline in Jamar grip strength dynamometry (preliminary efficacy). | Screening through to the last assessment at 10 months | Squeeze and grip strength will be measured using a hand held dynamometer (Kg). |
| Change from baseline in nerve conduction study with repetitive nerve stimulation test (preliminary efficacy). | Screening through to the last assessment at 10 months | The speed at which electrical signals travel through peripheral nerves will be assessed to identify nerve damage or dysfunction (meters/sec). |
| Change from baseline in clinical muscle histopathology on core needle muscle biopsy (preliminary efficacy). | Screening and at the end of treatment at Day 239. | 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. |
| Changes from baseline in muscle protein abundance and phosphorylation on core needle biopsy (preliminary efficacy). | Screening and at the end of treatment at Day 239. | Quantitative proteomics (including of phosphorylated proteins) will be used to measure muscle protein abundance and phosphorylation (preliminary efficacy). |
| Change from baseline in Quality Of Life (QOL)/patient reported outcomes measure (preliminary efficacy). | Screening through to the last assessment at 10 months | 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). |
| Changes from baseline in muscle metabolomics on core needle biopsy (preliminary efficacy). | Screening and at the end of treatment at Day 239. | Semi-quantitative metabolomics will be used to measure relative changes in muscle metabolite levels from baseline. |
| Change from baseline in muscle transcriptomic signature on core needle biopsy (preliminary efficacy). | Screening and at the end of treatment at Day 239. | RNA sequencing will be used to assess the muscle transcriptomic signature in response to treatment. |
Countries
United States
Contacts
PRINCIPAL_INVESTIGATORPerry B Shieh, M.D., Ph.D.
UCLA Medical Centre
Outcome results
None listed