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

Official title

A Phase 1b, Open Label, Single and Multiple Ascending Dose-escalation Study to Assess the Safety, Tolerability, Pharmacokinetics and Preliminary Efficacy of Subcutaneous Adenylosuccinic Acid (ASA) in Two Siblings With Adenylosuccinate Synthase 1 (ADSS1) Deficient Myopathy.

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

Interventions

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

Primary outcome measures

• Incidence and severity of all adverse events (AEs), treatment emergent adverse events (TAEs) and serious adverse events (SAEs). [Time frame: Screening through to the last assessment at 10 months.]
• Observed and changes from baseline in vital signs. [Time frame: Screening through to the last assessment at 10 months.]
• Observed and changes from baseline in 12-lead electrocardiogram (ECG). [Time frame: Screening through to the last assessment at 10 months.]
• Observed and changes from baseline in physical examination. [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. [Time frame: Screening through to last assessment at 10 months.]
• Observed and changes from baseline in pulmonary function. [Time frame: Screening through to the last assessment at 10 months.]
• Observed and changes from baseline in cardiac function. [Time frame: Screening through to the last assessment at 10 months.]
• Observed and changes from baseline in injection site monitoring. [Time frame: Screening through to the last assessment at 10 months.]

Secondary outcome measures (11)

• Plasma pharmacokinetic (PK) concentration of ASA-001. [Time frame: Day 1 through to Day 85 (visit 8).]
• Observed and changes from baseline in serum creatinine concentration (preliminary efficacy). [Time frame: Screening through to the last assessment at 10 months.]
• Change from baseline in Ten meter walk/run time (10MWT) (preliminary efficacy). [Time frame: Screening through to the last assessment at 10 months.]
• Change from baseline in Timed Up-and-Go (TUG) (preliminary efficacy). [Time frame: Screening through to the last assessment at 10 months.]
• Change from baseline in Jamar grip strength dynamometry (preliminary efficacy). [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). [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). [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). [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). [Time frame: Screening through to the last assessment at 10 months]
• Changes from baseline in muscle metabolomics on core needle biopsy (preliminary efficacy). [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). [Time frame: Screening and at the end of treatment at Day 239.]

Eligibility criteria

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).

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

N/A

Model

Single group

Masking

Open label

Primary purpose

Treatment

Study locations

United States · 1 center

• University of California Los Angeles (UCLA) — Los Angeles

Publications

• Rybalka E, Kourakis S, Bonsett CA, Moghadaszadeh B, Beggs AH, Timpani CA. Adenylosuccinic Acid: An Orphan Drug with Untapped Potential. Pharmaceuticals (Basel). 2023 May 31;16(6):822. doi: 10.3390/ph16060822. PMID 37375769
• Rybalka E, Park HJ, Nalini A, Baskar D, Polavarapu K, Durmus H, Xia Y, Wan L, Shieh PB, Moghadaszadeh B, Beggs AH, Mack DL, Smith AST, Hanna-Rose W, Jinnah HA, Timpani CA, Shen M, Upadhyay J, Brault JJ, Hall MD, Baweja N, Kakkar P. Current insights in ultra-rare adenylosuccinate synthetase 1 myopathy - meeting report on the First Clinical and Scientific Conference. 3 June 2024, National Centre for PMID 39593137

Identifiers

NCT: NCT07412821 · ASA-CS01

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗