A first-in-human study of UX053 in Patients with Glycogen Storage Disease type III (GSD III)

Phase 1

Conditions: Glycogen Storage Disease Type III (GSD III)
MedDRA version: 20.1Level: PTClassification code 10053250Term: Glycogen storage disease type IIISystem Organ Class: 10010331 - Congenital, familial and genetic disorders
Therapeutic area: Diseases [C] - Nutritional and Metabolic Diseases [C18]

Registration Number: EUCTR2021-000903-19-IT

Lead Sponsor: TRAGENYX PHARMACEUTICAL INC.

Brief Summary: Not available

Detailed Description: Not available

Recruitment & Eligibility

Status: Authorised-recruitment may be ongoing or finished

Sex: All

Target Recruitment: 30

Inclusion Criteria

1. Confirmed diagnosis of Glycogen Storage Disease type III (GSD III) (all subtypes) based on pathogenic mutations in the amylo-a-1,6-glucosidase 4-alpha-glucanotransferase (AGL) gene on both alleles or glycogen debranching enzyme (GDE) deficiency based on biopsy of liver, muscle, or fibroblasts
2. History of any of the following:
a. Severe hypoglycemia, defined as neuroglycopenia (eg, altered mental status, seizure, dizziness, slurred speech, blurry vision, abnormal behavior, perioral paresthesia, requiring intervention by a caregiver) or blood glucose < 54 mg/dL (3 mmol/L) within the last year
b. = 2 incidents of symptomatic hypoglycemia (defined as blood glucose < 70 mg/dL [3.9 mmol/L] if measured at the time of symptoms) within the last year, despite nutrition management
c. Ongoing liver injury, defined as alanine aminotransferase (ALT) > 2.5x the upper limit of normal (ULN) within the last year
3. ALT = 5x ULN during the 3 months prior to the Baseline Visit
4. Males or females = 18 years of age
5. After nutrition optimization (if necessary) for subjects in the repeat dose (RD) Period, during the beginning of the Screening Period, willing and able to maintain nutritional intake consistent with the nutrition guidelines based on expert recommendations for the remainder of the study
6. Willing and able to provide access to medical records surrounding medical treatment that occurred prior to enrollment
7. Willing and able to provide written informed consent, or in the case of adult subjects with cognitive limitation, provide written assent (if required) and written informed consent by a legally authorized representative after the nature of the study has been explained and prior to any test procedures or assessments
8. Females of childbearing potential must have a negative pregnancy test at Screening (ISV) and be willing to have additional pregnancy tests during the study. Subjects of childbearing potential or fertile males who are sexually active with partners of child-bearing potential must consent to use a highly effective contraceptive method, as described in Appendix 4 of the Protocol, from the Period following the signing of the informed consent through 30 days after last dose of study drug

Are the trial subjects under 18? no
Number of subjects for this age range:
F.1.2 Adults (18-64 years) yes
F.1.2.1 Number of subjects for this age range 27
F.1.3 Elderly (>=65 years) yes
F.1.3.1 Number of subjects for this age range 3

Exclusion Criteria

1. History of liver transplant, including hepatocyte cell therapy/transplant, or active listing for liver transplant
2. History of cirrhosis, or presence of any of the following:
a. Total bilirubin = 1.3 mg/dL and international normalized ratio (INR) = 1.3
b. Evidence of portal hypertension, including, but not limited to the following symptoms splenomegaly, ascites, thrombocytopenia, esophageal varices, or history of hepatic encephalopathy
c. Model for End Stage Liver Disease (MELD) score > 12
3. Current Hepatitis B or C infection or history of chronic Hepatitis B or C infection
4. Severe renal impairment defined as a glomerular filtration rate (GFR) = 29 mL/min
5. Any prior history of hepatocellular carcinoma or presence of liver adenoma > 5 cm at the longest diameter or > 3 cm and = 5 cm in size that has an annual growth rate of = 0.5 cm per year
6. Current or history of malignancies in the 3 years prior to the Screening Visit (ISV for RD)
7. Hospitalizations related to GSD III disease between the Screening (ISV for RD) and Baseline Visit
8. Known history of human immunodeficiency virus infection
9. Presence or history of any hypersensitivity reactions requiring medical evaluation and management (including injection/infusion associated reactions, such as lymphadenopathy) to UX053, its excipients, or any drug products that contain polysorbate or PEG. This may include mRNA-based vaccines that contain PEG or polysorbate
10. Significant cardiac disease, including heart failure with New York Heart Association (NYHA) Function Capacity III or IV or Objective Assessment C or D, unstable angina, or ejection fraction (EF) < 35%, or uncontrolled arrhythmia or resistant hypertension. Asymptomatic cardiomyopathy and left ventricular hypertrophy (LVH) are allowed
11. Presence or history of any co-morbid condition or abnormal labs that, in the view of the Investigator, places the subject’s safety at risk; places the subject at high risk of poor treatment compliance or not completing the study; or would significantly affect the interpretation of study results
12. Poorly controlled diabetes, defined as the presence of any of the following:
a. Hemoglobin A1C > 8%
b. History of diabetic nephropathy, neuropathy, or retinopathy
c. History of diabetic ketoacidosis during the past year
13. Poorly controlled hypothyroidism, based on the judgement of the Investigator or Ultragenyx, whichever is most conservative
14. History of chronic coagulopathy, thrombophilia, or disorder of complement activation
15. Use of concomitant medications that alter PT/INR, including warfarin and direct oral anticoagulants (eg, rivaroxaban, apixaban, and edoxaban). Patients who receive medications that affect platelet function, such as aspirin or clopidogrel, are allowed, unless they have comorbidities that in the judgment of the Investigator place them at undue risk to participate in the study.
16. Current treatment with long-term immunosuppressive medications. This includes subjects with autoimmune conditions managed with immunosuppressive medications and solid organ transplant recipients.
17. Active tuberculosis requiring treatment in the past 3 years
18. Symptomatic COVID-19 infection
19. History of active alcohol and/or drug abuse that in the Investigator’s assessment would impair the subject’s ability to comply with the protocol

Insufficient space, please refer to the Protocol for other criteria.

Study & Design

Study Type: Interventional clinical trial of medicinal product

Study Design: Not specified

Primary Outcome Measures

Name	Time	Method
Main Objective: Evaluate the safety of UX053 in adults with GSD III ;Secondary Objective: Characterize the PK of UX053 in adults with GSD III ;Primary end point(s): The incidence and severity of TEAEs, serious TEAE and related TEAEs in the SAD and RD Periods<br>;Timepoint(s) of evaluation of this end point: SAD Period: Adverse Events monitored from Screening through to D90. In the event of an ET, all efforts will be made to monitor the subject through the end of the study. At minimum, a safety follow-up phone call will occur within the 4 weeks following the subject’s last treatment. <br><br>RD Period: Adverse Events monitored from Screening through to W48. In the event of an ET, all efforts will be made to monitor the subject through the end of the study. At minimum, a safety follow-up phone call will occur within the 4 weeks following the subject’s last treatment.

Secondary Outcome Measures

Name	Time	Method
Secondary end point(s): PK parameters of AGL (amylo-a-1,6-glucosidase 4-alpha-glucanotransferase) mRNA and ATX95, including Tmax, Cmax, AUClast, AUCinf, AUCtau (RD Period only), RAUC (RD Period only), Tlast, T1/2, CL, Vss (SAD Period only);Timepoint(s) of evaluation of this end point: SAD Period: AGL mRNA and ATX95 D0, D1, D4, D7, D14, D21 and D28<br>RD Period: AGL mRNA and ATX95 W0, W1, W2, W8, W9, W10 and W12<br>

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