A clinical study of a virus transferring the gene for human Ornithine Transcarbamylase (OTC) in patients 12 years of age and older with late-onset OTC deficiency

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Ultragenyx Pharmaceutical Inc.

Participant type

Pediatric, Patients

Age range

0-17 years, 18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Congenital, Hereditary, and Neonatal Diseases and Abnormalities [C16], Diseases [C] - Nutritional and Metabolic Diseases [C18]

Trial duration

24 Jan 2023 → ongoing

Decision date (initial)

2024-10-04

Transition trial

Yes

Low-intervention

No

Rare-disease indication

Yes

Vulnerable population

Yes

Funding sources

Ultragenyx Pharmaceutical Inc.

External identifiers

EU CT number

2024-514337-38-00

EudraCT number

2020-003384-25

ClinicalTrials.gov

NCT05345171

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Prophylaxis, Safety, Pharmacodynamic, Efficacy, Therapy

To evaluate the efficacy of DTX301 on the improvement of OTC function by maintaining safe plasma ammonia levels

Secondary objectives 9

1. To evaluate the efficacy of DTX301 in Clinical Responder categories
2. To evaluate the effect of DTX301 on occurrence of HACs
3. To evaluate the effect of DTX301 on occurrence of ICEs
4. To evaluate the effect of DTX301 on plasma ammonia
5. To evaluate the effect of DTX301 on disease management
6. To evaluate the safety of DTX301
7. To characterize the immune response to OTC protein (anti-OTC antibodies)
8. To evaluate the long-term durability of DTX301
9. To evaluate the effect of DTX301 on plasma ammonia in patients who have an elevated plasma ammonia level at baseline

Conditions and MedDRA coding

Late-onset Ornithine transcarbamylase (OTC) deficiency

Study design 4 periods

Regulatory references

Scientific advice from competent authorities

European Medicines Agency

EMA paediatric investigation plan (PIP)

EMEA-002830-PIP01-20

Plan to share IPD

No

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 10

1. 1. Male or female patient 12 years of age or older at the time of signed informed consent.
2. 2. Provide informed consent after the nature of the study has been explained, and prior to any research-related procedures. If a minor, be willing and able (if possible) to provide assent and have a legally authorized representative provide informed consent after the nature of the study has been explained and prior to any research-related procedures.
3. 3. Confirmed clinical diagnosis of late-onset OTC deficiency with historical documentation by enzymatic (ie, liver biopsy), biochemical (ie, hyperammonemia in the presence of elevated plasma glutamine, low citrulline, and elevated spot urine orotic acid), or molecular testing (ie, OTC analysis).
4. 4. Documented history of ≥ 1 symptomatic hyperammonemia episode with ammonia level ≥ 100 μmol/L for confirmation of clinical disease.
5. 5. Patient is currently receiving ammonia scavenger therapy and/or protein-restricted diet, is free from symptomatic hyperammonemia, and has not required emergent active intervention for hyperammonemia within 4 weeks before screening/baseline.
6. 6. Plasma 24-hour ammonia (AUC0-24) is ≤ 4800 μmol*h/L at screening. If the ammonia AUC0-24 is inconsistent with the patient’s clinical status, the assessment may be repeated to ensure accurate results.
7. 7. If on ongoing daily ammonia scavenger therapy, must be at stable daily dose(s) for ≥ 4 weeks prior to screening
8. 8. If on a protein-restricted diet, must be on a stable protein-restricted diet as evidenced by a stable amount of total protein intake (ie, daily protein intake in grams per day does not vary more than 20%) for ≥ 4 weeks prior to screening.
9. 9. Willing and able to comply with study procedures and requirements, including periodic inpatient hospitalizations, frequent blood and urine collections, blood collections over a 24-hour period, questionnaires, cognitive assessments, and patient/caregiver reported outcome assessments. If a minor, must have a caregiver(s) willing and able to assist in all applicable study requirements.
10. 10. From the time written informed consent is provided through Week 28, females of childbearing potential and fertile males must consent to use highly effective contraception as defined by the United States Food and Drug Administration (FDA) and Clinical Trial Facilitation Coordination Group (CTFG) Recommendations Related to Contraception and Pregnancy in Clinical Trials. If female, agree not to become pregnant. If male, agree to not father a child or donate sperm.

Exclusion criteria 17

1. 1. Liver transplant, including hepatocyte cell therapy/transplant.
2. 2. History of liver disease as evidenced by any of the following: portal hypertension, ascites, splenomegaly, esophageal varices, hepatic encephalopathy, or a liver biopsy with evidence of stage 3 fibrosis.
3. 3. Significant hepatic inflammation or cirrhosis as evidenced by imaging or any of the following laboratory abnormalities: alanine aminotransferase (ALT) or aspartate aminotransferase (AST) > 1.5 × ULN, total bilirubin > 1.5 × ULN (except if patient has a diagnosis of Gilbert’s syndrome), alkaline phosphatase > 2.5 × ULN. Note: Any of the LFTs may be retested.
4. 4. Estimated glomerular filtration rate < 60 mL/min/1.73 m2 at screening by the CKD-EPI 2021 creatinine-based formula (Inker et al., 2021) for patients ≥ 18 years of age or the Schwartz bedside formula (Schwartz and Work, 2009) for patients < 18 years of age.
5. 5. Evidence of active hepatitis B virus (HBV) or hepatitis C virus (HCV) infection documented by current use of antiviral therapy for HBV or HCV or by hepatitis B surface antigen (HBsAg) or HCV RNA positivity. Note: Patients with a history of HCV infection must have documentation of 2 negative viral assays by PCR collected at least 6 months apart to be considered negative for HCV. Patients with a history of HCV infection who test positive for HCV RNA at screening can be rescreened once after they have been treated and have documentation of at least 2 negative samples collected at least 6 months apart.
6. 6. History of human immunodeficiency virus (HIV) infection AND any of the following: CD4+ cell count < 350 cells/mm3, change in antiretroviral therapy regimen within 6 months prior to Baseline (Day 0), or plasma viral load > 200 copies/mL, documented on 2 separate occasions, as measured by PCR.
7. 7. Active infection (viral or bacterial).
8. 8. Detectable pre-existing antibodies to the AAV8 capsid.
9. 9. History of a malignancy for which the patient has received treatment in the past 2 years, except for prostate cancer treated with watchful waiting or surgically removed nonmelanoma skin cancer.
10. 10. Any of the following that, in the judgment of the Investigator, places the patient at increased risk for adverse effects: - Known hypersensitivity to DTX301, its excipients, or its placebo - Known hypersensitivity to prednisolone, its excipients, or its placebo
11. 11. Chronic use of inhibitors of urea synthesis (eg, valproic acid) or drugs that significantly affect renal clearance (eg, probenecid).
12. 12. Presence or history of any condition that, in the view of the Investigator, would interfere with participation, pose undue risk, or confound interpretation of results, including but not limited to: - Underlying conditions that may require systemic corticosteroids if the condition worsens (eg, autoimmune disorders) - Patients in a catabolic state (eg, due to current infection), or in whom a catabolic state may be reasonably foreseeable (eg, due to planned procedures) - Patient is considered vulnerable by local regulations (eg, imprisoned or institutionalized)
13. 13. Marked neurological deficit or compromise that, in the Investigator’s opinion, would interfere with the patient’s safety or ability to participate in the study.
14. 14. Pregnant or breastfeeding or planning to become pregnant within 64 weeks after receiving DTX301 (ie, through Visit 28 of this study).
15. 15. Participation (current or previous) in another gene transfer study.
16. 16. Use of any investigational product within 3 months prior to screening, or during the study.
17. 17. Patients who meet any of the following criteria are not eligible to undergo the URT: - Unable to fast safely for 12 hours - History of HAC triggered by minimal vomiting - Age < 18 years at screening Note: Any patient < 18 years of age at screening will not undergo ureagenesis rate testing for the duration of study.

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 2

1. Plasma ammonia as measured by 24-hour ammonia (AUC0-24) at Week 36
2. Complete Responder rate at the final study visit after DTX301 exposure

Secondary endpoints 11

1. Percentage of Complete Responders or Responders after DTX301 exposure
2. Annualized event rate of HACs pre-DTX301 exposure vs post-DTX301 exposure
3. Annualized event Rate of ICEs pre-DTX301 exposure vs post-DTX301 exposure
4. Change from baseline to Week 36 in plasma ammonia (AUC0-24)
5. Change in plasma ammonia (AUC0-24) after DTX301 exposure
6. Percentage of patients who have achieved complete management response (CMR) or management response (MR) after DTX301 exposure
7. Change in baseline disease management (dietary protein and total scavenger medication use) with plasma ammonia (AUC0-24) (comparison between those with a reduction of elevated plasma ammonia [AUC0-24] at baseline vs those without)
8. Incidence of TEAEs, TESAEs, treatment-related TEAEs, treatment-related TESAEs, and AESIs
9. Incidence of anti-OTC antibodies
10. Long-term durability of response based upon number of Complete Responders or Responders that have ≥ 2 consecutive visits as a Complete Responder or Responder and do not return to a lower Responder status for > 1 consecutive visit
11. Change in plasma ammonia as measured by 24-hour ammonia (AUC0-24) at Week 64 PEA-2 for patients who have an elevated ammonia AUC0-24 at baseline

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 2

Placebo 2

Auxiliary 2

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Ultragenyx Pharmaceutical Inc.

Sponsor organisation

Ultragenyx Pharmaceutical Inc.

Address

60 Leveroni Court Suite 200

City

Novato

Postcode

94949-5746

Country

United States

Scientific contact point

Organisation

Ultragenyx Pharmaceutical Inc.

Contact name

Medical Information

Public contact point

Organisation

Ultragenyx Pharmaceutical Inc.

Contact name

Ultragenyx trial information group

Third parties 18

Locations

6 EU/EEA countries · 10 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 51 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

5 submissions — initial application plus substantial / non-substantial modifications