A First-in-Human, Open-Label, Dose-Escalation Study to Evaluate the Safety and Tolerability of Gene Therapy With TTX-381 for the Ocular Manifestations Associated With Neuronal Ceroid Lipofuscinosis Type 2 (CLN2) Disease

This is a first-in-human, open-label, single ascending dose study of TTX-381 for the treatment of ocular manifestations of CLN2 (Batten disease).

Study Overview

• Status: Recruiting
• Conditions: Neuronal Ceroid Lipofuscinosis Type 2
• Intervention / Treatment: Genetic: TTX-381

Detailed Description

This is a first-in-human, open-label, single ascending dose study of TTX-381, a gene therapy for the potential treatment of ocular manifestations of CLN2 (Batten disease). TTX-381 is being studied as a potential treatment of ocular manifestations of neuronal ceroid lipofuscinosis type 2 (CLN2) disease. Children with CLN2 disease have a non-working gene (set of instructions) that causes an enzyme called tripeptidyl-peptidase 1 (TPP1) to be missing or not working in their bodies. Without enough TPP1, cells cannot break down certain molecules in the body, so these storage materials build up and start to hurt the body, particularly the central nervous system (the brain and spine) and retinal cells (eyes); cause seizures; and change how children with CLN2 disease grow, act, think, and see. After eligibility has been confirmed, the participant's eyes will be assigned as the treated eye and the control fellow eye. Due to the symmetry in the clinical course of CLN2 ocular disease, untreated fellow eyes will serve as controls for the contralateral, treated eyes. Participants will be followed in this study for 5 years after TTX-381 administration.

• Study Type: Interventional
• Enrollment (Estimated): 16
• Phase: Phase 2; Phase 1

Contacts and Locations

• Study Contact: Name: Tern Therapeutics Patient Advocacy; Phone Number: 202-644-8488; Email: patientadvocacy@terntx.com

Study Locations

• Germany
  • Hamburg, Germany
    • Recruiting
    • University Medical Center Hamburg-Eppendorf (UKE)- Childrens Hospital
    • Contact: Prof. Dr. med. Angela Schulz; Phone Number: +49 (0)40 7410-20440; Email: ncl-sprechstunde@uke.de
    • Principal Investigator: Prof. Dr. med. Angela Schulz
• United Kingdom
  • London, United Kingdom, Wc1N 3JH
    • Recruiting
    • Greater Ormond Street Hospital
    • Principal Investigator: Robert Henderson, MD
    • Contact: Email: research.ophthalmology@gosh.nhs.uk

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 1 year to 12 years (Child)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

A participant is eligible to be included in the study only if all of the following criteria apply:

• Has biallelic CLN2 mutations.
• Has decreased leukocyte TPP1 activity.
• Has clinical signs or symptoms consistent with CLN2 disease (eg, developmental delay, developmental decline, seizure, vision loss, or other signs/symptoms) OR an older sibling with confirmed CLN2 diagnosis.
• Is currently receiving biweekly ICV ERT treatment with cerliponase alfa.
• Meets the following baseline disease condition according to age and CRT as assessed by SD-OCT and confirmed by CRC:

Participants in the phase of accelerated decline in CRT:

1. CRT at baseline ≤210 μm and
2. CRT at baseline ≥140 μm in both eyes and

3. Age ≤84 months,

   • Is willing to adhere to the protocol and 5-year visit schedule.
   • Sexually active female participants of childbearing potential (following menarche) or fertile male participants (following puberty) must be willing to use a medically accepted form of contraception from Screening Visit 2 until 6 weeks after vector administration.

OR

• Was previously administered TTX-381.
• Upon retrospective review, met the above criteria at the time of administration of TTX-381. IDMC may consider exceptions to this when weighing whether to retrospectively enroll a participant who has received TTX-381.
• Has been recommended for enrollment into the clinical trial by IDMC

Exclusion Criteria:

Participants are excluded from the study if any of the following criteria apply:

• Any ocular or systemic condition that, in the opinion of the investigator, would prevent administration and evaluation of the investigational product or interpretation of participant safety or study results (eg, significant lens or corneal opacities, glaucoma, amblyopia, gross retinal anatomical abnormality, etc).
• Difference in screening CRT measurement between the right and left eye >10μm.
• Prior Grade 3 or 4 hypersensitivity reaction, eg, bronchospasm and hypotension requiring intravenous treatment, cardiac dysfunction, anaphylaxis to ICV cerliponase alfa infusion.
• Any other contraindication to the administration of ICV cerliponase alfa, including ventriculo-peritoneal shunt, acute intracerebroventricular access device leakage, device failure, or device-related infection that would impact ability to receive ICV cerliponase alfa.
• Prior participation in a gene therapy study. A subject who has received subretinal TTX-381 under a compassionate use protocol may be enrolled if the PI, Medical Monitor, and Sponsor all agree that he/she can safely and successfully participate in the study and the IDMC has approved their enrollment.
• Prior participation in another ocular clinical trial, except an intravitreal cerliponase alfa trial where a subject has received a maximum of 3 injections and the PI, Medical Monitor, and Sponsor all agree that he/she can safely and successfully participate in the study after a washout period of 3 or more months.
• Prior intraocular injections of any kind, with the following two exceptions. A subject who has received a maximum of 3 intravitreal injections of cerliponase alfa may be enrolled in the study if the PI, Medical Monitor, and Sponsor all agree that he/she can safely and successfully participate in the study after a washout period of 3 or more months. A subject who has received subretinal TTX-381 under a compassionate use protocol may be enrolled if the PI, Medical Monitor, and Sponsor all agree that he/she can safely and successfully participate in the study and the IDMC has approved their enrollment.
• Participation in a nonocular clinical study with an investigational drug in the past 6 months prior to screening, except for intracerebroventricular cerliponase alfa.
• Ocular surgery within the prior 6 months except as above for subretinal TTX-381 administration.
• Prior bone marrow transplant. Use of the following medications within the 30 days prior to treatment: gemfibrozil, mycophenolate, prednisone or other steroids for the intended purpose of treating NCL (not including asthma indications), flupirtine.
• Known sensitivity or contraindications to medications planned for use in the peri-operative period.
• Contraindications to systemic immunosuppression.
• Severe renal insufficiency as determined by an estimated glomerular filtration rate (eGFR) < 30 mL/min/1.73 m2, based on creatinine, at Screening. If the laboratory determines that the creatinine level is less than the lower limit of assay validation or detection, then the lowest limit cutoff value will be used to estimate eGFR.
• Severe hepatic insufficiency as determined by alanine aminotransferase (ALT) or aspartate aminotransferase (AST) > 3 × upper limit of normal (ULN) or total bilirubin > 1.5 × ULN at Screening Visit 1, unless the subject has a previously known history of Gilbert's syndrome and a fractionated bilirubin that shows conjugated bilirubin < 35% of total bilirubin.
• Mutations in another CLN gene.
• Mutation in another gene associated with inherited retinal disease.
• Contraindications to intraocular surgery (eg, severe coagulopathy).
• Positive urine pregnancy test at Screening (applying only to females of childbearing potential).
• Any other condition that would not allow the potential participant to complete follow-up examinations during the study or, in the opinion of the investigator, makes the potential participant unsuitable for the study.
• The participant had a positive polymerase chain reaction (PCR) viral test for severe acute respiratory syndrome coronavirus 2 (SARS-CoV2 PCR) within the last 4 weeks before signing the informed consent form (ICF) or has persistent coronavirus disease (COVID-19) symptoms regardless of when the last SARS-CoV2 PCR viral test was performed or when the infection occurred.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Sequential Assignment
• Masking: Single

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Cohort 1: Main Treatment Arm; 2×10^10 GC/eye	Genetic: TTX-381; One time subretinal dose in study eye; Other Names: Gene Therapy (AAV9.CB7.hCLN2)
Experimental: Cohort 2: Main Treatment Arm; 6×10^10 GC/eye	Genetic: TTX-381; One time subretinal dose in study eye; Other Names: Gene Therapy (AAV9.CB7.hCLN2)
Experimental: Expansion Cohort; Expansion cohort, dose level 2×10^10 GC/eye as determined by Independent Data Monitoring Committee.	Genetic: TTX-381; One time subretinal dose in study eye; Other Names: Gene Therapy (AAV9.CB7.hCLN2)

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Ocular and overall AE and SAEs through Day 360	To evaluate the safety and tolerability of TTX-381 through Day 360 in participants with Neuronal Ceroid Lipofuscinosis Type 2 (CLN2) disease	360 days

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
To evaluate the effect of TTX-381 on area of EZ loss	To evaluate the effect of TTX-381 on area of EZ loss as measured by SD-OCT	Day 180, Day 360
To evaluate the effect of TTX-381 on central subfield photoreceptor layer thickness	To evaluate the effect of TTX-381 on central subfield photoreceptor layer thickness as measured by SD-OCT	Day 180, Day 360
To measure TTX-381 transgene product (tripeptidyl peptidase 1 [TPP1]) in aqueous humor	To measure TTX-381 transgene product (tripeptidyl peptidase 1 [TPP1]) in aqueous humor	Day 90, Day 360
To evaluate shedding of TTX-381 in urine and tears	To evaluate shedding of TTX-381 in urine and tears	Day 360

Collaborators and Investigators

• Sponsor: Tern Therapeutics, LLC

Study record dates

Study Major Dates

• Study Start (Actual): May 17, 2023
• Primary Completion (Estimated): July 30, 2026
• Study Completion (Estimated): July 30, 2031

Study Registration Dates

• First Submitted: March 17, 2023
• First Submitted That Met QC Criteria: March 17, 2023
• First Posted (Actual): March 30, 2023

Study Record Updates

• Last Update Posted (Actual): December 18, 2025
• Last Update Submitted That Met QC Criteria: December 17, 2025
• Last Verified: February 1, 2025

More Information

Terms related to this study

• Keywords: Gene Therapy; Batten Disease; CLN2
• Additional Relevant MeSH Terms: Nervous System Diseases; Metabolism, Inborn Errors; Genetic Diseases, Inborn; Metabolic Diseases; Neurodegenerative Diseases; Heredodegenerative Disorders, Nervous System; Lipid Metabolism Disorders; Lipid Metabolism, Inborn Errors; Lipidoses; Congenital, Hereditary, and Neonatal Diseases and Abnormalities; Nutritional and Metabolic Diseases; Neuronal Ceroid-Lipofuscinoses; Investigative Techniques; Therapeutics; Biological Therapy; Genetic Techniques; Genetic Engineering; Genetic Therapy
• Other Study ID Numbers: TTX-381-1102; 2021-000173-92 (EudraCT Number)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: Yes