TTX-381 for Neuronal ceroid lipofuscinosis type 2 (CLN2) | Ocular manifestations of CLN2 disease

Inclusion criteria

• {"criterion_text":"- Has biallelic CLN2 mutations.\n- OR 1. Was previously administered TTX-381.\n- 3. Has been recommended for enrollment into the clinical trial by IDMC\n- In all cases, written informed consent of the parent(s) or legally authorized representative(s) is required.\n- 2. 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.\n- Has decreased leukocyte TPP1 activity.\n- 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.\n- Is currently receiving biweekly ICV ERT treatment with cerliponase alfa.\n- Is ≥24 months and ≤84 months of age\n- 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: a.\tCRT at baseline ≤210 µm and b.\tCRT at baseline ≥140 µm in both eyes\n- Is willing to adhere to the protocol and 5-year visit schedule.\n- 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."}

Exclusion criteria

• {"criterion_text":"- 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).\n- Contraindications to intraocular surgery (eg, severe coagulopathy).\n- Positive urine pregnancy test at Screening (applying only to females of childbearing potential).\n- Difference in screening CRT measurement between the right and left eye >10 μm.\n- 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.\n- 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.\n- Age <24 months and >84 months\n- Prior Grade 3 or 4 hypersensitivity reaction, eg, bronchospasm and hypotension requiring intravenous treatment, cardiac dysfunction, anaphylaxis to ICV cerliponase alfa infusion.\n- 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.\n- 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.\n- 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.\n- Prior bone marrow transplant.\n- 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.\n- Participation in a nonocular clinical study with an investigational drug in the past 6 months prior to screening, except for intracerebroventricular cerliponase alfa.\n- Ocular surgery within the prior 6 months except as above for subretinal TTX-381 administration.\n- Known or expected difficult airway\n- 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.\n- Known sensitivity or contraindications to medications planned for use in the peri-operative period.\n- Contraindications to systemic immunosuppression.\n- 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.\n- 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.\n- Mutations in another CLN gene.\n- Mutation in another gene associated with inherited retinal disease, if known."}

Primary endpoints

• {"endpoint_text":"- Ocular and overall AEs and SAEs through Day 360","definition_or_measurement_approach":"Adverse events (AEs) and serious adverse events (SAEs) recorded and assessed through Day 360."}

Secondary endpoints

• {"endpoint_text":"- Change from baseline in area of EZ loss as measured by SD-OCT at Day 180","definition_or_measurement_approach":"Area of ellipsoid zone (EZ) loss measured by spectral domain-optical coherence tomography (SD-OCT) at Day 180; change from baseline."}
• {"endpoint_text":"- Change from baseline in area of ellipsoid zone (EZ) loss as measured by SD-OCT at Day 360","definition_or_measurement_approach":"Area of ellipsoid zone (EZ) loss measured by SD-OCT at Day 360; change from baseline."}
• {"endpoint_text":"- Change from baseline in central subfield PR layer thickness as measured by SD-OCT at Day 180","definition_or_measurement_approach":"Central subfield photoreceptor (PR) layer thickness measured by SD-OCT at Day 180; change from baseline."}
• {"endpoint_text":"- Change from baseline in central subfield photoreceptor (PR) layer thickness as measured by SD-OCT at Day 360","definition_or_measurement_approach":"Central 1 mm diameter centered at fovea photoreceptor (PR) layer thickness measured by SD-OCT at Day 360; change from baseline."}
• {"endpoint_text":"- Measurement of TTX-381 TPP1 in aqueous humor at Day 90","definition_or_measurement_approach":"Measurement of TTX-381 transgene product (TPP1) concentration in aqueous humor at Day 90."}
• {"endpoint_text":"- Measurement of TTX-381 TPP1 in aqueous humor at Day 360","definition_or_measurement_approach":"Measurement of TTX-381 transgene product (TPP1) concentration in aqueous humor at Day 360."}
• {"endpoint_text":"- TTX-381 detected by qPCR in urine and tears","definition_or_measurement_approach":"Detection of TTX-381 vector by quantitative PCR (qPCR) in urine and tears."}
• {"endpoint_text":"- Anti-AAV9 antibodies in serum","definition_or_measurement_approach":"Detection of anti-AAV9 antibodies in serum."}
• {"endpoint_text":"- ATPA in serum and CSF","definition_or_measurement_approach":"Detection/measurement of ATPA in serum and cerebrospinal fluid (CSF)."}

Germany

Earliest CTIS Part Ii Submission Date

10-06-2025

Latest Decision Or Authorization Date

03-07-2025

Processing Time Days

23

Number Of Sites

1

Number Of Participants

5

Primary sponsor

Full Name

Tern Therapeutics LLC

Organisation Type

Pharmaceutical company

Country Of Registered Address

United States

Contract research organisations

Name

Merit CRO Inc.

Responsibilities

Medical image analysis

Name

Fortrea Inc.

Responsibilities

sponsorDuties codes: 1,10,11,5,6,7,8

Name

4G Clinical B.V.

Responsibilities

sponsorDuties code: 3

Name

Propharma Group The Netherlands B.V.

Responsibilities

sponsorDuties code: 12

Third parties

• {"country":"Netherlands","full_name":"Propharma Group The Netherlands B.V.","duties_or_roles":"sponsorDuties codes: 12","organisation_type":"Pharmaceutical company"}
• {"country":"United States","full_name":"Red Nucleus Solutions LLC","duties_or_roles":"sponsorDuties code: 15; value: Endpoint: MyDay CLN2 Vision app for video collection","organisation_type":"Pharmaceutical company"}
• {"country":"Netherlands","full_name":"4G Clinical B.V.","duties_or_roles":"sponsorDuties code: 3","organisation_type":"Non-Pharmaceutical company"}
• {"country":"Switzerland","full_name":"Labcorp Central Laboratory Services SARL","duties_or_roles":"sponsorDuties code: 4","organisation_type":"Pharmaceutical company"}
• {"country":"United States","full_name":"Merit CRO Inc.","duties_or_roles":"sponsorDuties code: 15; value: Medical image analysis","organisation_type":"Pharmaceutical company"}
• {"country":"United States","full_name":"Fortrea Inc.","duties_or_roles":"sponsorDuties codes: 1,10,11,5,6,7,8","organisation_type":"Pharmaceutical company"}