A study to evaluate the safety and tolerability of TTX-381 in participants with ocular manifestations of CLN2 disease

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Tern Therapeutics LLC

Participant type

Pediatric, Patients

Age range

0-17 years

Gender

Male and Female

Therapeutic area

Diseases [C] - Nervous System Diseases [C10]

Decision date (initial)

2025-07-03

Transition trial

No

Low-intervention

No

Rare-disease indication

Yes

Vulnerable population

Yes

Funding sources

Tern Therapeutics LLC

External identifiers

EU CT number

2025-521175-31-00

ClinicalTrials.gov

NCT05791864

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Dose response, Safety, Pharmacokinetic, Efficacy, Others, Pharmacodynamic

To evaluate the safety and tolerability of TTX-381 through Day 360 in participants with CLN2 disease

Secondary objectives 9

1. To evaluate the effect of TTX-381 on area of EZ loss at Day 180 as measured by SD-OCT
2. To evaluate the effect of TTX-381 on area of ellipsoid zone (EZ) loss at Day 360 as measured by spectral domain-optical coherence tomography (SD-OCT)
3. To evaluate the effect of TTX-381 on central subfield photoreceptor layer thickness at Day 180 as measured by SD-OCT
4. To evaluate the effect of TTX-381 on central subfield (central 1 mm diameter centered at fovea) photoreceptor layer thickness at Day 360 as measured by SD-OCT
5. To measure TTX-381 transgene product (TPP1) in aqueous humor at Day 90
6. To measure TTX-381 transgene product (TPP1) in aqueous humor at Day 360
7. To evaluate shedding of TTX-381 in urine and tears
8. To detect anti-AAV9 antibodies in serum after subretinal administration of TTX-381
9. To detect ATPA in serum and CSF

Conditions and MedDRA coding

Ocular manifestations of Neuronal Ceroid Lipofuscinosis (CLN) Type 2

Regulatory references

Scientific advice from competent authorities

Paul-Ehrlich-Institut

Plan to share IPD

No

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 12

1. Has biallelic CLN2 mutations.
2. 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.
3. Has decreased leukocyte TPP1 activity.
4. 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.
5. Is currently receiving biweekly ICV ERT treatment with cerliponase alfa.
6. Is ≥24 months and ≤84 months of age
7. 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. CRT at baseline ≤210 µm and b. CRT at baseline ≥140 µm in both eyes
8. Is willing to adhere to the protocol and 5-year visit schedule.
9. 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.
10. OR 1. Was previously administered TTX-381.
11. 3. Has been recommended for enrollment into the clinical trial by IDMC
12. In all cases, written informed consent of the parent(s) or legally authorized representative(s) is required.

Exclusion criteria 23

1. 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).
2. Prior bone marrow transplant.
3. 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.
4. Known sensitivity or contraindications to medications planned for use in the peri-operative period.
5. Contraindications to systemic immunosuppression.
6. 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.
7. 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.
8. Mutations in another CLN gene.
9. Mutation in another gene associated with inherited retinal disease, if known.
10. Contraindications to intraocular surgery (eg, severe coagulopathy).
11. Positive urine pregnancy test at Screening (applying only to females of childbearing potential).
12. Difference in screening CRT measurement between the right and left eye >10 μm.
13. 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.
14. 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.
15. Age <24 months and >84 months
16. Prior Grade 3 or 4 hypersensitivity reaction, eg, bronchospasm and hypotension requiring intravenous treatment, cardiac dysfunction, anaphylaxis to ICV cerliponase alfa infusion.
17. 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.
18. 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.
19. 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.
20. 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.
21. Participation in a nonocular clinical study with an investigational drug in the past 6 months prior to screening, except for intracerebroventricular cerliponase alfa.
22. Ocular surgery within the prior 6 months except as above for subretinal TTX-381 administration.
23. Known or expected difficult airway

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. Ocular and overall AEs and SAEs through Day 360

Secondary endpoints 9

1. Change from baseline in area of EZ loss as measured by SD-OCT at Day 180
2. Change from baseline in area of ellipsoid zone (EZ) loss as measured by SD-OCT at Day 360
3. Change from baseline in central subfield PR layer thickness as measured by SD-OCT at Day 180
4. Change from baseline in central subfield photoreceptor (PR) layer thickness as measured by SD-OCT at Day 360
5. Measurement of TTX-381 TPP1 in aqueous humor at Day 90
6. Measurement of TTX-381 TPP1 in aqueous humor at Day 360
7. TTX-381 detected by qPCR in urine and tears
8. Anti-AAV9 antibodies in serum
9. ATPA in serum and CSF

Investigational products

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

Test 2

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Tern Therapeutics LLC

Sponsor organisation

Tern Therapeutics LLC

Address

1200 G Street Northwest Ste 800

City

Washington

Postcode

20005-6705

Country

United States

Scientific contact point

Organisation

Tern Therapeutics LLC

Contact name

Chief Medical Officer

Public contact point

Organisation

Tern Therapeutics LLC

Contact name

Chief Medical Officer

Third parties 6

Locations

1 EU/EEA country · 1 investigational sites

By country

Investigational sites

Application history

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