Tern Therapeutics Presents Positive Twelve-Month Data from Dose Escalation Cohorts in Phase I/II Trial of TTX-381
No SAEs related to study drug or administration procedure during 1+ year follow-up
Rapid, durable, and dose-dependent increases in TPP1 transgene levels to therapeutic range
Photoreceptor preservation in all treated eyes
12-month control period for participants in Cohorts 1 and 2 is complete; enrollment in expansion cohort is underway
Tern Therapeutics, LLC (“Tern”), a biotechnology company developing transformative one-time gene therapies for rare diseases, reported positive twelve-month clinical data relating to the safety and efficacy of its TTX-381 program at the 19th International Congress on Neuronal Ceroid Lipofuscinosis (NCL) in Queensland, Australia.
"While enzyme replacement therapy is available for treatment of central nervous system manifestations of CLN2 disease, allowing children with CLN2 to live longer and better lives, rapid vision loss remains a high unmet need in this population" said Christina Ohnsman, M.D., Chief Medical Officer of Tern, who presented the data at NCL. "The safety and efficacy data presented today support that TTX-381, a one-time gene therapy, is a promising treatment that may prevent further vision loss in these children. We look forward to concluding enrollment of our expansion cohort and learning more about TTX-381."
TTX-381 Phase I/II Clinical Trial Data
An open-label, dose-escalation study of TTX-381 is ongoing with clinical trial sites in the United Kingdom and Germany. One-year data were presented from the Phase I/II portion of the clinical trial, including 6 participants across two dose level cohorts, 2.0x1010 GC (genome copies) per eye (Cohort 1; n=3) and 6.0x1010 GC per eye (Cohort 2; n=3). The dose escalation cohorts are fully enrolled, and enrollment in an expansion cohort is ongoing.
Safety and Tolerability
As of the data cut-off on August 31, 2025, TTX-381 was reported to be well tolerated across both cohorts at Dose Level 1 (2x1010 GC/eye; n=3) and Dose Level 2 (6x1010 GC/eye; n=3) with no serious adverse events (SAEs) related to the drug or subretinal administration procedure in the six participants. Time of post-administration follow-up included a minimum of 12-months for all 6 participants.
TPP1 Concentration in Aqueous Humor (AH)
In CLN2 Batten disease, tripeptidyl peptidase 1 (TPP1) deficiency results in degeneration of nerve cells, particularly in the brain and retina. In the ongoing TTX-381 clinical trial, TPP1 levels in AH are measured using a validated bioanalytical immunoassay at baseline and on Days 30, 90, and 360 post-administration, and levels are compared to baseline, untreated fellow eyes, and samples from healthy non-CLN2 donors. All participants had either undetectable or trace concentrations of TPP1 in both the treated and untreated fellow eyes at baseline, and TPP1 levels rapidly increased in treated eyes by Day 30. By Day 90 post-administration of TTX-381, five of six participants’ treated eyes had AH TPP1 levels that reached or exceeded the normative reference range established in healthy non-CLN2 donors, and levels were maintained through Day 360 (last time point available). TPP1 levels in AH at Day 90 were 28-fold higher in treated eyes administered Dose Level 2 compared with Dose Level 1, demonstrating a dose-dependent response to TTX-381. Untreated eyes continued to have undetectable or trace concentrations of TPP1 in all participants at all timepoints.
Anatomic Data from SD-OCT Imaging
Evidence indicates that photoreceptor degeneration, the cause of vision loss in CLN2 patients, is strikingly symmetrical in both eyes and first detectable in the ellipsoid zone (EZ). Area of EZ loss has been recognized to be a clinically meaningful surrogate for vision loss, with areas of EZ loss corresponding closely with blind spots in the visual field. Longitudinal SDOCT imaging was performed to evaluate photoreceptor health, specifically the area of EZ loss as well as the thickness of the photoreceptor layer in the central retina. While photoreceptors continued to degenerate rapidly in untreated eyes, these retinal cells were preserved in treated eyes through Day 360. Specifically, area of EZ loss resolved (improved) in 2/6 treated eyes, remained stable in 2/6 treated eyes, and had a small increase (~ 2-fold) in 1/6 treated eyes at Day 360, as compared with baseline. In contrast, area of EZ loss in untreated eyes enlarged by 5- to 27-fold compared with baseline at 1 year. One participant did not have sufficient EZ loss in either eye at Day 360 to evaluate the difference from baseline. Central photoreceptor layer thickness remained stable or increased (improved) in 6/6 treated eyes at Day 360 compared with baseline, in contrast with progressive photoreceptor layer thinning (worsening) in 6/6 untreated eyes. The difference between each pair of treated and fellow, untreated eyes in change from baseline in central photoreceptor layer thickness ranged from 20-92% at 1 year.
About TTX-381
TTX-381 is an investigational one-time AAV9 gene therapy designed to deliver a working copy of the TPP1 gene directly to the retina to provide a durable source of TPP1 to maintain the health of the retina and address vision loss in people with CLN2 disease. Vision loss in CLN2 disease rapidly progresses to blindness, and there is currently no available treatment for the ocular manifestations of CLN2 disease. The open-label clinical trial designed to evaluate the safety and efficacy of TTX-381 is active and enrolling participants in an expansion cohort. Learn more at euclinicaltrials.eu (EUCT number: 2025-521175-31-00) and clinicaltrials.gov (NCT05791864).
