Transposon Announces Phase 2 Results for TPN-101 in C9orf72-Related ALS/FTD

Transposon Therapeutics, a biotech firm focused on developing new oral treatments for neurodegenerative and aging-related diseases, announced final results from its Phase 2 trial of TPN-101 in amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) linked to the C9orf72 gene mutation. The study confirmed TPN-101's safety and indicated potential disease-modifying effects in these conditions. These results are consistent with earlier findings in patients with Progressive Supranuclear Palsy (PSP), showing TPN-101’s capacity to reduce neuroinflammation and neurodegeneration by inhibiting the activity of LINE-1, a human-specific retrotransposon implicated in various neurodegenerative diseases and aging.

ALS is a devastating neurodegenerative disease with a typical survival period of two to three years, primarily causing death through respiratory failure. Vital Capacity (VC) is a crucial respiratory function measure linked to mortality in ALS patients. In the study, participants with C9-ALS who received TPN-101 exhibited about a 50% slower decline in VC over 24 weeks compared to those on placebo. When placebo participants transitioned to TPN-101 during an open-label period, their VC decline rate was less than half compared to the placebo phase, aligning closely with the original TPN-101 group’s results. Overall, the 48-week changes in both groups were significantly better than expected based on historical data in similar populations.

Regarding the Revised ALS Functional Rating Scale (ALSFRS-R), the decline was similar between the TPN-101 and placebo groups during the initial 24-week period. However, during the subsequent 24-week open-label extension, the decline in the original TPN-101 group was less than half compared to the initial period, and much lower than the placebo group. Over 48 weeks, the decline in the TPN-101 group was about 40% less than predicted based on historical data, suggesting a broader clinical benefit from extended treatment.

Dr. Merit Cudkowicz, Chair of Neurology at Massachusetts General Hospital and principal investigator in the study, emphasized the encouraging results of TPN-101 across several critical endpoints, underlining its potential as a treatment for C9-ALS. The study also found that C9-ALS patients treated with TPN-101 had lower levels of neurofilament light chain (NfL) – a key biomarker of neurodegeneration – compared to the placebo group after the double-blind period. These findings were consistent at both 24 and 48 weeks and supported by similar outcomes in a Phase 2 study for PSP. Additionally, TPN-101 reduced other neurodegeneration and neuroinflammation biomarkers, including neurofilament heavy chain (NfH), interleukin 6 (IL-6), neopterin, and osteopontin.

A meta-analysis combining data from C9-ALS and PSP patients in the Phase 2 studies revealed a statistically significant reduction in NfL levels with TPN-101 compared to placebo at Week 24. This consistency in biomarker improvements across different conditions supports the treatment hypothesis that these diseases share a common pathophysiology related to LINE-1 activity.

Dennis Podlesak, CEO of Transposon, highlighted the limited treatment options currently available for ALS patients and noted the promising benefits TPN-101 demonstrated across multiple measures. He stated that these results justify progressing TPN-101 to a Phase 3 registration study for C9-ALS. Moreover, the company plans to advance TPN-101 for treating PSP, Alzheimer's disease, and other neurodegenerative and autoimmune disorders, with the goal of providing innovative therapies to improve patients' lives.

Transposon will present detailed data from this study at upcoming scientific meetings. The Phase 2 study involved 42 participants and included a six-week screening, a 24-week double-blind treatment, a 24-week open-label treatment, and a follow-up visit four weeks post-treatment.

TPN-101 specifically inhibits LINE-1 reverse transcriptase, which promotes LINE-1 replication. Dysregulation of this process can lead to an overproduction of LINE-1 DNA, triggering immune responses contributing to neurodegenerative, autoimmune, and aging-related diseases. ALS is characterized by progressive muscle weakness and loss of ability to speak, eat, move, or breathe, with a mean survival of two to three years. FTD affects the frontal/temporal cortex, leading to behavioral and personality changes, emotional issues, and difficulties in walking, communicating, or working, with a mean survival of nine years.