Transposon Therapeutics presented promising results from its Phase 2 clinical trial of TPN-101, an experimental medication for amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD), at the 35th International Symposium on ALS/MND. The trial, which concluded in July, suggests that TPN-101 may offer a disease-modifying effect for individuals with ALS and FTD, particularly those with a C9orf72 genetic mutation.
Targeting Retrotransposons in Neurodegenerative Diseases
Unlike many experimental medicines targeting proteins, TPN-101 targets retrotransposons, specifically LINE-1 elements. These genetic elements can self-replicate within a genome through reverse transcription, potentially damaging cells if unregulated. Dysfunction in proteins associated with diseases like FTD can lead to LINE-1 dysregulation, contributing to neurodegeneration in ALS-FTD disorders and progressive supranuclear palsy (PSP).
TPN-101 inhibits the reverse transcription capability of LINE-1 elements, aiming to modify the course of neurodegenerative diseases. The Phase 2 trial initially employed a double-blind method, where participants received either TPN-101 or a placebo, followed by an open-label extension where all participants received TPN-101.
Efficacy Measures in ALS Patients
Researchers assessed efficacy in ALS patients using several key measures:
- Vital Capacity (VC): Measurement of air exhaled after maximum inhalation.
- ALS Functional Rating Scale, Revised (ALSFRS-R): Questionnaire assessing physical functioning and symptom progression.
- Neurofilament Light Chain (NfL): A biomarker for neuron damage.
During the double-blind phase, participants receiving TPN-101 experienced approximately 50% less decline in vital capacity compared to the placebo group (-8.4% vs. -16.5%). While ALSFRS-R scores were similar between the groups during this phase, the TPN-101 group showed less decline during the open-label phase, suggesting long-term effectiveness. Furthermore, TPN-101 recipients had lower NfL levels than those receiving the placebo.
The study also indicated that TPN-101 reduced other biomarkers of neurodegeneration and neuroinflammation, including neurofilament heavy chain and osteopontin.
Consistent Data Across ALS/FTD and PSP Trials
The findings from the ALS/FTD trial align with data from a separate trial evaluating TPN-101 in PSP patients. That trial also demonstrated a reduction in key biomarkers like NfL and osteopontin. An analysis at week 24 showed a statistically significant decrease in NfL levels compared to placebo groups.
"The effects of TPN-101 across multiple key endpoints in this study are encouraging and represent an important step forward in finding a potential treatment for this serious illness," said Merit Cudkowicz, MD, Chair of the Department of Neurology at Massachusetts General Hospital and principal investigator of the study. "I look forward to advancing the development of TPN-101 and what that could mean for people living with C9-ALS."
Transposon Therapeutics plans to advance TPN-101 into a Phase 3 registration study for C9-ALS, while also exploring its potential in other neurodegenerative and autoimmune disorders, including Alzheimer’s disease.
