Transposon Therapeutics announced positive final results from its Phase 2 study of TPN-101 in patients with amyotrophic lateral sclerosis (ALS) and/or frontotemporal dementia (FTD) related to hexanucleotide repeat expansion in the C9orf72 gene (C9orf72-related ALS/FTD). The study demonstrated a favorable safety profile for TPN-101 and showed clinical signs of disease-modifying effects, aligning with previous findings in Progressive Supranuclear Palsy (PSP). These effects are attributed to TPN-101's mechanism of action, which involves reducing neuroinflammation and neurodegeneration by blocking the activity of LINE-1.
Impact on Vital Capacity in ALS Patients
The Phase 2 trial included 42 participants. ALS, a uniformly fatal neurodegenerative disease, sees respiratory failure as the most common cause of death. Vital Capacity (VC) serves as an objective measure of respiratory function and correlates with mortality. The study found that C9-ALS participants treated with TPN-101 experienced approximately 50% less decline in VC compared to those treated with placebo over 24 weeks (LS mean change -8.4% vs -16.5%). Furthermore, when the placebo group was switched to TPN-101 during the open-label period, the decline in VC over the subsequent 24 weeks (-7.2%) was less than half that observed while on placebo and comparable to the original TPN-101 group during the double-blind period. Overall, the 48-week changes in both groups were lower than expected based on natural history in similar study populations.
Effects on ALSFRS-R and Biomarkers
The Revised ALS Functional Rating Scale (ALSFRS-R) decline was comparable between the TPN-101 and placebo groups during the 24-week double-blind period (LS mean -7.2 points vs -6.7). However, during the 24-week open-label extension period, the decline on the ALSFRS-R in the original TPN-101 group was less than half that during the initial 24-week period and less than half that of the placebo group during both study periods. The decline in ALSFRS-R in the original TPN-101 group over the entire 48 weeks was approximately 40% less than expected based on natural history data, indicating a global clinical benefit with longer treatment.
In C9-ALS participants, those treated with TPN-101 had lower levels of neurofilament light chain (NfL) compared with placebo at the end of the double-blind period. NfL is a primary biomarker of neurodegeneration. A meta-analysis of the combined C9-ALS and PSP populations from the two Phase 2 studies of TPN-101 showed a statistically significant NfL-lowering effect of TPN-101 versus placebo at Week 24 (p = 0.034). TPN-101 also demonstrated lowering effects on additional biomarkers of neurodegeneration and neuroinflammation, including neurofilament heavy chain (NfH), interleukin 6 (IL-6), neopterin, and osteopontin.
Future Plans for TPN-101
"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, M.D., Chair of the Massachusetts General Hospital Department of Neurology. Dennis Podlesak, Chairman and Chief Executive Officer of Transposon, stated that the company plans to rapidly advance TPN-101 into a Phase 3 registration study for the treatment of C9-ALS, citing impactful benefits across multiple functional and biomarker measures. Transposon also intends to advance TPN-101 for the treatment of PSP, Alzheimer's disease and other neurodegenerative and autoimmune disorders.
