Phase 2 Study Results of TPN-101 for C9orf72-Related ALS and/or FTD

SAN DIEGO, July 24, 2024 - Transposon Therapeutics, a biopharma firm focused on developing innovative oral treatments for neurodegenerative and age-related diseases such as Alzheimer's, has revealed conclusive findings from its Phase 2 trial of TPN-101. The study targeted patients suffering from amyotrophic lateral sclerosis (ALS) and/or frontotemporal dementia (FTD) linked to hexanucleotide repeat expansion in the C9orf72 gene (C9orf72-related ALS/FTD). Results affirmed TPN-101's stellar safety profile and indicated potential disease-modifying benefits, consistent with earlier findings in Progressive Supranuclear Palsy (PSP) patients. These outcomes are attributed to TPN-101's ability to reduce neuroinflammation and neurodegeneration by inhibiting the activity of LINE-1, a retrotransposon typically repressed in healthy individuals but active in many neurodegenerative disorders.

ALS is a severe, inevitably fatal neurodegenerative illness characterized by a mean survival period of two to three years, with respiratory failure being the primary cause of death. Vital Capacity (VC), an indicator of respiratory health, correlates with mortality in ALS patients. In the 24-week trial, participants with C9-ALS treated with TPN-101 showed roughly a 50% slower decline in VC compared to those on placebo (-8.4% vs -16.5%). When placebo group members switched to TPN-101 during an open-label phase, their VC decline over the subsequent 24 weeks (-7.2%) was comparable to the initial TPN-101 group and much lower than while on placebo. Overall, the 48-week VC decline in both groups was less than anticipated, based on historical data.

Evaluation through the Revised ALS Functional Rating Scale (ALSFRS-R) revealed similar declines between TPN-101 and placebo groups during the initial 24 weeks (-7.2 points vs -6.7). Yet, during the open-label extension, the TPN-101 group's decline was less than half of their initial 24-week period and significantly lower than that of the placebo group. Over 48 weeks, the TPN-101 group's ALSFRS-R decline was approximately 40% less than expected, suggesting a broad clinical benefit from extended treatment.

Dr. Merit Cudkowicz, Chair of Neurology at Massachusetts General Hospital and principal investigator of the Phase 2 trial for C9orf72-related ALS/FTD, expressed optimism about the study's results. "The effects of TPN-101 across multiple endpoints are promising and signify a crucial advancement towards a potential treatment for this serious condition," she said, emphasizing the importance of further development.

Participants with C9-ALS treated with TPN-101 exhibited lower levels of neurofilament light chain (NfL), a key marker of neurodegeneration, compared to the placebo group at the study's conclusion. These NfL results at both 24 and 48 weeks align with previous outcomes from the company's PSP Phase 2 study. Additional biomarkers such as neurofilament heavy chain (NfH), interleukin 6 (IL-6), neopterin, and osteopontin also showed reductions, indicating TPN-101's broader impact on neurodegeneration and neuroinflammation.

A meta-analysis combining data from the C9-ALS and PSP Phase 2 studies demonstrated a statistically significant NfL-lowering effect of TPN-101 at Week 24. The consistency of these biomarker improvements across different conditions underscores the theory that these diseases share a common LINE-1-related pathology.

Dennis Podlesak, CEO of Transposon, expressed enthusiasm about the findings. "Given the limited treatment options for ALS and the significant benefits shown by TPN-101, we are eager to advance it to a Phase 3 registration study for C9-ALS treatment," he stated. He also highlighted the company's commitment to exploring TPN-101's potential for PSP, Alzheimer's, and other neurodegenerative and autoimmune disorders.

Transposon Therapeutics plans to present detailed study data at future scientific conferences.

The Phase 2 study in C9orf72-related ALS/FTD was a multicenter, randomized, double-blind, placebo-controlled trial featuring an open-label phase. Participants were randomly assigned to receive either 400 mg of TPN-101 or a placebo daily. The study included a six-week screening period, a 24-week double-blind phase, a 24-week open-label phase, and a follow-up visit four weeks post-treatment.

Transposon Therapeutics, Inc. is dedicated to developing groundbreaking therapies for neurodegenerative and age-related diseases. Their leading compound, TPN-101, uniquely targets LINE-1 reverse transcriptase, providing a novel approach to treating neurodegenerative and autoimmune conditions.