TPN-101 Demonstrates Disease-Modifying Effects on C9orf72-Related ALS/FTD

Merit Cudkowicz, MD

Newly announced data from a phase 2 study (NCT04993755) of patients with amyotrophic lateral sclerosis (ALS) and/or frontotemporal dementia (FTD) related to hexanucleotide repeat expansion in the C9orf72 gene (C9orf72-related ALS/FTD) showed that treatment with investigational TPN-101 was safe, with slowed decline in disease progression. TPN-101, an agent that specifically inhibits the LINE-1 reverse transcriptase that promotes LINE-1 replication, resulted in lowering of neurofilament light and improvements in vital capacity (VC), a measure of respiratory function.¹

The randomized, placebo-controlled, parallel-group, 2-arm study included 42 participants who were randomly assigned to receive 400 mg of TPN-101 or placebo for a 24-week double-blind period, followed by a 24-week open-label extension (OLE). Results showed that the decline in ALS Functional Rating Scale-Revised (ALSFRS-R) was comparable between active (least square [LS] mean, –7.2) and placebo (–6.7) groups during the double-blind period; however, during the OLE, the decline in the original TPN-101 group was less than half that during the initial 24-week period and less than half of the placebo group during both study periods.

For those who continued on TPN-101 through the entire 48 weeks, results showed a 40% less decline in ALSFRS-R in comparison with natural history data, indicating a global clinical benefit with longer treatment. In addition, over the 48-week period, changes in VC in both those who continued TPN-101 and those who crossed over were lower than expected based on natural history in similar study populations.

"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,” principal investigator Merit Cudkowicz, MD, professor of neurology at Harvard Medical School and chair of the department of neurology at Massachusetts General Hospital, said in a statement.¹ "I look forward to advancing the development of TPN-101 and what that could mean for people living with C9-ALS."

TPN-101, the most potent known inhibitor of LINE-1 reverse transcriptase, is also in development for other conditions including progressive supranuclear palsy (PSP) and Aicardi goutieres syndrome. LINE-1 elements are a class of retrotransposable elements that in humans are capable of replicating and moving to new locations within the genome. According to the company, when this process becomes dysregulated, LINE-1 reverse transcriptase drives over production of LINE-1 DNA, triggering innate immune responses that contribute to neurodegenerative, autoimmune, and aging-related disease pathology.

After 24 weeks, data showed that patients with C9-ALS treated with TPN-101 showed a 50% less decline in VC compared with placebo (LS mean change, –8.4% vs –16.5%). Participants who switched from placebo to TPN-101 during the OLE showed a decline in VC over the following 24 weeks (–7.2%) that was less than half that while on placebo and comparable to that in the original TPN-101 group during the double-blind period.

At the end of the 24-week double-blind period, TPN-101-treated patients demonstrated lowered levels of several biomarkers, including NfL, neurofilament heavy chain, interleukin-6, neopterin, and osteopontin. The changes in NfL at weeks 24 and 48 were consistent with a phase 2 study of TPN-101 in PSP, which had data released earlier this year. In that trial (NCT04993768), treatment with TPN-101 in patients with PSP resulted in a 18.4% reduction in NfL levels in cerebrospinal fluid (CSF) as compared with placebo at 24 weeks. Additionally, the agent showed a 51.6% reduction in interleukin-6 levels in CSF as compared with placebo at 24 weeks.

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A meta-analysis of the combined C9-ALS and PSP populations from the 2 phase 2 studies revealed a significant NfL-lowering effect with TPN-101 over the 24 weeks (P = .034). Transposon noted that the consistency of biomarker improvements across both studies evaluating patients with different clinical conditions supports the treatment hypothesis that these diseases share a common LINE-1 related pathophysiology.

"Today there are very limited treatment options for ALS patients and based on these results that show patients treated with TPN-101 experience impactful benefits across multiple functional and biomarker measures, we plan to rapidly advance TPN-101 into a Phase 3 registration study for the treatment of C9-ALS,” Dennis Podlesak, chairmand and chief executive officer at Transposon, said in a statement.¹ "In addition to ALS, we are committed to advancing TPN-101 for the treatment of PSP, Alzheimer's disease and other neurodegenerative and autoimmune disorders with the goal of providing new and innovative therapies that can significantly improve the lives of those battling these devastating diseases."

The previously completed study of TPN-101 in PSP was a double-blind, placebo-controlled, parallel-group, 4-arm trial with an OLE. Patients (n = 42) were randomly assigned to receive doses of 100 mg, 200 mg, or 400 mg of TPN-101, or placebo. Presented at the 2024 International Conference on Alzheimer’s and Parkinson’s Disease, patients treated with the active agent for the entire 48-week trial duration also revealed a stabilization of clinical symptoms as measured by the PSP Rating Scale (PSPRS) between weeks 24 and 48. In contrast, the participants on placebo from weeks 1 to 24 continued to show a worsening of PSPRS between weeks 24 and 48.²

REFERENCES
1. Transposon Announces Final Results from a Phase 2 Study of TPN-101 for the Treatment of C9orf72-Related Amyotrophic Lateral Sclerosis and/or Frontotemporal Dementia. Transposon Therapeutics. July 24, 2024. Accessed August 1, 2024. https://www.prnewswire.com/news-releases/transposon-announces-final-results-from-a-phase-2-study-of-tpn-101-for-the-treatment-of-c9orf72-related-amyotrophic-lateral-sclerosis-andor-frontotemporal-dementia-302204851.html
2. Transposon Announces Final Results from a Phase 2 Study of its LINE-1 Reverse Transcriptase Inhibitor TPN-101 for the Treatment of Progressive Supranuclear Palsy and Interim Results from a Phase 2 Study of TPN-101 for the Treatment of C9orf72-Related Amyotrophic Lateral Sclerosis and/or Frontotemporal Dementia. News Release. Transposon Therapeutics. Published February 13, 2024. Accessed August 1, 2024. https://www.prnewswire.com/news-releases/transposon-announces-final-results-from-a-phase-2-study-of-its-line-1-reverse-transcriptase-inhibitor-tpn-101-for-the-treatment-of-progressive-supranuclear-palsy-and-interim-results-from-a-phase-2-study-of-tpn-101-for-the-treatmen-302060254.html