TPN-101 improves ALS/FTD caused by C9orf72 gene mutations

Transposon Therapeutics plans Phase 3 trial for PSP; hopes for one for ALS/FTD

Andrea Lobo, PhD avatar

by Andrea Lobo, PhD |

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TPN-101, an investigational oral molecule developed by Transposon Therapeutics, reduced multiple biomarkers of neuroinflammation and neurodegeneration, and slowed respiratory decline in some people with amyotrophic lateral sclerosis (ALS) and/or frontotemporal dementia (FTD).

That’s according to an interim analysis of a Phase 2a clinical trial (NCT04993755) that’s testing TPN-101 in people with ALS/FTD caused by C9orf72 gene mutations. The analysis was conducted after all the patients completed the six-month randomized period.

The treatment also showed meaningful benefits in biomarker and clinical outcomes in a completed Phase 2a trial (NCT04993768) in people with progressive supranuclear palsy (PSP), a progressive condition that results from damage in brain areas that control body movements, coordination, or cognitive functions.

Researchers plan to advance TPN-101 to a Phase 3 study that might support its approval in PSP. Pending positive final results from the ALS/FTD trial, a Phase 3 trial might also launch for this indication.

“Based on the groundbreaking study results shown by TPN-101 in both PSP and ALS/FTD, we plan to rapidly advance TPN-101 into a Phase 3 registration study for the treatment of PSP, and potentially ALS/FTD as well, pending final confirmatory study results,” Dennis Podlesak, chairman and CEO of Transposon, said in a company press release.

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Gene Therapy Lowers Toxic RNA Due to C9ORF72 Mutations in ALS

How does TPN-101 work in ALS. FTD?

In ALS and FTD, the toxic accumulation of certain proteins outside the nucleus is believed to cause the activation of certain transposable elements — pieces of viral DNA incorporated in human DNA thousands of years ago that are able to jump around to different regions in the genome.

These transposable elements aren’t normally active in healthy adult cells. When activated, they can lead to major genetic disruption, which triggers an antiviral immune response in cells that can ultimately result in nerve cell death.

TPN-101, known as censavudine, is designed to inhibit the LINE-1 reverse transcriptase, an enzyme involved in activating transposable elements, which should ease inflammation and neurodegeneration in ALS/FTD. As this enzyme is more active in people carrying C9orf72 mutations, the most common genetic cause of both ALS and FTD, TPN-101 is believed to be helpful to them.

The ongoing Phase 2a trial was initiated in 2021 to evaluate TPN-101’s safety and efficacy in 42 adults with C9orf72-associated ALS/FTD.

The participants were first randomly assigned to receive 400 mg TPN-101 or a placebo, once daily for 24 weeks, or about six months. They were then able to transition to the trial’s open-label part, where all are receiving TPN-101 for another 24 weeks.

The trial’s main goal is to see if the therapy is safe and well tolerated. Secondary goals include measures of TPN-101’s pharmacological properties, along with changes in biomarker levels and in disease progression.

Results from the predefined interim analysis demonstrated TPN-101 exerted an impact on key biomarkers of neurodegeneration, neuroinflammation, and microglial activation over the first 24 weeks. Microglia are the brain’s resident immune cells and are thought to participate in the inflammation that drives ALS.

The therapy also had an effect on vital capacity, a measure of respiratory function that correlates with mortality in ALS patients, according to the company.

“Transposon’s founding mission was to establish human proof-of-concept that dysregulation of retrotransposable elements in neurodegenerative diseases such as PSP, ALS and Alzheimer’s disease can be addressed with a new class of LINE-1 reverse transcriptase inhibitors,” said Eckard Weber, MD, Transposon’s founder and chief innovation officer. “The results obtained with TPN-101 … show for the first time that neurodegenerative diseases that involve LINE-1 dysregulation are treatable with a specific inhibitor of this important novel target.”