TPN-101 shows long-term benefits in C9orf72-related ALS in trial
Oral therapy seen to safely slow disease progression with 1 year’s treatment
Nearly a year of treatment with TPN-101, an investigational oral molecule from Transposon Therapeutics, safely slowed disease progression and lung function decline in people with amyotrophic lateral sclerosis (ALS) related to C9orf72 mutations.
That’s according to final data from a Phase 2a study (NCT04993755) that tested TPN-101 against a placebo in 42 adults with C9orf72-related ALS (C9-ALS) and/or frontotemporal dementia (FTD).
Participants who received TPN-101 also had greater reductions in markers of nerve damage, the data showed. Overall, the findings support the company’s plans to advance the treatment candidate into a Phase 3 trial that may support TPN-101’s approval for C9orf72-related ALS, or simply C9-ALS, Transposon stated in a press release.
“Patients treated with TPN-101 experience impactful benefits across multiple functional and biomarker measures,” said Dennis Podlesak, Transposon’s CEO. “We plan to rapidly advance TPN-101 into a Phase 3 registration study for the treatment of C9-ALS.”
TPN-101 tested in 42 adults with ALS related to C9orf72 mutations
ALS and the related condition FTD — a group of brain diseases that mainly affect brain areas associated with personality, behavior, and language — are marked by the presence of abnormal protein deposits, which cause retrotransposons like LINE-1 to become active. Retrotransposons are pieces of genetic material, mostly remnants of viral DNA that got incorporated into the human genome during evolution, that normally stay silent due to tight regulation.
When activated, retrotransposons produce DNA products that the cell processes as if they were viruses. This triggers a heightened immune response that leads to inflammation and neurodegeneration, contributing to the progression of ALS and FTD.
TPN-101 is designed to block the LINE-1 reverse transcriptase enzyme that helps activate those DNA products. By doing so, TPN-101 is expected to stop the immune response and protect nerve cells from damage, slowing disease progression.
The therapy is believed to be particularly helpful in people with C9orf72 mutations, who generally have a more active LINE-1 reverse transcriptase enzyme.
The now-completed Phase 2a clinical trial was designed to assess the safety and early signs of efficacy in people with ALS and/or FTD who carried those mutations. Participants were first given daily 400 mg TNP-101 or a placebo for 24 weeks, or about six months, followed by an open-label extension in which all received TPN-101 for an additional 24 weeks.
An analysis conducted after all patients had completed the initial six-month period showed that TPN-101 reduced key biomarkers of neurodegeneration and neuroinflammation, and also slowed respiratory function decline, compared with the placebo.
Respiratory function was assessed with a measure called vital capacity, which examines the maximum amount of air that’s exhaled after a full breath inhalation. As a person’s muscles get weaker, the amount of air that can be exhaled decreases, and this is an important predictor of survival in ALS patients.
Transposon now shared data from the trial’s full year. In the randomized part, patients on TPN-101 experienced 50% less decline in vital capacity than did those on the placebo (8.4% vs. 16.5%). Further, when participants on the placebo started on TPN-101 in the open-label period, their decline (7.2%) became similar to the group who had started on the active treatment.
Importantly, in both groups, lung function decline over the total 48 weeks was less than expected for the natural course of the disease.
Benefits seen vs. declines expected based on natural history
Over the study’s first six months, no differences were seen between groups in disease progression rates, as measured by the ALS Functional Rating Scale-Revised (ALSFRS-R). However, over the next six months, those who were always on TPN-101 progressed about twice as slowly as did the placebo group in any treatment period.
During the entire 48 weeks, functional decline slowed by about 40% in TPN-101-treated patients than would be expected based on natural history data, suggesting long-term benefits.
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.
One year of treatment with TPN-101 also resulted in lower levels of neurofilament light chain, a biomarker of nerve cell damage, as well as reductions in other biomarkers of inflammation and neurodegeneration, compared with the placebo.
“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, principal investigator in the Phase 2 study.
“I look forward to advancing the development of TPN-101 and what that could mean for people living with C9-ALS,” said Cudkowicz, who chairs the Massachusetts General Hospital Department of Neurology at Harvard Medical School in Boston.
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