Transposon Therapeutics’ TPN-101 for Progressive Supranuclear Palsy Gets Fast Tracked


The FDA granted fast track designation to TPN-101, an investigational therapy for progressive supranuclear palsy, based on promising phase 2a study results.

Dennis Podlesak  (Credit: Transposon)

Dennis Podlesak

(Credit: Transposon)

The FDA has granted Fast Track designation to Transposon Therapeutics’ TPN-101, an investigational therapy that inhibits the LINE-1 reverse transcriptase that promotes LINE-1 replication, for progressive supranuclear palsy (PSP), according to a recent announcement.1 The designation was supported by data from a phase 2a study (NCT04993768) assessing TPN-101 in patients with PSP.

In the trial, TPN-101 reduced levels of neurofilament light chain (NfL) and showed dose-related reductions in interleukin 6 (IL-6) cytokine levels as well as osteopontin levels at 48 weeks. Patients who switched to 400-mg TPN-101 from placebo reported a reduction of NfL in the cerebrospinal fluid (CSF) from weeks 24 to 48 similar to that observed in the patients who received the 400-mg dose from weeks 1 to 24. Those treated with 400-mg TPN-101 for the entire 48-week treatment period had no increase of NfL levels in the CSF from weeks 1 to 48.2

"Fast track designation for TPN-101 is an important acknowledgement by the FDA of the critical need to find an effective treatment for PSP, a rare and devastating neurological disorder with no approved treatment options," Dennis Podlesak, chairman and chief executive officer at Transposon, said in a statement.1 "We look forward to working collaboratively with the FDA to advance the development of TPN-101 as rapidly as possible for the treatment of PSP and other neurodegenerative diseases including ALS and Alzheimer disease."

The phase 2 study is a multicenter, randomized, double-blind, placebo-controlled, parallel-group, 4-arm trial with an open-label treatment phase among patients with PSP. Investigators randomly assigned participants (n = 42) to receive daily doses of 100 mg, 200 mg, or 400 mg of TPN-101, or placebo. The trial included a 6-week screening period, a 24-week double-blind treatment period, a 24-week open label treatment period, and a follow-up visit 4 weeks post-treatment. The company noted that they have completed all phases of the study, including the 24-week, open-label treatment period.

Top Clinical Takeaways

  • TPN-101 has shown promising results in reducing neurofilament light chain (NfL) and interleukin 6 (IL-6) levels in patients with progressive supranuclear palsy (PSP).
  • The fast track designation by the FDA highlights the urgent need for effective treatments for PSP, a rare neurodegenerative disease with no approved therapies.
  • Clinical symptom stabilization observed in patients treated with TPN-101 suggests a delay in clinical benefit onset, underscoring the importance of continued long-term treatment.

READ MORE: FDA Grants Fast Track Designation to PET Tau Tracer APN1607 for Progressive Supranuclear Palsy

Presented at the 2024 International Conference on Alzheimer’s and Parkinson’s Disease (AD/PD), held March 5-9 in Lisbon, Portugal, patients treated with TPN-101 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 48.2 In contrast, the participants on placebo from weeks 1 to 24 continued to show a worsening of the PSPRS between weeks 24 and 48. The company noted that these findings suggest a delay of clinical benefit onset of at least 24 weeks following the start of treatment, and lagging behind the early effects on biomarkers observed in weeks 1 to 24.

"There are no effective treatments for PSP, a uniformly fatal disease that is similarly prevalent to ALS," principal investigator Adam Boxer, MD, PhD, endowed professor in memory and aging in the department of neurology at the University of California, San Francisco, said in a statement.2 "The effects of TPN-101 on CSF NfL concentrations, as well as other exploratory CSF biomarkers, have not previously been observed in any PSP trial and support further investigation of clinical treatment effects in a larger study."

In the study's predefined interim analysis, TPN-101 showed an 18.4% reduction in NfL levels in CSF as compared with placebo at 24 weeks. In the same treatment group, TPN-101 also showed a 51.6% reduction in IL-6 levels in CSF as compared with placebo at 24 weeks. The company noted that once-daily oral dosing of TPN-101 was well-tolerated at all dose levels among participants.3

"No previously tested drug has shown an effect on NfL levels in patients with PSP, a progressive neurological disorder with no approved treatment options to stop or even slow progression of the disease," Andrew Satlin, MD, chief medical officer at Transposon, said in a statement.3 "The lowering of CSF NfL levels seen in this interim analysis provides biomarker evidence of a treatment effect on neurodegeneration. We are excited about the potential of TPN-101 as a much-needed treatment option for patients with PSP. In addition, we believe these findings open the door to an entirely new therapeutic approach to treating Alzheimer and other neurodegenerative diseases."

1. Transposon Receives US FDA Fast Track Designation for TPN-101 for Progressive Supranuclear Palsy. News Release. Transposon Therapeutics. Published May 21, 2024. Accessed May 24, 2024.
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 May 24, 2024.
3. Transposon Announces Interim Results from a Phase 2 Study of TPN-101 for the Treatment of Progressive Supranuclear Palsy to be Presented at the AD/PD™ 2024 International Conference on Alzheimer's and Parkinson's Diseases. News Release. Transposon Therapeutics. Published November 14, 2023. Accessed May 24, 2024.
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