A Phase 2a Study of TPN-101 in Patients With C9ORF72 ALS/FTD

A Phase 2a Study of TPN-101 in Patients With Amyotrophic Lateral Sclerosis (ALS) and/or Frontotemporal Dementia (FTD) Associated With Hexanucleotide Repeat Expansion in the C9orf72 Gene (C9ORF72 ALS/FTD)

This is a Phase 2a study to assess the the safety and tolerability of TPN-101 in patients with Amyotrophic Lateral Sclerosis (ALS) and/or Frontotemporal Dementia (FTD) Associated with Hexanucleotide Repeat Expansion in the C9orf72 gene (C9ORF72 ALS/FTD).

Study Overview

• Status: Completed
• Conditions: Amyotrophic Lateral Sclerosis; Frontotemporal Dementia
• Intervention / Treatment: Drug: TPN-101, 400 mg/day; Drug: Placebo

Detailed Description

This is a Phase 2a multi-center, randomized, double-blind, placebo-controlled parallel-group, 2-arm study with a long-term, open-label treatment phase in patients with C9ORF72 ALS and/or FTD. This study includes 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.

• Study Type: Interventional
• Enrollment (Actual): 42
• Phase: Phase 2

Contacts and Locations

Study Locations

• Belgium
  • Flemish Brabankt
    • Leuven, Flemish Brabankt, Belgium, 3000
      • VIB-KU Leuven Center for Brain & Disease Research
• France
  • Lille, France, 59037
    • CHU Lille - CMRR Hôpital Roger Salengro
  • Limoges, France, 87042
    • CHU Dupuytren, Limoges
  • Paris, France, 75013
    • Groupe Hospitalier Pitie-Salpetriere - La Federation de Maladies du Systeme Nerveux
• Germany
  • Baden-Wurttemberg
    • Ulm, Baden-Wurttemberg, Germany, 89081
      • Universitaetsklinikum Ulm - Klinik fuer Neurologie
• Spain
  • Barcelona, Spain, 08025
    • Hospital De La Santa Creu I Sant Pau
  • Barcelona, Spain, 08035ES
    • Hospital Universitario Vall d'Hebron
  • Valencia, Spain, 46026
    • Hospital Universitari i Politècnic La Fe
  • A Coruña
    • Santiago de Compostela, A Coruña, Spain, 15706ES
      • Complejo Hospitalario Universitario de Santiago (CHUS)
• United States
  • California
    • La Jolla, California, United States, 92037
      • University of California San Diego
    • Orange, California, United States, 92868
      • University of California Irvine - ALS & Neuromuscular Center
    • San Francisco, California, United States, 94158
      • UCSF Neurosciences Clinical Research Unit (NCRU)
  • Maryland
    • Baltimore, Maryland, United States, 21287
      • John Hopkins University
    • Baltimore, Maryland, United States, 21287
      • Johns Hopkins Outpatient Center
  • Massachusetts
    • Boston, Massachusetts, United States, 02114
      • Massachusetts General Hospital (MGH) - Amyotrophic Lateral Sclerosis (ALS) Multidisciplinary Clinic
  • Minnesota
    • Rochester, Minnesota, United States, 55905
      • Mayo Family Clinic Northwest
  • New York
    • New York, New York, United States, 10021
      • Hospital for Special Surgery
    • New York, New York, United States, 10032
      • Columbia University Medical Center - The Neurological Institute of New York
  • North Carolina
    • Chapel Hill, North Carolina, United States, 27599
      • The University of North Carolina at Chapel Hill, Department of Neurology

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Documentation of a clinical genetic test demonstrating a hexanucleotide repeat expansion (HRE) in the C9orf72 gene
• Has a reliable caregiver/informant to accompany the patient to all study visits

For patients with ALS (with or without FTD):

• Diagnosis of ALS (probable, possible, laboratory-supported probable or definite) according to the World Federation of Neurology revised E1 Escorial criteria
• Onset of weakness within 3 years prior to Screening
• Slow vital capacity (SVC) ≥ 60% of predicted normal adjusted for sex, age, and height (from the sitting position)
• Able to perform reproducible pulmonary function tests.
• ALS Functional Rating Scale-Revised (ALSFRS-R) ≥ 30 and score of 3 or 4 on Item #3 (swallowing) at Screening

For patients with FTD:

• A gradual, progressive decline in behavior, language, or motor function consistent with mild cognitive impairment, mild behavioral impairment, mild cognitive/behavioral impairment, behavioral variant FTD, primary progressive aphasia, or amnestic syndrome
• CDR Dementia Staging Instrument plus National Alzheimer's Coordinating Center Behavior and Language Domains (CDR plus NACC FTLD) global score of 0.5-2.0 at Screening

Exclusion Criteria:

• Presence of other significant neurological or psychiatric disorders
• History of clinically significant brain abnormality
• Clinically significant medical illness
• Tracheostomy or diaphragmatic pacing
• Autoimmune disease requiring treatment or management (quiescent rheumatoid arthritis, psoriasis, or controlled Type 1 diabetes are acceptable)
• History of human immunodeficiency virus (HIV) or hepatitis B infection, or any active infection during Screening, unless the patient will have been symptom-free for at least 30 days prior to randomization

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Double

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Placebo Comparator: Placebo	Drug: Placebo; Placebo once daily for 24 weeks (double-blind treatment) followed by 400 mg/day TPN-101 for 24 weeks (open-label treatment).
Experimental: TPN-101, 400 mg/day	Drug: TPN-101, 400 mg/day; 400 mg/day of study investigational drug TPN-101 once daily for 24 weeks (double-blind treatment) followed by 400 mg/day TPN-101 for 24 weeks (open-label treatment).

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Assess the safety and tolerability of TPN-101 in patients with C9ORF72 amyotrophic lateral sclerosis (ALS)/frontotemporal dementia (FTD)	Incidence and severity of spontaneously reported treatment-emergent adverse events (TEAEs) associated with TPN-101 v. placebo administered for up to 48 weeks in patients with C9ORF72 ALS/FTD	48 weeks

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Assess the pharmacokinetics of TPN-101 as measured by concentrations of TPN-101 in plasma and cerebrospinal fluid (CSF)		48 weeks
Assess the pharmacodynamic effect of TPN-101 on neurodegeneration as measured by changes in the levels of CSF and blood neurofilament light (NfL)		48 weeks
Assess the clinical effect of TPN-101 as measured by changes in score on the Amyotrophic Lateral Sclerosis Functional Rating Scale-Revised (ALSFRS-R)	The ALSFRS-R measures speech, salivation, swallowing, handwriting, cutting food and handling utensils (with or without gastrostomy), dressing and hygiene, turning in bed and adjusting bed clothes, walking, climbing, stairs, and breathing. Scores range from 0 to 40, with higher scores indicating that more function is retained.	48 weeks

Collaborators and Investigators

• Sponsor: Transposon Therapeutics, Inc.

Publications and helpful links

General Publications

• Nicodemus J, Liu CS, Ransom L, Tan V, Romanow W, Jimenez N, Chun J. Sequence Diversity and Encoded Enzymatic Differences of Monocistronic L1 ORF2 mRNA Variants in the Aged Normal and Alzheimer's Disease Brain. J Neurosci. 2025 Jun 18;45(25):e2298242025. doi: 10.1523/JNEUROSCI.2298-24.2025.

Study record dates

Study Major Dates

• Study Start (Actual): October 1, 2021
• Primary Completion (Actual): August 17, 2023
• Study Completion (Actual): September 1, 2023

Study Registration Dates

• First Submitted: July 19, 2021
• First Submitted That Met QC Criteria: July 29, 2021
• First Posted (Actual): August 6, 2021

Study Record Updates

• Last Update Posted (Actual): April 3, 2026
• Last Update Submitted That Met QC Criteria: April 2, 2026
• Last Verified: April 1, 2026

More Information

Terms related to this study

• Keywords: ALS; FTD
• Additional Relevant MeSH Terms: Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Mental Disorders; Neuromuscular Diseases; Metabolic Diseases; Neurocognitive Disorders; Dementia; Neurodegenerative Diseases; Spinal Cord Diseases; TDP-43 Proteinopathies; Proteostasis Deficiencies; Motor Neuron Disease; Frontotemporal Lobar Degeneration; Nutritional and Metabolic Diseases; Amyotrophic Lateral Sclerosis; Frontotemporal Dementia
• Other Study ID Numbers: TPN-101-C9-201

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No