Biotechnology company Transposon Therapeutics presented the results from its successful phase 2 clinical trial of its experimental medication for ALS/FTD at the 35^th International Symposium on ALS/MND. The trial of the drug TPN-101 concluded in July, with the company sharing its data at conferences as it prepares for the next phase of clinical testing.

ALS Trial Participants Showed Improvement in Key Measures

While proteins are common biological targets for experimental medicine for FTD, ALS, and other neurodegenerative diseases, TPN-101 instead targets genetic elements known as “retrotransposons.” Retrotransposons are unique in that they are capable of moving or self-replicating within a genome through a process known as “reverse transcription,” which can damage cells if unregulated. Proteins associated with diseases like FTD can lead to dysregulation of a type of retrotransposon known as LINE-1, contributing to neurodegeneration in diseases like ALS-FTD disorders or progressive supranuclear palsy (PSP).

TPN-101 works by inhibiting LINE-1 elements’ capability to carry out reverse transcription, which the company hopes will have a disease-modifying effect on people with neurodegenerative diseases. According to the company’s original announcement in July, TPN-101 showed signs of the desired disease-modifying effects in people with ALS or FTD with a C9orf72 genetic mutation.

In reviewing efficacy in people with ALS, the researchers relied on screening tools and measures such as:

• Vital capacity (VC): A measurement of the amount of air that can be exhaled from the lungs after maximum inhalation.
• ALS Functional Rating Scale, Revised (ALSFRS-R): A questionnaire that measures the physical functioning and the progression of symptoms for people with ALS.
• Neurofilament light chain (NfL): A protein fragment that acts as a biomarker for damage to neuron components.

The study operated at first using the “double-blind” method, where half of the participants received an active drug and the remainder received a placebo, before transitioning to an “open-label extension,” where all participants received TPN-101. The researchers recorded promising results across all three measures:

• VC: Participants who received TPN-101 during the double-blind stage experienced approximately 50% less decline in vital capacity than people who were treated with a placebo: -8.4% vs. -16.5%
• ALSFRS-R: During the double-blind period, ALSFRS-R scales were roughly the same between the placebo and drug cohorts. However, during the open-label phase, the group that originally received TPN-101 experienced less decline than the placebo group during the double-blind period, hinting at the drug’s effectiveness over the long term.
• NfL: Participants who received TPN-101 had lower levels of NfL than those who received the placebo during the double-blind period.

In addition to positive data across the three measures noted above, researchers noted that TPN-101 also lowered certain biomarkers of neurodegeneration and neuroinflammation, such as neurofilament heavy chain and osteopontin.

“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 Massachusetts General Hospital Department of Neurology Chair Merit Cudkowicz, MD, principal investigator of the study. “I look forward to advancing the development of TPN-101 and what that could mean for people living with C9-ALS.”

While the data from participants with C9-FTD has not been released yet, the positive results from people with C9-ALS can provide insights into the efficacy of TPN-101 for FTD.

ALS-FTD Data Consistent with Data from PSP Study

The data from the ALS/FTD trial is consistent with the data from the company’s other trial evaluating TPN-101 in people with PSP. The trial, which released final results in February, showed that the drug similarly reduced levels of key biomarkers like NfL and osteopontin. An analysis of the results of both trial groups at week 24 showed a statistically significant decrease of NfL levels compared to the placebo groups.

The success of TPN-101 in these phase 2 trials not only reflects the drug’s promise but also highlights that ALS/FTD and PSP share a common LINE-1 pathophysiology. Recognizing this overlap, Transposon chairman and CEO Dennis Podlesak noted that the company would continue exploring the drug’s use in other diseases.

“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,” said Podlesak. “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”

Companies like Transposon are working to explore potential interventions and diagnostic tools for FTD. Recently, South Korean company GemVax & KAEL announced the results from its phase 2a clinical trial evaluating a drug for PSP.

Do you want to get involved in FTD research? Clinical trials are just one of the ways you can help scientists bring the world closer to an FTD-free future. Visit AFTD’s Studies Seeking Participants page to learn more.