TPN-101 treatment reduced the rate of
decline of Vital Capacity by 50% compared to placebo after 24
weeks, an objective respiratory measure that correlates with
mortality in patients with ALS
Treatment with TPN-101 also showed a slowing
of ALS disease progression as measured by the ALSFRS-R global
clinical scale
TPN-101 had lowering effects on key biomarkers
of neurodegeneration and neuroinflammation, including NfL, NfH, and
IL-6
Meta-analysis of the combined patient
populations from the company's Phase 2 studies in C9orf72-related
ALS/FTD and PSP showed a statistically significant NfL-lowering
effect of TPN-101
Transposon plans to advance TPN-101 into a
Phase 3 registration study for C9orf72-related-ALS
SAN
DIEGO, July 24, 2024 /PRNewswire/ -- Transposon
Therapeutics, a biotechnology company developing a platform of
novel, orally administered therapies for the treatment of
neurodegenerative and aging-related diseases, including Alzheimer's
disease, today announced final results from its Phase 2 study of
TPN-101 in patients with amyotrophic lateral sclerosis (ALS) and/or
frontotemporal dementia (FTD) related to hexanucleotide repeat
expansion in the C9orf72 gene (C9orf72-related ALS/FTD). Final
results from this study confirmed the excellent safety profile of
TPN-101 and showed clinical signs of disease-modifying effects in
patients with these disorders, which align with previously reported
safety and therapeutic activity in patients with Progressive
Supranuclear Palsy (PSP). These findings are consistent with
TPN-101's reduction of neuroinflammation and neurodegeneration
through blocking the activity of LINE-1, a human-specific
retrotransposon that is no longer adequately suppressed in many
neurodegenerative disorders and aging.
ALS is a progressive and uniformly fatal
neurodegenerative disease with a mean survival of two-to-three
years. Respiratory failure is the most common cause of death for
people with ALS. Vital Capacity (VC) is an objective measure
of respiratory function that correlates with mortality in these
patients. After 24 weeks, C9-ALS participants treated with TPN-101
experienced approximately 50% less decline in VC compared to those
treated with placebo (LS mean change -8.4% vs -16.5%). When
the participants in the placebo group were switched to TPN-101
during the open-label period, the decline in VC over the following
24 weeks (-7.2%) was less than half that while on placebo and
comparable to that in the original TPN-101 group during the
double-blind period. Overall, the 48-week changes in both groups
were lower than expected based on natural history in similar study
populations.
The decline on the Revised ALS Functional Rating
Scale (ALSFRS-R) was comparable between the TPN-101 and placebo
groups during the 24-week double-blind period (LS mean -7.2 points
vs -6.7). However, during the 24-week open-label extension
period, the decline on the ALSFRS-R in the original TPN-101
group was less than half that during the initial 24-week period and
less than half that of the placebo group during both study periods.
The decline in ALSFRS-R in the original TPN-101 group over the
entire 48 weeks was approximately 40% less than expected based on
natural history data, indicating a global clinical benefit with
longer treatment.
"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, M.D., Chair of the Massachusetts
General Hospital Department of Neurology, Julieanne Dorn Professor
of Neurology at Harvard Medical School,
and principal investigator in the Phase 2 study of TPN-101 for
C9orf72-related ALS/FTD. "I look forward to advancing the
development of TPN-101 and what that could mean for people living
with C9-ALS."
In participants with C9-ALS, those treated with
TPN-101 had lower levels of neurofilament light chain (NfL)
compared with placebo at the end of the double-blind period. NfL is
the primary biomarker of neurodegeneration, and the NfL results at
both Weeks 24 and 48 are consistent with findings from the
company's Phase 2 study of TPN-101 for the treatment of PSP.
TPN-101 also had lowering effects on additional biomarkers
of neurodegeneration and neuroinflammation, including
neurofilament heavy chain (NfH), interleukin 6 (IL-6), neopterin,
and osteopontin.
A meta-analysis of the combined C9-ALS and PSP
populations from the two Phase 2 studies of TPN-101 showed a
statistically significant NfL-lowering effect of TPN-101 versus
placebo at Week 24 (p = 0.034). The consistency of biomarker
improvements in these two studies evaluating patients with
different clinical conditions supports the treatment hypothesis
that these diseases share a common LINE-1-related
pathophysiology.
"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," said Dennis Podlesak,
Chairman and Chief Executive Officer of Transposon. "In addition
to ALS, 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."
Transposon intends to present detailed data from
this study at upcoming scientific meetings.
About the Phase 2 Study in C9orf72-related
ALS/FTD
The Phase 2 study in C9orf72-related ALS/FTD is
multi-center, randomized, double-blind, placebo-controlled
parallel-group, two-arm study with an open-label treatment phase in
patients with C9orf72-related ALS and/or FTD. Participants (n=42)
were randomized to receive daily doses of 400 mg of TPN-101 or
placebo. The study includes a six-week screening period, a 24-week
double-blind treatment period, a 24-week open label treatment
period, and a follow-up visit four weeks post-treatment. All phases
of the study, including the 24-week open label treatment period,
have been completed. Further information on the study can be
accessed at ClinicalTrials.gov.
About TPN-101
TPN-101 specifically inhibits the LINE-1 reverse
transcriptase that promotes LINE-1 replication. LINE-1 elements are
a class of retrotransposable elements that in humans are
uniquely capable of replicating and moving to new locations within
the genome. When this process becomes dysregulated, LINE-1 reverse
transcriptase drives overproduction of LINE-1 DNA, triggering
innate immune responses that contribute to neurodegenerative,
autoimmune and aging-related disease pathology.
About ALS and FTD
ALS is a neurodegenerative disease characterized
by progressive muscle weakness, loss of ability to speak, eat, move
or breathe. FTD is a progressive frontal / temporal cortex disease
associated with behavior and personality changes, emotional
problems, and difficulty walking, communicating or working. With
onset commonly in middle age or earlier, patients with ALS have a
mean survival of two-to-three years. Patients with FTD have a mean
survival of nine years.
About Transposon
Transposon Therapeutics, Inc. is a clinical-stage
biopharmaceutical company developing a platform of novel therapies
for the treatment of neurodegenerative and aging-related diseases,
including Alzheimer's disease. The company's lead clinical
compound, TPN-101, is first-in-class to address LINE-1
reverse transcriptase for treating neurodegenerative and
autoimmune diseases. The company also has a discovery platform
supporting a deep pipeline of novel therapies to address additional
indications.
Contact:
Rick
Orr
Transposon Therapeutics, Inc.
(858) 535-4821
rorr@transposonrx.com
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SOURCE Transposon Therapeutics