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 andInterim Results from a Phase 2 Study of TPN-101 for the Treatment of C9orf72-Related
Amyotrophic Lateral Sclerosis and/or Frontotemporal Dementia
TPN-101 is the first PSP treatment to reduce NfL and IL-6 levels, key biomarkers ofneurodegeneration and neuroinflammation in PSP
Participants treated with TPN-101 for the entire 48-week study in PSP showed astabilization of their clinical symptoms as measured by the PSPRSIn the Phase 2 study of C9orf72-related ALS/FTD, TPN-101 showed effects on key
biomarkers of neurodegeneration, neuroinflammation and microglial activation,including NfL, Tau, UCHL1, YKL-40 and osteopontin
TPN-101 also showed a clinical effect on Vital Capacity, an objective respiratory
measure that correlates with mortality in patients with ALS
Transposon plans to advance TPN-101 to a Phase 3 registration study for PSP andis expanding the development of TPN-101 into Alzheimer’s disease
SAN DIEGO, California, February 13, 2024 – Transposon Therapeutics, a biotechnology
company developing a platform of novel, orally administered therapies for the treatment ofneurodegenerative and aging-related diseases including Alzheimer’s disease, today announced
final results from its Phase 2 study of TPN-101 for the treatment of progressive supranuclear
palsy (PSP). The company also announced interim 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).
Transposon will present final results from its Phase 2 study in PSP in a poster presentation at thehybrid AD/PD™ 2024: 18th International Conference on Alzheimer’s and Parkinson’s Diseases.
The meeting will take place online and in Lisbon, Portugal, from March 5-9, 2024.
Final Phase 2 PSP Study Results
Final 48-week results from the Phase 2 study in PSP confirm and extend the 24-week interim
results that showed TPN-101 is the first treatment for PSP to reduce levels of neurofilament lightchain (NfL), a key biomarker of neurodegeneration in tauopathies such as PSP and Alzheimer’s
disease. Participants treated with placebo from weeks 1 to 24 and then switched to 400 mg TPN101 at week 24 experienced a reduction of NfL in the cerebrospinal fluid (CSF) from weeks 24
to 48 that was similar to that observed in the group of participants receiving the 400 mg dosefrom weeks 1 to 24. Participants treated with 400 mg TPN-101 for the entire 48-week treatment
period showed no increase of NfL levels in the CSF from weeks 1 to 48. In contrast, NfL levelsin the CSF are reported to increase by 9-18% annually in natural history studies of PSP.
1The 48-week results also showed further dose-related reductions in interleukin 6 (IL-6) cytokinelevels, as well as reductions in levels of osteopontin. IL-6 is a biomarker of neuroinflammationthat is elevated in PSP and correlates with disease progression and severity. Osteopontin levels
correlate with cognitive deficit in Alzheimer’s disease patients and lowering of osteopontin may
predict cognitive improvement.
Participants treated with TPN-101 for the entire 48-week trial duration showed a stabilization of
their clinical symptoms as measured by the PSP Rating Scale (PSPRS) between weeks 24 and48. In contrast, participants who had been on placebo from weeks 1 to 24 continued to show aworsening of the PSPRS between weeks 24 and 48, suggesting a delay of clinical benefit onsetof at least 24 weeks after start of drug treatment, and lagging behind the early effects onbiomarkers seen in weeks 1 to 24.
“There are no effective treatments for PSP, a uniformly fatal disease that is similarly prevalent toALS,” said Adam Boxer, M.D., Ph.D., Endowed Professor in Memory and Aging in theDepartment of Neurology at the University of California, San Francisco and principal
investigator in the Phase 2 study of TPN-101 for PSP. “The effects of TPN-101 on CSF NfL
concentrations, as well as other exploratory CSF biomarkers, have not previously been observedin any PSP trial and support further investigation of clinical treatment effects in a larger study.”Interim Phase 2 C9orf72-Related ALS/FTD Study Results
Results from the pre-defined interim analysis of the Phase 2 study in C9orf72-related ALS/FTD
demonstrated the impact of TPN-101 treatment on key biomarkers of neurodegeneration,neuroinflammation, and microglial activation including NfL, tau, UCHL1, YKL-40, andosteopontin from baseline to 24 weeks. The data also showed a clinical effect on Vital Capacity,
an objective respiratory measure that correlates with mortality in patients with ALS. Notably,C9orf72-related ALS/FTD is a TDP-43 protein pathology associated with nuclear displacementof TDP-43 in the central nervous system. TDP-43 pathology also occurs in about 50% ofpatients with Alzheimer’s disease.
“Transposon’s founding mission was to establish human proof-of-concept that dysregulation ofretrotransposable elements in neurodegenerative diseases such as PSP, ALS and Alzheimer’s
disease can be addressed with a new class of LINE-1 reverse transcriptase inhibitors,” statedEckard Weber, M.D., Founder and Chief Innovation Officer of Transposon. “The results
obtained with TPN-101 in both PSP and ALS/FTD show for the first time that neurodegenerative
diseases that involve LINE-1 dysregulation are treatable with a specific inhibitor of thisimportant novel target. We look forward to advancing the development of TPN-101 into
registration studies to address this devastating and rapidly growing disease category.”“Given the large unmet needs in PSP and ALS, these promising results highlight the therapeuticpotential of TPN-101 for both disorders,” added Murali Doraiswamy, MBBS, FRCP, Professorof Psychiatry and Geriatrics at Duke University and chair of Transposon’s clinical advisoryboard. “These data also provide key validation of targeting LINE-1 to treat other tauopathies
such as Alzheimer's disease.”2

“Based on the groundbreaking study results shown by TPN-101 in both PSP and ALS/FTD, weplan to rapidly advance TPN-101 into a Phase 3 registration study for the treatment of PSP, andpotentially ALS/FTD as well, pending final confirmatory study results,” said Dennis Podlesak,Chairman and Chief Executive Officer of Transposon. “Importantly, the totality of the results
across both studies also provides compelling scientific rationale for targeting LINE-1 to treat
Alzheimer’s disease. Based on these findings, we are expanding our development efforts into
Alzheimer’s disease with the goal of bringing a novel drug treatment to patients that remain indire need of an effective new therapeutic option.”
About AD/PD 2024
The hybrid AD/PD 2024: 18th International Conference on Alzheimer’s and Parkinson’s Diseases
will take place online and in Lisbon, Portugal, from March 5-9, 2024. Transposon will present
final results from its Phase 2 study in PSP in a poster presentation (abstract #433) at AD/PD
2024 entitled: “A Phase 2a Study of TPN-101, a Nucleoside Reverse Transcriptase Inhibitor, inPatients with Progressive Supranuclear Palsy.” For more information, please visit the AD/PD
2024 website.
About the Phase 2 Study in PSP
The Phase 2 study in PSP is a multi-center, randomized, double-blind, placebo-controlled,parallel-group, 4-arm study with an open-label treatment phase in patients with PSP.
Participants (n=42) were randomized to receive daily doses of 100 mg, 200 mg or 400 mg ofTPN-101, or placebo. The 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 posttreatment. All phases of the study, including the 24-week open label treatment period, have beencompleted. Further information on the study can be accessed at ClinicalTrials.gov.
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, 2-arm study with an open-label treatment phase in patientswith C9orf72-related ALS and/or FTD. Participants (n=42) were randomized to receive daily
doses of 400 mg of TPN-101 or placebo. Similar to the Phase 2 study in PSP, 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. The predefined interim analysis
was performed after all patients completed the 24-week double-blind portion of the study. The
open-label extension of the study is ongoing, with subjects and investigators blinded to theoriginal treatment assignment. Further information on the study can be accessed atClinicalTrials.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 capableof replicating and moving to new locations within the genome. When this process becomesdysregulated, LINE-1 reverse transcriptase drives overproduction of LINE-1 DNA, triggering

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innate immune responses that contribute to neurodegenerative, autoimmune and aging-relateddisease pathology.
About PSPPSP is a rare and fatal tauopathy with no approved treatment options. PSP mainly affects people
in their mid- to late-60s and is characterized by early postural instability and falls, vertical gazepalsy, akinesia, rigidity, pseudobulbar palsy, and frontal dysfunction with cognitive andbehavioral changes. The mean survival for individuals with PSP is 6 to 7 years.
About ALS and FTD
ALS is a neurodegenerative disease characterized by progressive muscle weakness, loss ofability to speak, eat, move or breathe. FTD is a progressive frontal / temporal cortex diseaseassociated 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 only 3 years. Patients with FTD have a mean survival of 9 years.
About Transposon
Transposon Therapeutics, Inc. is a clinical-stage biopharmaceutical company developing aplatform 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 toaddress additional indications. Dr. Doraiswamy chairs the company’s clinical advisory board
and has received compensation/stock options for his role.
Contact:
Rick Orr
Transposon Therapeutics, Inc.
(858) 535-4821
rorr@transposonrx.com

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