UCHL1

TPN-101 is the first PSP treatment to reduce NfL and IL-6 levels, key biomarkers of neurodegeneration and neuroinflammation in PSP Participants treated with TPN-101 for the entire 48-week study in PSP showed a stabilization of their clinical symptoms as measured by the PSPRS In 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 and is expanding the development of TPN-101 into Alzheimer's disease SAN DIEGO, Feb. 12, 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 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 the hybrid 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 light chain (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 TPN-101 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 dose from 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 levels in the CSF are reported to increase by 9-18% annually in natural history studies of PSP. The 48-week results also showed further dose-related reductions in interleukin 6 (IL-6) cytokine levels, as well as reductions in levels of osteopontin. IL-6 is a biomarker of neuroinflammation that 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 and 48. In contrast, participants who had been on placebo from weeks 1 to 24 continued to show a worsening of the PSPRS between weeks 24 and 48, suggesting a delay of clinical benefit onset of at least 24 weeks after start of drug treatment, and lagging behind the early effects on biomarkers seen in weeks 1 to 24. "There are no effective treatments for PSP, a uniformly fatal disease that is similarly prevalent to ALS," said Adam Boxer, M.D., Ph.D., Endowed Professor in Memory and Aging in the Department 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 observed in 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, and osteopontin 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 displacement of TDP-43 in the central nervous system. TDP-43 pathology also occurs in about 50% of patients with Alzheimer's disease. "Transposon's founding mission was to establish human proof-of-concept that dysregulation of retrotransposable 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," stated Eckard 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 this important 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 therapeutic potential of TPN-101 for both disorders," added Murali Doraiswamy, MBBS, FRCP, Professor of Psychiatry and Geriatrics at Duke University and chair of Transposon's clinical advisory board. "These data also provide key validation of targeting LINE-1 to treat other tauopathies such as Alzheimer's disease." "Based on the groundbreaking study results shown by TPN-101 in both PSP and ALS/FTD, we plan to rapidly advance TPN-101 into a Phase 3 registration study for the treatment of PSP, and potentially 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 in dire 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, in Patients 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 of TPN-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 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 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 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. 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 the original treatment assignment. 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 PSP PSP 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 gaze palsy, akinesia, rigidity, pseudobulbar palsy, and frontal dysfunction with cognitive and behavioral 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 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 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 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. 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 View original content to download multimedia: SOURCE Transposon Therapeutics

-- Analysis in The Journal of Neurology, Neurosurgery and Psychiatry demonstrate the direct effect of UPLIZNA on levels of sNFL and sGFAP, two key biomarkers strongly associated with NMOSD attacks and disability -- DUBLIN--(BUSINESS WIRE)-- Horizon Therapeutics plc (Nasdaq: HZNP) today announced the publication of new data from the Phase 3 N-MOmentum pivotal trial of UPLIZNA, which offer insights on serum biomarkers that signal acute attacks and disability worsening associated with NMOSD and illustrate the role of UPLIZNA in reducing these biomarker levels, potentially reducing the frequency and severity of these attacks. The results of this analysis are published in The Journal of Neurology, Neurosurgery and Psychiatry. NMOSD is most notably associated with acute attacks, which can cause irreversible damage to the optic nerve, spinal cord, brain and brain stem. Disease management goals are focused on prevention of attacks, as well as understanding and tracking biomarkers that could signal these attacks. The N-MOmentum pivotal trial of UPLIZNA, which demonstrated the effects of the treatment in reducing the attacks associated with NMOSD, included analyses of biomarkers linked to disease activity and neuronal injury: serum neurofilament light chain (sNfL, a structural protein increasingly recognized as a signal of neuronal injury), serum glial fibrillary acidic protein (sGFAP, a marker previously found to correlate with NMOSD attacks), ubiquitin C-terminal hydrolase L1 (sUCHL1), and tau (sTau). The trial identified important biomarker trends associated with NMOSD attacks. Throughout the 28-week randomized controlled trial period (RCP) and the two-year open-label follow-up period, the concentration of all four biomarkers increased during NMOSD attacks, and in the days leading up to attacks. Of the four biomarkers evaluated in the trial, sNfL measured at the time of attack was the strongest predictor of worsening disability during and after attacks (as measured by Expanded Disability Status Scale, or EDSS). The strong link suggests that higher sNfL levels may be associated with more severe attacks and increased risk of residual disability. However, only levels of sGFAP were determined to be predictive of future attacks, building upon prior research studying that biomarker in particular. “This analysis provides valuable insights into how we can improve care for people with NMOSD by integrating easily accessible serum biomarker assessments into treatment decision-making,” said Orhan Aktas, M.D., Professor at the Department of Neurology, Medical Faculty at Heinrich-Heine-University, Düsseldorf, Germany. “Conducting assessments of the sNfL biomarker during an attack can inform clinicians about the attack severity and the likelihood of residual disability in the patient, and therefore may guide therapeutic interventions to help preserve their long-term outcomes. Combination with other select serum biomarkers such as sGFAP may further increase prediction of clinical activity and, thus, prognosis in this devastating disorder.” Importantly, biomarker changes among UPLIZNA-treated participants in the trial reinforced the effects of this medicine. Compared with placebo, UPLIZNA was shown to hinder biomarker elevation during attacks while reducing biomarker levels over time in the absence of attacks. Participants treated with UPLIZNA had significantly lower levels of sNfL at the end of the RCP compared to placebo (22% vs. 45% of participants with sNfL levels above 16 mg/mL, respectively), and numerically lower levels of the other three biomarkers. Among patients who did experience attacks, those treated with UPLIZNA had lower biomarker levels during attacks versus those who received placebo, reflecting potentially less severe events, and sGFAP levels were significantly lower with UPLIZNA among those who did not experience attacks versus placebo. “These findings support the strong clinical pro UPLIZNA as a leading therapeutic option for NMOSD, with compelling evidence of its direct effects on critical biomarkers that signal disease activity and disability,” said Kristina Patterson, M.D., Ph.D., senior medical director, neuroimmunology medical affairs, Horizon. “The availability of these data in a rare and challenging disease like NMOSD can inform disease management strategies and contribute to improved outcomes for this population over time.” About Neuromyelitis Optica Spectrum Disorder (NMOSD) NMOSD is a unifying term for neuromyelitis optica (NMO) and related syndromes. NMOSD is a rare, severe, relapsing, neuroinflammatory autoimmune disease that attacks the optic nerve, spinal cord, brain and brain stem.1-2 Approximately 80% of all patients with NMOSD test positive for anti-AQP4 antibodies.3 AQP4-IgG binds primarily to astrocytes in the central nervous system and triggers an escalating immune response that results in lesion formation and astrocyte death.4 Anti-AQP4 autoantibodies are produced by plasmablasts and plasma cells. These B-cell populations are central to NMOSD disease pathogenesis, and a large proportion of these cells express CD19.5 Depletion of these CD19+ B cells is thought to remove an important contributor to inflammation, lesion formation and astrocyte damage. Clinically, this damage presents as an NMOSD attack, which can involve the optic nerve, spinal cord and brain.4-6 Loss of vision, paralysis, loss of sensation, bladder and bowel dysfunction, nerve pain and respiratory failure can all be manifestations of the disease.7 Each NMOSD attack can lead to further cumulative damage and disability.8-9 NMOSD occurs more commonly in women and may be more common in individuals of African and Asian descent.10-11 About UPLIZNA INDICATION UPLIZNA is indicated for the treatment of neuromyelitis optica spectrum disorder (NMOSD) in adult patients who are anti-aquaporin-4 (AQP4) antibody positive. IMPORTANT SAFETY INFORMATION UPLIZNA is contraindicated in patients with: A history of life-threatening infusion reaction to UPLIZNA Active hepatitis B infection Active or untreated latent tuberculosis WARNINGS AND PRECAUTIONS Infusion Reactions: UPLIZNA can cause infusion reactions, which can include headache, nausea, somnolence, dyspnea, fever, myalgia, rash or other symptoms. Infusion reactions were most common with the first infusion but were also observed during subsequent infusions. Administer pre-medication with a corticosteroid, an antihistamine and an anti-pyretic. Infections: The most common infections reported by UPLIZNA-treated patients in the randomized and open-label periods included urinary tract infection (20%), nasopharyngitis (13%), upper respiratory tract infection (8%) and influenza (7%). Delay UPLIZNA administration in patients with an active infection until the infection is resolved. Increased immunosuppressive effects are possible if combining UPLIZNA with another immunosuppressive therapy. The risk of Hepatitis B Virus (HBV) reactivation has been observed with other B-cell-depleting antibodies. Perform HBV screening in all patients before initiation of treatment with UPLIZNA. Do not administer to patients with active hepatitis. Although no confirmed cases of Progressive Multifocal Leukoencephalopathy (PML) were identified in UPLIZNA clinical trials, JC virus infection resulting in PML has been observed in patients treated with other B-cell-depleting antibodies and other therapies that affect immune competence. At the first sign or symptom suggestive of PML, withhold UPLIZNA and perform an appropriate diagnostic evaluation. Patients should be evaluated for tuberculosis risk factors and tested for latent infection prior to initiating UPLIZNA. Vaccination with live-attenuated or live vaccines is not recommended during treatment and after discontinuation, until B-cell repletion. Reduction in Immunoglobulins: There may be a progressive and prolonged hypogammaglobulinemia or decline in the levels of total and individual immunoglobulins such as immunoglobulins G and M (IgG and IgM) with continued UPLIZNA treatment. Monitor the level of immunoglobulins at the beginning, during, and after discontinuation of treatment with UPLIZNA until B-cell repletion especially in patients with opportunistic or recurrent infections. Fetal Risk: May cause fetal harm based on animal data. Advise females of reproductive potential of the potential risk to a fetus and to use an effective method of contraception during treatment and for 6 months after stopping UPLIZNA. Adverse Reactions: The most common adverse reactions (at least 10% of patients treated with UPLIZNA and greater than placebo) were urinary tract infection and arthralgia. For additional information on UPLIZNA, please see the Full Prescribing Information at . About Horizon Horizon is a global biotechnology company focused on the discovery, development and commercialization of medicines that address critical needs for people impacted by rare, autoimmune and severe inflammatory diseases. Our pipeline is purposeful: We apply scientific expertise and courage to bring clinically meaningful therapies to patients. We believe science and compassion must work together to transform lives. For more information on how we go to incredible lengths to impact lives, visit and follow us on Twitter, LinkedIn, Instagram and Facebook. Forward-Looking Statements This press release contains forward-looking statements, including statements regarding the potential benefits of UPLIZNA, future use of biomarker analyses and Horizon’s research and development plans. These forward-looking statements are based on management's expectations and assumptions as of the date of this press release and actual results may differ materially from those in these forward-looking statements as a result of various factors. These factors include, but are not limited to, risks regarding whether future results of clinical trials will be consistent with preliminary results or results of prior trials or other data or Horizon’s expectations, the risks associated with clinical development and adoption of novel medicines and risks related to competition or other factors that may change physician treatment strategies. For a further description of these and other risks facing Horizon, please see the risk factors described in Horizon’s filings with the United States Securities and Exchange Commission, including those factors discussed under the caption “Risk Factors” in those filings. Forward-looking statements speak only as of the date of this press release and Horizon undertakes no obligation to update or revise these statements, except as may be required by law. References Ajmera MR, Boscoe A, Mauskopf J, Candrilli SD, Levy M. Evaluation of comorbidities and health care resource use among patients with highly active neuromyelitis optica. J Neurol Sci. 2018;384:96-103. What is NMO? Accessed April 15, 2021. Guthyjacksonfoundation.org. What We Know About NMO. Accessed Aug. 2, 2022. Sumairafoundation.org. Liu Y, et al. A tract-based diffusion study of cerebral white matter in neuromyelitis optica reveals widespread pathological alterations. Mult Scler. 2011;18(7):1013-1021. Chihara N, et al. Interleukin 6 signaling promotes anti-aquaporin-4 autoantibody production from plasmablasts in neuromyelitis optica. PNAS. 2011;108(9):3701-3706. Duan T, Smith AJ, Verkamn AS. Complement-independent bystander injury in AQP4-IgG seropositive neuromyelitis optica produced by antibody dependent cellular cytotoxicity. Acta Neuropathologica Comm. 2019;7(112). Beekman J, et al. Neuromyelitis optica spectrum disorder: patient experience and quality of life. Neural Neuroimmunol Neuroinflamm. 2019;6(4):e580. Kimbrough DJ, et al. Treatment of neuromyelitis optica: review and recommendations. Mult Scler Relat Disord. 2012;1(4):180-187. Baranello RJ, Avasarala, JR. Neuromyelitis optica spectrum disorders with and without aquaporin 4 antibody: Characterization, differential diagnosis, and recent advances. J Neuro Ther. 2015;1(1):9-14. Wingerchuk DM. Neuromyelitis optica: effect of gender. J Neurol Sci. 2009;286(1-2):18-23. Flanagan EP, et al. Epidemiology of aquaporin-4 autoimmunity and neuromyelitis optica spectrum. Ann Neurol. 2016;79(5):775-783.

The new blood test will run on Abbott's Alinity i laboratory instrument and helps doctors evaluate patients with mild traumatic brain injury (mTBI), commonly known as concussion, by ruling out the need for a CT scan Abbott’s blood test evaluates TBI. (Credit: Tatiana from Pixabay) US-based medical technology company Abbott has received the US Food and Drug Administration (FDA) approval for its new laboratory blood test that measures traumatic brain injury (TBI). The blood test, dubbed i-STAT TBI, runs on the company’s Alinity i laboratory instrument and allows clinicians to rapidly assess individuals with mild TBIs, also known as concussions. It measures the levels of Ubiquitin C-terminal Hydrolase L1 (UCH-L1) and Glial Fibrillary Acidic Protein (GFAP) in blood plasma and serum. UCH-L1 and GFAP are two complementary biomarkers, whose elevated concentrations are closely associated with brain injury. The test is intended to help determine if patients, aged 18 years and above, with suspected mild traumatic brain injury within 12 hours of injury, need a CT scan of the head. The i-STAT TBI blood test is designed to provide test results within 18 minutes, with 96.7% sensitivity and 99.4% negative predictive value. It is already approved in the European Union (EU) and has been available in markets outside the US since 2021, said the medical technology firm. Abbott diagnostics business medical director Beth McQuiston said: “People sometimes minimise a hit to the head, thinking it’s no big deal. Others wonder if a visit to the doctor or emergency room for a possible concussion will provide them with meaningful answers or care. “Now that this test will be widely available in labs across the country, medical centres will be able to offer an objective blood test than can aid in concussion assessment. “That’s great news for both doctors and people who are trying to find out if they have suffered a traumatic brain injury.” Abbott developed the blood-based lab test in collaboration with the US Department of Defence (DoD), which has been developing a solution for TBI detection. The DoD, through US Army Medical Research and Development Command’s (USAMRDC) US Army Medical Materiel Development Activity (USAMMDA), supported the test run on the i-STAT Alinity platform. According to the company, i-STAT TBI Plasma is the first rapid blood test for concussion, and its FDA approval will enhance TBI testing in hospitals and laboratories across the US.