First Characterization of a TDP-43 PET Tracer Published in Nature Communications Showing Potential of AC Immune’s ACI-19626 in Precision Medicine Aggregated TDP-43 is a pathological hallmark of neurodegenerative diseases including ALS, FTD and LATE, and a co-pathology in Alzheimer’s and Parkinson’s diseasesPET imaging of aggregated TDP-43 could facilitate precision medicine in these diseases, whose shared clinical features complicate differential diagnosis, potentially delaying therapyBased on specificity, ...

Summary of Conference Call on Gene Therapy for Neurodegenerative Diseases Industry Overview - The conference focused on gene therapy applications for neurodegenerative diseases, featuring speakers from three companies: Mira, uniQure, and Passage Bio [1][2][6]. Key Points by Company Mira - **Company Overview**: Mira specializes in genetic medicines, focusing on local delivery of small doses to treat severe indications, which enhances safety and reduces costs [2]. - **Recent Milestones**: Mira has two pivotal studies and two awaiting Biologics License Application (BLA) filings, including treatments for rare and common eye diseases and a Parkinson's treatment that has shown three positive studies [3][4]. - **Innovative Approach**: The company utilizes AI technology to analyze data from the largest neurohospital in Europe, demonstrating physiological changes in the brain related to their Parkinson's treatment [4][24]. - **Potential Applications**: Mira's gene therapy can convert glutamate to GABA, potentially treating various neurodegenerative diseases by calming hyperactive neurons [22][24]. uniQure - **Company Overview**: uniQure is a pioneer in genomic medicine, known for developing the first approved AAV gene therapies, including Glybera and Hemgenix [6][9]. - **Lead Program**: The company is focused on Huntington's disease, utilizing a platform called MyCure to suppress the aberrant Huntingtin protein [8]. - **Clinical Findings**: In a study involving 45 patients, uniQure reported a 75% statistically significant slowing of disease progression based on the UHDRS [9]. - **Regulatory Plans**: A pre-BLA meeting is expected in Q4, with a BLA submission planned for Q1 of the following year [9]. Passage Bio - **Company Overview**: Passage Bio is based on technology from the University of Pennsylvania, focusing on gene therapy for frontotemporal dementia and Huntington's disease [14]. - **Clinical Approach**: The company delivers AAV1 via a minimally invasive procedure, showing high levels of target engagement and stabilization of neurofilaments [14][15]. - **Future Directions**: Passage Bio is also developing a preclinical program targeting the DNA damage response pathway in Huntington's disease [15]. Challenges in Gene Therapy - **Delivery Issues**: The primary challenge remains delivering therapies to the correct brain regions, especially for diseases like Huntington's [18][19]. - **Slow Disease Progression**: Designing clinical studies for slowly progressing neurodegenerative diseases is difficult, as changes in function are hard to detect [19][20]. - **Heterogeneity**: Variability among patients complicates the assessment of treatment efficacy, necessitating innovative statistical methods to account for differences [31][32]. Regulatory Considerations - **FDA Flexibility**: The FDA is showing increased willingness to consider alternative trial designs and endpoints for rare diseases with high unmet needs [44][46]. - **Natural History Data**: Utilizing natural history datasets can help in understanding disease progression and support regulatory submissions [30][31]. Safety Concerns - **Patient Safety**: The panel acknowledged the importance of safety in gene therapy, especially following recent patient deaths in trials [35][37]. - **Local Delivery Advantages**: Localized delivery methods may reduce systemic exposure and associated risks, as demonstrated by lower doses used in certain therapies [38][41]. Access and Implementation - **Training and Infrastructure**: Successful implementation of gene therapies will depend on training healthcare providers and establishing treatment centers [52][54]. - **Data-Driven Adoption**: Strong clinical data will be crucial for gaining acceptance among medical professionals and ensuring broad access to therapies [55][56]. Conclusion - The conference highlighted the potential of gene therapy in treating neurodegenerative diseases, the challenges faced in delivery and study design, and the evolving regulatory landscape that may facilitate the development of these innovative treatments [1][17][42].

Summary of Conference Call on Gene Therapy for Neurodegenerative Diseases Companies Involved - **MeiraGTx Holdings** - **uniQure** - **Passage Bio** Key Points and Arguments MeiraGTx Holdings - Focuses on genetic medicines for inherited and larger indications, utilizing local delivery of small doses to enhance safety and reduce costs [2][3] - Owns in-house manufacturing facilities, which supports the rapid development of their programs [2] - Two pivotal studies and two awaiting BLA filings, including treatments for rare and common eye diseases and a Parkinson's treatment that has shown three positive studies [3][4] - Partnership with an AI company to analyze data from the largest neurohospital in Europe, demonstrating physiological changes in the brain with their Parkinson's treatment [4][24] uniQure - A pioneer in genomic medicine with two approved AAV gene therapies: Glybera for lipoprotein lipase deficiency and Hemgenix for hemophilia B [6] - Lead program focuses on Huntington's disease, utilizing a platform called MyCure to suppress the aberrant huntingtin protein [9] - Clinical testing of AMT-130 has shown a 75% statistically significant slowing of disease progression over three years [10] - Plans to hold a pre-BLA meeting in Q4 and submit a BLA in Q1 of the following year [10] Passage Bio - Focuses on gene therapy for frontotemporal dementia patients with GRN mutations, using AAV1 delivered via a minimally invasive procedure [15] - Demonstrated high levels of target engagement and stabilization of plasma neurofilaments [15] Challenges in Gene Therapy for Neurodegenerative Diseases - Delivery to the right location in the brain remains a significant challenge, especially for diseases like Huntington's [18][19] - Slow progression of neurodegenerative diseases complicates the design of clinical studies to detect meaningful changes [19][20] - Heterogeneity among patients complicates the assessment of treatment effects [32][34] Safety Considerations - Local delivery methods may reduce systemic exposure and associated risks compared to systemic therapies [39][40] - Smaller doses and targeted delivery are believed to enhance safety profiles [42] Regulatory Aspects - The FDA is showing increased flexibility in evaluating gene therapies for rare diseases, allowing for single-arm studies with supportive evidence [44][45] - Emphasis on using natural history data and biomarkers to assess treatment effectiveness [31][33] Access and Implementation Challenges - The complexity of procedures may limit access, but strong data can encourage training and adoption among healthcare providers [53][55] - Existing surgical techniques can facilitate the implementation of new therapies, particularly in diseases with significant unmet needs [55][56] Other Important Insights - AI technology is being utilized to analyze large datasets to identify physiological changes and improve the robustness of clinical trial endpoints [25][35] - The potential for gene therapy to address multiple neurodegenerative diseases by altering brain circuitry is highlighted [22][24]

Core Insights - Alterity Therapeutics announced positive results from the ATH434-201 Phase 2 clinical trial for Multiple System Atrophy (MSA), demonstrating clinically meaningful efficacy in modifying disease progression at both 50 mg and 75 mg doses [1][2][3] Company Overview - Alterity Therapeutics is a biotechnology company focused on developing disease-modifying treatments for neurodegenerative diseases, particularly MSA and Parkinson's disease [4][8] - The lead candidate, ATH434, is an oral agent designed to inhibit the aggregation of pathological proteins implicated in neurodegeneration, showing preclinical efficacy in reducing α-synuclein pathology and restoring normal iron balance in the brain [4][8] Clinical Trial Details - The ATH434-201 Phase 2 clinical trial was a randomized, double-blind, placebo-controlled study involving 77 adults, assessing the efficacy, safety, and pharmacokinetics of ATH434 over 12 months [5][6] - Results indicated that ATH434 produced clinically and statistically significant improvements on the modified Unified Multiple System Atrophy Rating Scale (UMSARS) Part I, with additional positive trends in motor performance and patient-reported outcomes [5][6] Efficacy and Safety - ATH434 demonstrated target engagement by reducing iron accumulation in MSA-affected brain regions, with both dose levels showing a favorable safety profile comparable to placebo [2][5] - The study reported no serious adverse events attributed to ATH434, reinforcing its tolerability [2][6] Regulatory Status - ATH434 has received Fast Track Designation and Orphan Drug Designation from the U.S. FDA and the European Commission for the treatment of MSA, highlighting its potential as a significant therapeutic option in a market with currently no approved disease-modifying treatments [4][8]

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Core Insights - Vigil Neuroscience presented topline clinical data from the Phase 1 SAD/MAD trial of VG-3927, a potential treatment for Alzheimer's disease, at the AD/PD™ 2025 International Conference [1][2] Group 1: VG-3927 Overview - VG-3927 is an orally bioavailable small molecule TREM2 agonist with high potency and CNS penetrance, designed to target multiple contributors to Alzheimer's disease progression [2][8] - The drug's unique mechanism as both an agonist and a positive allosteric modulator may enhance microglial responses to aggregated amyloid and tau without increasing inflammation [8] Group 2: Phase 1 Trial Results - The Phase 1 trial included 115 participants, demonstrating a favorable safety and tolerability profile with no serious adverse events reported [5][7] - VG-3927 showed a predictable and dose-dependent pharmacokinetic profile, supporting once-daily dosing with an estimated cerebral spinal fluid to unbound plasma ratio of 0.91 [5][11] Group 3: Mechanism of Action - VG-3927 activates TREM2, engaging the brain's immune system to counteract multiple pathologies associated with Alzheimer's disease [3][4] - The drug promotes microglial uptake of both Aβ and Tau, indicating broad efficacy potential beyond targeting a single driver of Alzheimer's pathology [4][6] Group 4: Future Development Plans - Vigil Neuroscience plans to advance VG-3927 into Phase 2 development in the third quarter of 2025, aiming to provide a differentiated therapeutic option for Alzheimer's disease [2][6]