SLC7A5

Recent successful meeting with the FDA provides path to file for accelerated approval and subsequent conversion to full approval Plan to submit biologics license application (BLA) early in 2025 under the accelerated approval pathway New Phase 1/2 data will be presented this week at SSIEM 2024 demonstrating robust and durable biomarker responses and positive effects on clinical outcomes Sept. 03, 2024 -- Denali Therapeutics Inc. (Nasdaq: DNLI) today announced the outcome of a recent successful meeting with the Center for Drug Evaluation and Research (CDER) division of the U.S. Food and Drug Administration (FDA) providing a path to filing a biologics license application (BLA) for accelerated approval and subsequent conversion to full approval for tividenofusp alfa (DNL310) for the treatment of MPS II (Hunter syndrome). Agreement was reached that cerebrospinal fluid heparan sulfate (CSF HS) is reasonably likely to predict clinical benefit and can be used as a surrogate endpoint to support accelerated approval for tividenofusp alfa in MPS II. Based on discussions with CDER, Denali will include preclinical and clinical data on biomarkers (CSF HS and neurofilament light (NfL)) and safety in the BLA for tividenofusp alfa as a treatment of MPS II and intends to submit the BLA under the accelerated approval pathway in early 2025. “We thank CDER for a positive and collaborative discussion and their guidance on CSF HS as a surrogate biomarker, which we see as a significant step towards accelerating development of medicines for individuals and families living with MPS II,” said Carole Ho, MD, Chief Medical Officer of Denali. “This milestone reflects a collective effort across the patient community, academia and industry to communicate the science and advocate for faster paths to effective treatments addressing these devastating rare diseases. We are excited by the potential to deliver a new MPS treatment sooner using the accelerated approval pathway. We also look forward to plans for conversion to full approval following completion of the global Phase 2/3 COMPASS study, and we are grateful for the continued participation and commitment of patients, clinicians, and study teams involved in the tividenofusp alfa clinical studies.” “The Phase 1/2 data show that treatment with tividenofusp alfa produces robust and durable effects, with normalization of key disease biomarkers and improvement or stabilization in associated CNS and somatic clinical endpoints,” said Barbara Burton, MD, Professor of Pediatrics, Genetics, Genomics and Metabolism at Feinberg School of Medicine in Chicago, who will present the Phase 1/2 data at the SSIEM conference. “The totality of data support Denali's plans to file for accelerated approval of tividenofusp alfa with the potential to address a critical unmet need for CNS-penetrant therapies in MPS II.” Denali also announced new interim data from the Phase 1/2 study being presented at the Symposium of the Society for the Study of Inborn Errors of Metabolism (SSIEM 2024) taking place September 3-6, 2024, in Porto, Portugal. The presentations include data from additional study participants (N=37) and longer duration of treatment with tividenofusp alfa (up to Week 129) as well as new analyses on biomarkers and clinical outcomes. Highlights are summarized as follows: CSF HS: 90% mean reduction in CSF HS from baseline at Week 24 with all participants having normal or near normal levels at Week 24. CSF HS reduction was sustained through Week 104. Urine GAGs: Proportion of participants with normal total urine glycosaminoglycans (GAGs) (colorimetric method) increased from 5% of participants at baseline to 77% at Week 24, and the effect was sustained through Week 129. Importantly, the majority of patients were on standard of care prior to switching to tividenofusp alfa, without a protocol defined washout period, suggesting additional urine GAG reduction with tividenofusp alfa treatment. Serum NfL: Significant and sustained reduction of serum NfL from baseline with all participants who had reached Week 129 having normal or near normal levels, suggesting a reduction of neuronal injury in participants with MPS II. More rapid NfL reductions were associated with younger age. Clinical Outcomes: Improvement or stabilization in adaptive behavior and cognitive scores, hearing, liver volume, and growth outcomes were observed. Safety: Tividenofusp alfa was generally well tolerated, with a safety profile that continues to support development as a treatment for MPS II. MPS II, also called Hunter syndrome, is a rare genetic disease that affects over 2,000 individuals, primarily males, world-wide, and leads to behavioral, cognitive, and physical symptoms ultimately resulting in shortened lifespan. MPS II is caused by mutations in the iduronate-2-sulfatase (IDS) gene, which leads to a deficiency of the IDS enzyme responsible for the breakdown of the glycosaminoglycans (GAGs) heparan and dermatan sulfate in lysosomes. Symptoms often begin emerging around age two and include physical complications, including organ dysfunction, joint stiffness, hearing loss and impaired growth leading to short stature, and neurocognitive symptoms with impaired development. The disease is characterized by a buildup of GAGs in lysosomes — the part of the cell that breaks down materials including GAGs. The current standard of care enzyme replacement therapy partially treats the physical symptoms but does not cross the blood-brain barrier (BBB), and as a result, cognitive and behavioral symptoms experienced by the majority of patients with MPS II are not addressed. Therapies that address behavioral, cognitive, and physical manifestations of the disease are one of the greatest unmet needs for the MPS community. Tividenofusp alfa (DNL310) is a fusion protein composed of IDS fused to Denali’s proprietary Enzyme Transport Vehicle (ETV), which is engineered to cross the BBB via receptor-mediated transcytosis into the brain and to enable broad delivery of IDS into cells and tissues throughout the body with the goal of addressing the behavioral, cognitive, and physical manifestations of MPS II. In March 2021, the U.S. Food and Drug Administration granted Fast Track designation to DNL310 for the treatment of patients with MPS II. In May 2022, the European Medicines Agency granted DNL310 Priority Medicines designation. DNL310 is an investigational product candidate and has not been approved by any Health Authority. Based on supportive clinical and preclinical data to date, Denali is enrolling the Phase 2/3 COMPASS study in North America, South America, Europe, and Australia. The Phase 2/3 COMPASS study is expected to enroll 54 participants with MPS II with and without neuronopathic disease. The participants are randomized 2:1 to receive either tividenofusp alfa (DNL310) or idursulfase, respectively. Cohort A includes children ages 2 to 6 with neuronopathic disease; Cohort B includes children ages 6 to 26 without neuronopathic disease. More information about the COMPASS study can be found here. The blood-brain barrier (BBB) is essential in maintaining the brain’s microenvironment and protecting it from harmful substances and pathogens circulating in the bloodstream. Historically, the BBB has posed significant challenges to drug development for central nervous system diseases by preventing most drugs from reaching the brain in therapeutically relevant concentrations. Denali’s Transport Vehicle (TV) platform is a proprietary technology designed to effectively deliver large therapeutic molecules such as antibodies, enzymes, proteins, and oligonucleotides across the BBB after intravenous administration. The TV technology is based on engineered Fc domains that bind to specific natural transport receptors, such as transferrin receptor and CD98 heavy chain amino acid transporter, which are expressed at the BBB and deliver the TV and its therapeutic cargo to the brain through receptor-mediated transcytosis. In animal models, antibodies and enzymes engineered with the TV technology demonstrate more than 10- to 30-fold greater brain exposure than similar antibodies and enzymes without this technology. Oligonucleotides engineered with the TV technology demonstrate more than a 1,000-fold greater brain exposure in primates than systemically delivered oligonucleotides without this technology. Improved exposure and broad distribution in the brain may increase therapeutic efficacy by enabling widespread achievement of therapeutically relevant concentrations of product candidates. The TV platform has been clinically validated and three TV-enabled programs are currently in clinical development. Denali Therapeutics is a biopharmaceutical company developing a broad portfolio of product candidates engineered to cross the blood-brain barrier for neurodegenerative diseases and lysosomal storage diseases. Denali pursues new treatments by rigorously assessing genetically validated targets, engineering delivery across the blood-brain barrier, and guiding development through biomarkers that demonstrate target and pathway engagement. Denali is based in South San Francisco. For additional information, please visit www.denalitherapeutics.com. The content above comes from the network. if any infringement, please contact us to modify.

MELBOURNE, Australia, Sept. 4, 2024 /PRNewswire/ -- Telix Pharmaceuticals Limited (ASX: TLX, Telix, the Company) today announces that the Company's IPAX-1 Phase I study has been published in Neuro-Oncology Advances, confirming the safety and tolerability profile, and early efficacy of TLX101 therapy, in combination with external beam radiation therapy (EBRT) in recurrent glioblastoma (GBM), the most common and aggressive form of primary brain cancer. TLX101 (4-L-[ 131I] iodo-phenylalanine, or 131I-IPA) is a systemically administered targeted radiation therapy that targets L-type amino acid transporter 1 (LAT1), which is typically over-expressed in GBM. In the first peer-reviewed publication of the IPAX-1 study, Professor Josef Pichler and colleagues report that single or fractionated doses of TLX101 plus EBRT were associated with acceptable tolerability and specific tumour-targeting in patients with recurrent GBM. Authors explain that the study delivered encouraging preliminary efficacy data, demonstrating a median overall survival (OS) of 13 months from the initiation of treatment, or 23 months from initial diagnosis. Given that GBM has a median survival from initial diagnosis of 12-15 months, authors conclude that findings from the IPAX-1 study "support further investigation into the use of TLX101 plus EBRT, including its potential as a first line treatment". Key findings of the IPAX-1 study, outlined in the paper, include: All dosing regimens were well tolerated. Organ-absorbed radiation doses in the red bone marrow (0.38 Gy) and kidney (1.28 Gy) confirmed no radiation-based toxicity. Stable disease with MRI[1] assessment was observed in 4 of 9 patients at 3 months post-treatment (3-month follow-up, 1 patient did not reach protocol-mandated end of study), yielding a response rate of 44.4%. At the 3-month follow-up, 6 patients demonstrated metabolic stable disease with 18F-FET PET imaging. Median progression-free survival was 4.3 months (95% confidence interval, 3.3–4.5), while median OS was 13 months from the initiation of treatment (95% confidence interval, 7.1–27), or 23 months from initial diagnosis. Metabolic tumour responses were determined using Telix's investigational PET[2] agent for glioma imaging, TLX101-CDx (Pixclara®[3], 18F-floretyrosine or 18F-FET). Professor Josef Pichler, Kepler University Hospital, Austria, Principal Investigator in the IPAX-1, IPAX-2 and IPAX-Linz studies, and lead author, commented, "A significant unmet need exists for well-tolerated and efficacious treatments for patients with glioblastoma. The results from this Phase I study demonstrate the favourable safety and tolerability profile and preliminary efficacy of TLX101 in combination with second-line EBRT, in patients with recurrent glioblastoma. Following treatment with TLX101 plus EBRT, stable disease was observed in 44% of patients at 3 months post-treatment and median progression-free survival was 4.3 months, with no confirmed radiation toxicity. The overall survival improvement trend seen in this patient population clearly warrants further investigation into the use of TLX101 plus EBRT, including its potential as a first-line treatment. These studies are now well advanced." Dr David N Cade, Chief Medical Officer at Telix said, "We believe that TLX101 has significant potential to improve outcomes for patients living with glioblastoma – a disease in urgent need of new treatment options. In the front-line setting, the standard of care has not advanced materially in almost two decades, and in recurrent disease, no standard treatment exists. We are encouraged by these data, which show that TLX101, in combination with EBRT, is well tolerated at the doses tested, with preliminary clinical evidence demonstrating an anti-tumour effect and disease stabilisation - outcomes that are very important for this advanced patient population. Telix is pleased to be at the forefront of developing a new therapy for glioblastoma, and we welcome the excellent work conducted by Professor Pichler and his colleagues to progress this." The IPAX-2 and IPAX-Linz studies in the front-line and recurrent settings continue to progress well in combination with standard of care, and using Telix's Pixclara®3 investigational PET agent as companion diagnostic. Data from IPAX-1, together with these studies, will inform the design of Telix's future registration-enabling trial for TLX101. The Neuro-Oncology Advances publication is available online at: About TLX101 TLX101 is Telix's LAT1-targeting investigational therapy for patients with brain cancer. TLX101 therapy utilises a small molecule approach due to the need to cross the blood brain barrier, the normal protective barrier that prevents many potential drug candidates entering the brain. TLX101 has received orphan drug designation in the U.S. and Europe for the treatment of glioma. About the IPAX series of studies IPAX-1 was a multicenter, open-label, single-arm Phase I study to evaluate TLX101 plus EBRT in patients with recurrent GBM. The primary objective of the IPAX-1 study was to evaluate the safety and tolerability profile of intravenous TLX101 administered concurrently with second line EBRT. Secondary objectives were to determine optimal dosing, biodistribution and radiation absorption into the tumour, as well as assess preliminary efficacy through clinical and imaging-based assessment of tumour response. ClinicalTrials.gov ID: NCT03849105. IPAX-2 is a Phase I study of TLX101 in combination with post-surgical standard of care treatment in patients with newly diagnosed GBM. Active, dosing patients. ClinicalTrials.gov ID: NCT05450744. IPAX-Linz is a Phase II investigator-initiated trial of TLX101 in combination with EBRT in patients with recurrent high-grade gliomas (HGG), including GBM. Active, dosing patients. About Telix Pharmaceuticals Limited Telix is a biopharmaceutical company focused on the development and commercialisation of therapeutic and diagnostic radiopharmaceuticals and associated medical devices. Telix is headquartered in Melbourne, Australia, with international operations in the United States, Europe (Belgium and Switzerland), and Japan. Telix is developing a portfolio of clinical and commercial stage products that aims to address significant unmet medical needs in oncology and rare diseases. Telix is listed on the Australian Securities Exchange (ASX: TLX). Telix's lead imaging product, gallium-68 (68Ga) gozetotide injection (also known as 68Ga PSMA-11 and marketed under the brand name Illuccix®), has been approved by the U.S. Food and Drug Administration (FDA)[4], by the Australian Therapeutic Goods Administration (TGA) [5], and by Health Canada[6]. No other Telix product has received a marketing authorisation in any jurisdiction. Visit for further information about Telix, including details of the latest share price, announcements made to the ASX, investor and analyst presentations, news releases, event details and other publications that may be of interest. You can also follow Telix on X and LinkedIn. Telix Investor Relations Ms. Kyahn Williamson Telix Pharmaceuticals Limited SVP Investor Relations and Corporate Communications Email: [email protected] Legal Notices You should read this announcement together with our risk factors, as disclosed in our most recently filed reports with the Australian Securities Exchange (ASX) or on our website. The information contained in this announcement is not intended to be an offer for subscription, invitation or recommendation with respect to securities of Telix Pharmaceuticals Limited (Telix) in any jurisdiction, including the United States. The information and opinions contained in this announcement are subject to change without notification. To the maximum extent permitted by law, Telix disclaims any obligation or undertaking to update or revise any information or opinions contained in this announcement, including any forward-looking statements (as referred to below), whether as a result of new information, future developments, a change in expectations or assumptions, or otherwise. No representation or warranty, express or implied, is made in relation to the accuracy or completeness of the information contained or opinions expressed in the course of this announcement. This announcement may contain forward-looking statements that relate to anticipated future events, financial performance, plans, strategies or business developments. Forward-looking statements can generally be identified by the use of words such as "may", "expect", "intend", "plan", "estimate", "anticipate", "believe", "outlook", "forecast" and "guidance", or the negative of these words or other similar terms or expressions. Forward-looking statements involve known and unknown risks, uncertainties and other factors that may cause our actual results, levels of activity, performance or achievements to differ materially from any future results, levels of activity, performance or achievements expressed or implied by these forward-looking statements. Forward-looking statements are based on Telix's good-faith assumptions as to the financial, market, regulatory and other risks and considerations that exist and affect Telix's business and operations in the future and there can be no assurance that any of the assumptions will prove to be correct. In the context of Telix's business, forward-looking statements may include, but are not limited to, statements about: the initiation, timing, progress and results of Telix's preclinical and clinical trials, and Telix's research and development programs; Telix's ability to advance product candidates into, enrol and successfully complete, clinical studies, including multi-national clinical trials; the timing or likelihood of regulatory filings and approvals for Telix's product candidates, manufacturing activities and product marketing activities; Telix's sales, marketing and distribution and manufacturing capabilities and strategies; the commercialisation of Telix's product candidates, if or when they have been approved; Telix's ability to obtain an adequate supply of raw materials at reasonable costs for its products and product candidates; estimates of Telix's expenses, future revenues and capital requirements; Telix's financial performance; developments relating to Telix's competitors and industry; and the pricing and reimbursement of Telix's product candidates, if and after they have been approved. Telix's actual results, performance or achievements may be materially different from those which may be expressed or implied by such statements, and the differences may be adverse. Accordingly, you should not place undue reliance on these forward-looking statements. ©2024 Telix Pharmaceuticals Limited. The Telix Pharmaceuticals®, Illuccix® and Pixclara®3 names and logos are trademarks of Telix Pharmaceuticals Limited and its affiliates – all rights reserved. Logo -

SOUTH SAN FRANCISCO, Calif., Aug. 14, 2024 (GLOBE NEWSWIRE) -- Denali Therapeutics Inc. (Nasdaq: DNLI), a biopharmaceutical company developing a broad portfolio of product candidates engineered to cross the blood-brain barrier (BBB) for the treatment of neurodegenerative and lysosomal storage diseases, today announced publication of nonclinical data in the August 14, 2024 issue of Science Translational Medicine (link) demonstrating the ability of the Oligonucleotide Transport Vehicle (OTV) platform to achieve broad biodistribution of antisense oligonucleotides (ASOs) in the central nervous system (CNS) and skeletal and cardiac muscle following intravenous (IV) administration. Oligonucleotides, such as ASOs, are designed to modify gene expression and hold promise as therapeutics for neurological disorders. A major challenge in their development, however, is that oligonucleotides are unable to cross the BBB on their own. Currently, oligonucleotides must be delivered directly to the CNS through invasive routes such as intrathecal delivery and still may not distribute uniformly throughout the brain where treatment is needed. Denali invented the Transport Vehicle (TV) platform to overcome the challenge of the BBB and deliver multiple types of therapeutic cargo across the BBB, including antibodies, enzymes, and other proteins. The TV platform has been clinically validated and three TV-enabled programs are currently in clinical development. “This is the first publication of data showing that ASOs can be delivered uniformly throughout the primate CNS and to muscle via a less invasive route of intravenous administration enabled by the TV platform,” said Joseph Lewcock, Ph.D., Chief Scientific Officer of Denali. “Across modalities, enhanced brain uptake with uniform distribution throughout the CNS is a defining hallmark of the TV. Publication of our OTV research is a significant milestone supporting TV platform expansion as we advance our first two OTV programs towards the clinic for Alzheimer’s disease and Parkinson’s disease.” In the Science Translational Medicine article, Denali scientists describe using OTV, which is an engineered TV conjugated to an ASO, for delivery of therapeutic molecules to the mouse and nonhuman primate brain. The data show that OTV can successfully cross the BBB following IV administration and provide cumulative and sustained knockdown of the ASO target gene expression across multiple CNS regions and all major cell types, including endothelial cells, neurons, astrocytes, microglia, and oligodendrocytes. Additionally, OTV enabled knockdown of the ASO target gene expression in historically difficult to target peripheral muscle tissues, including skeletal and cardiac muscle. In comparison to other clinically relevant ASO delivery platforms, including direct delivery of a non-TV-enabled ASO to the cerebrospinal fluid, systemic OTV enabled a much more uniform ASO biodistribution profile and knockdown of the target. About Denali’s Transport Vehicle Platform The blood-brain barrier (BBB) is essential in maintaining the brain’s microenvironment and protecting it from harmful substances and pathogens circulating in the bloodstream. Historically, the BBB has posed significant challenges to drug development for central nervous system diseases by preventing most drugs from reaching the brain in therapeutically relevant concentrations. Denali’s Transport Vehicle (TV) platform is a proprietary technology designed to effectively deliver large therapeutic molecules such as antibodies, enzymes, proteins, and oligonucleotides across the BBB after intravenous administration. The TV technology is based on engineered Fc domains that bind to specific natural transport receptors, such as transferrin receptor and CD98 heavy chain amino acid transporter, which are expressed at the BBB and deliver the TV and its therapeutic cargo to the brain through receptor-mediated transcytosis. In animal models, antibodies and enzymes engineered with the TV technology demonstrate more than 10- to 30-fold greater brain exposure than similar antibodies and enzymes without this technology. Oligonucleotides engineered with the TV technology demonstrate more than a 1,000-fold greater brain exposure in primates than systemically delivered oligonucleotides without this technology. Improved exposure and broad distribution in the brain may increase therapeutic efficacy by enabling widespread achievement of therapeutically relevant concentrations of product candidates. The TV platform has been clinically validated and three TV-enabled programs are currently in clinical development. About Denali Therapeutics Denali Therapeutics is a biopharmaceutical company developing a broad portfolio of product candidates engineered to cross the blood-brain barrier for neurodegenerative diseases and lysosomal storage diseases. Denali pursues new treatments by rigorously assessing genetically validated targets, engineering delivery across the blood-brain barrier, and guiding development through biomarkers that demonstrate target and pathway engagement. Denali is based in South San Francisco. For additional information, please visit www.denalitherapeutics.com. Special Note to Reporters More information, including a copy of the paper, can be found online at the Science Translational Medicine press package at https://www.eurekalert.org/press/medpak/. Cautionary Note Regarding Forward-Looking Statements This press release contains forward-looking statements within the meaning of the Private Securities Litigation Reform Act of 1995. Forward-looking statements expressed or implied in this press release include, but are not limited to, statements regarding Denali's plans, timelines, and expectations related to its OTV programs and planned clinical trials; Denali's expectations regarding the therapeutic potential of its TV platform; and statements made by Denali's Chief Scientific Officer. Actual results are subject to risks and uncertainties and may therefore differ materially from those indicated by these forward-looking statements, including due to risks related to: Denali’s dependence on successful development of its BBB platform technology and TV-enabled product candidates; Denali’s ability to conduct or complete clinical trials on expected timelines; the risk of significant adverse events, toxicities, or other undesirable side effects; the risk that results from early clinical biomarker studies will not translate to clinical benefit in late clinical studies; developments relating to Denali’s competitors and its industry; Denali’s ability to obtain, maintain, or protect intellectual property rights; and other risks and uncertainties. In light of these risks, uncertainties, and assumptions, the forward-looking statements in this press release are inherently uncertain and may not occur, and actual results could differ materially and adversely from those anticipated or implied in the forward-looking statements. Accordingly, you should not rely upon forward-looking statements as predictions of future events. Information regarding additional risks and uncertainties may be found in Denali’s Annual and Quarterly Reports on Forms 10-K and 10-Q filed with the Securities and Exchange Commission (SEC) on February 28, 2024 and August 1, 2024, respectively, and Denali’s future reports to be filed with the SEC. Denali does not undertake any obligation to update or revise any forward-looking statements, to conform these statements to actual results, or to make changes in Denali’s expectations, except as required by law. Investor and Media Contact: Laura Hansen, Ph.D. Vice President, Investor Relations (650) 452-2747 hansen@dnli.com Source: Denali Therapeutics Inc.