Idursulfase

SOUTH SAN FRANCISCO, CA, USA I February 06, 2025 I Denali Therapeutics Inc. (NASDAQ: DNLI), today announced the primary analysis of the Phase 1/2 study in 47 participants with Hunter syndrome (MPS II) in the 24-week treatment period and additional long-term follow-up of its investigational therapeutic tividenofusp alfa (DNL310). These data, along with recent Breakthrough Therapy designation, further support the company’s plan to submit a biologics license application (BLA) in early 2025 for accelerated approval and deliver this potential treatment to the Hunter syndrome community in late 2025 or early 2026. The Phase 1/2 results are being presented this week at the 21st Annual WORLD Symposium™ conference in San Diego, California. “Longer-term clinical data add to confidence that normalization of key biomarkers endures over time and that treatment with tividenofusp alfa is associated with continued improvement in hearing, cognition and behavior, which is meaningful to affected individuals and their families,” said Joseph Muenzer, M.D., Ph.D., Director of the Muenzer MPS Center and Professor in Pediatric Genetics at the University of North Carolina at Chapel Hill School of Medicine as well as an investigator in the Phase 1/2 study. “I look forward to new treatment options urgently needed by the Hunter syndrome community that effectively address the full spectrum of the disease.” “Our primary analysis in 47 participants with MPS II and the additional long-term data in up to more than four years, support the potential of tividenofusp alfa to address neurocognitive, behavioral, and physical effects for all individuals living with MPS II. We are working as fast as possible to enable tividenofusp alfa as a treatment option for individuals living with MPS II and enable access for them and their families,” said Carole Ho, M.D., Chief Medical Officer of Denali. “We expect the progress achieved in our Hunter syndrome program to inform and accelerate additional therapeutics programs in our lysosomal storage disease portfolio, including Sanfilippo syndrome Type A (MPS IIIA).” The additional Phase 1/2 long-term data demonstrated that treatment with tividenofusp alfa led to substantial and significant reductions to normal and near-normal levels in central nervous system and peripheral biomarkers of disease, including cerebrospinal fluid (CSF) and urine heparan sulfate, and neurofilament light (NfL), a well-established marker of neurodegeneration. Clinical outcomes included normal liver volume after 24 weeks, hearing threshold improvement in all tested frequencies, and skill gains in most participants on measures of adaptive behavior and cognition. Administration of tividenofusp alfa was generally well tolerated in study participants. Most treatment-related adverse events (TEAEs) were mild or moderate, including infusion-related reactions (IRRs), anemia, vomiting, pyrexia, respiratory infections, and rash. Serious TEAEs in three participants (6.4%) were manageable, with resolution or stabilization with continued treatment. One participant discontinued treatment for reasons related to a moderate IRR and other non-treatment-related adverse events​. Denali also supported additional research relating to Hunter syndrome (MPS II) at the WORLD Symposium™ conference. Research presented by Barbara Burton, M.D., Professor of Pediatrics, Genetics, Genomics and Metabolism at Feinberg School of Medicine in Chicago identified unmet needs including limitations of existing treatments across disease manifestations and the challenges in care associated with diagnosis and continuation of care. Denali researchers also presented research at the conference demonstrating that age-based levels of CSF and urine biomarkers in Hunter syndrome (MPS II) were elevated above biomarker levels at pediatric age-based reference intervals. About Hunter Syndrome (MPS II) Hunter syndrome (MPS II) is a rare genetic disease that affects over 2,000 individuals in commercially accessible geographies, primarily males, and leads to physical, cognitive, and behavioral symptoms. Hunter syndrome is caused by mutations in the iduronate-2-sulfatase (IDS) gene, which leads to a deficiency of the IDS enzyme. Symptoms often begin emerging around age two and include physical complications, including organ dysfunction, joint stiffness, hearing loss and impaired growth, and neurocognitive symptoms with impaired development. The disease is characterized by a buildup of glycosaminoglycans (GAGs) in lysosomes — the part of the cell that breaks down materials including GAGs. The current standard of care, enzyme replacement therapy, partially treats physical symptoms but does not cross the blood-brain barrier, and as a result, cognitive and behavioral symptoms experienced by the majority of individuals with Hunter syndrome are not addressed. Therapies that address the range of behavioral, cognitive, and physical manifestations of the disease are recognized as an unmet need for the Hunter syndrome community. 1 About Tividenofusp Alfa and the Phase 2/3 COMPASS Study Tividenofusp alfa (or DNL310) is composed of the iduronate 2-sulfatase (IDS) enzyme fused to Denali’s proprietary Enzyme TransportVehicle™ (ETV), uniquely designed to deliver IDS into the brain and the body, with the goal of addressing behavioral, cognitive, and physical symptoms of Hunter syndrome (MPS II). The U.S. Food and Drug Administration has granted Fast Track and Breakthrough Therapy designations to tividenofusp alfa for development in the treatment of Hunter syndrome (MPS II). The European Medicines Agency has granted Priority Medicines designation to tividenofusp alfa. The Phase 2/3 COMPASS study is enrolling participants with MPS II in North America, South America, and Europe to support global approval. Participants are randomized 2:1 to receive either tividenofusp alfa or idursulfase, respectively. Enrollment of the planned 33 participants with neuronopathic MPS II in Cohort A has been completed; Denali has increased the sample size of Cohort A by nine participants, bringing the total to 42 participants. Cohort B continues to enroll participants with non-neuronopathic MPS II. More information about the COMPASS study can be found here . Tividenofusp alfa is an investigational therapeutic candidate and has not been approved for use by any Health Authority. 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 . SOURCE: Denali Therapeutics

Denali plans to submit the drug, tividenofusp alfa, for accelerated approval early this year in the hopes that the treatment will become available to patients by the end of 2025 or early 2026.\n After winning a breakthrough therapy designation for its Hunter syndrome enzyme replacement therapy, Denali Therapeutics is climbing closer to its goal of accelerated approval by unveiling data showing the drug met its primary safety endpoints and reduced key biomarkers of the disease.Treated patients also experienced long-term improvements in their hearing and cognition, the company said in a Feb. 6 release. The phase 1/2 open-label trial enrolled 47 boys around the age of 5. Patients received weekly intravenous infusions of the drug, tividenofusp alfa (tivi), in either fixed or escalating doses. The primary analysis looked at data after 24 weeks of treatment, with the long-term follow-up planned for about five years. So far, some patients have more than three years of follow-up.Denali will present the phase 1/2 results at the 21st Annual WORLDSymposium conference in San Diego, California.The trial\'s primary endpoints are the rates of adverse events and infusion-related reactions, as well as other safety indicators, according to the presentation.Side effects were common, with 72% of patients experiencing mild to moderate treatment-emergent adverse events, according to the presentation. In the 24-week treatment period, the most common adverse events were infusion-related reactions, anemia, vomiting, fever, upper respiratory infection and rash.Though three patients experienced serious but manageable adverse events—and one patient discontinued treatment due in part to a reaction to the drug infusion—the trial met its safety expectations, the company said in the release.The company plans to submit the drug for accelerated approval early this year in the hopes that the treatment will become available to patients by the end of 2025 or early 2026, Denali said in its Feb. 6 press release.“Safety and tolerability endpoints are met and we consider tividenofusp alfa to be ‘well tolerated,’” Denali said in an emailed comment to Fierce Biotech. Hunter syndrome is rare and the trial is small, so there are no pre-defined standards for the safety endpoints to be compared against, Denali said.  \"Today’s update is in line with prior updates and reinforces tivi’s potential as a best-in-class treatment option for Hunter syndrome, including normalization of multiple central and peripheral markers,\" analysts from William Blair wrote on Feb. 6. \"While early and in a limited number of patients, these appear to be translating to clinical benefit.\"Hunter syndrome, also called mucopolysaccharidosis type II (MPS II), is characterized by patients\' inability to break down certain sugars, which leads to tissue and organ damage that ultimately causes stiff joints, delayed growth and an enlarged spleen and liver, among other symptoms. The disease can also lead to cognitive and behavioral problems, and in severe cases, patients may not survive beyond their teenage years.There is one approved enzyme replacement therapy for Hunter syndrome in Takeda’s Elaprase. The Japanese drugmaker acquired the medicine when it bought Shire Pharmaceuticals in 2019.In the latest presentation, Denali said that patients saw a sharp decline of the biomarker heparan sulfate in both their cerebrospinal fluid and urine after 24 weeks, with levels dropping by an average of about 90% from baseline. These lower levels persisted for as long as 153 and 177 weeks, respectively, according to the biotech. Heparan sulfate is a liver sugar that patients with Hunter syndrome have difficulty breaking down.Tivi also restored patients’ liver volumes to normal and reduced levels of neurofilament, a sign of neuron damage, in the blood, according to the presentation. Neurofilament levels increased slightly at 24 weeks, a data point that drew scrutiny from analysts when first presented as an exploratory endpoint in 2021. By 49 weeks, neurofilament dropped by about 20%, with the decline then escalating to more than 70% in subsequent measurements, according to Denali. The investigators also tested patients’ hearing using pure tone average, a measurement of hearing sensitivity at sound frequencies important for speech. At 24 weeks, the volume a sound needed to be played in order for patients to respond dropped by an average of nearly nine decibels. In the eight patients tested at 153 weeks, the threshold dropped by more than 12 decibels.Patients also saw statistically significant improvements in two tests of cognition and behavior, the Bayley Scales of Infant and Toddler Development and the Vineland Adaptive Behavior Scales, Denali said.“Our primary analysis in 47 participants with MPS II and the additional long-term data in up to more than four years support the potential of tividenofusp alfa to address neurocognitive, behavioral and physical effects for all individuals living with MPS II,” Denali chief medical officer Carole Ho, M.D., said in the release. “We expect the progress achieved in our Hunter syndrome program to inform and accelerate additional therapeutics programs in our lysosomal storage disease portfolio, including Sanfilippo syndrome Type A.”While Denali plans to submit tivi for accelerated approval early this year, the company is also continuing its investigation of the drug in an ongoing phase 2/3 double-blind, randomized trial in about 54 pediatric and young adult patients with Hunter syndrome.Tivi is a version of the iduronate 2-sulfatase enzyme that is engineered to penetrate the blood-brain barrier by binding to transferrin receptor 1, which normally shuttles iron into the brain. Editor\'s note: This story was updated at 2:15 p.m. ET on Feb. 6 to include an analyst note.