Mucopolysaccharidosis II

SOUTH SAN FRANCISCO, CA, USA I April 02, 2025 I Denali Therapeutics Inc. (NASDAQ: DNLI), today announced that the company’s initiation of a rolling submission of a biologics license application (BLA) for accelerated approval of tividenofusp alfa for the treatment of Hunter syndrome (MPS II) has been received by the Center for Drug Evaluation and Research (CDER) of the U.S. Food and Drug Administration (FDA). Denali continues to have regular, collaborative, and productive engagement with CDER and is aligned with CDER on the content of the BLA data package, including the use of cerebrospinal fluid heparan sulfate (CSF HS) as a surrogate endpoint to support an accelerated approval, as well as the full approval conversion path. Denali expects to complete the BLA submission in the first half of May 2025 and continues to prepare for a potential commercial launch in the U.S. in late 2025 or early 2026. “We are grateful to the FDA for their ongoing support of our BLA filing and continued dedication to advance new medicines,” said Carole Ho, M.D., Chief Medical Officer of Denali. “This regulatory milestone brings us closer to our goal of delivering a new treatment option to the Hunter syndrome community as we continue to listen, learn, and seek their advice in bringing tividenofusp alfa to patients. Our progress has broader positive implications supporting the expansion of our Enzyme TransportVehicle franchise of next-generation enzyme replacement therapies to treat the brain and body. In this context, we appreciate the ongoing and productive collaboration with CDER through the START program as we align on an accelerated development and approval path for DNL126 for the potential treatment of Sanfilippo syndrome.” About Hunter Syndrome (MPS II) Hunter syndrome (MPS II) is a rare genetic disease that affects over 2,000 individuals worldwide, 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 patients with Hunter syndrome are not addressed. Therapies that address the range of cognitive, behavioral, and physical manifestations of the disease are recognized as an unmet need for this patient community. 1 About Tividenofusp Alfa 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. More information about the COMPASS study can be found here . Tividenofusp alfa is an investigational therapeutic and has not been approved for use by any Health Authority. About Sanfilippo Syndrome Type A (MPS IIIA) MPS III, also called Sanfilippo syndrome, is a rare, genetic lysosomal storage disease that causes neurodegeneration. There are four main types of MPS III, depending on the enzyme affected. Type A is caused by genetic defects that result in reduction in the activity of N-sulfoglucosamine sulfohydrolase (SGSH), an enzyme responsible for degrading heparan sulfate in the lysosome. There are no approved treatments for MPS IIIA. About DNL126 (ETV:SGSH) DNL126 (ETV:SGSH) is an intravenously administered, Enzyme TransportVehicle™ (ETV)-enabled SGSH replacement therapy designed to cross the BBB via receptor-mediated transcytosis into the brain and to enable broad delivery of SGSH into cells and tissues throughout the body with the goal of addressing the behavioral, cognitive, and physical manifestations of MPS IIIA. DNL126 is an investigational therapeutic and has not been approved for use by any Health Authority. About the Phase 1/2 study of DNL126 Denali is conducting a multicenter, open-label, Phase 1/2 study to assess the safety, tolerability, pharmacokinetics, pharmacodynamics, and exploratory clinical efficacy of DNL126 in participants with MPS IIIA. The core study period is approximately 6 months and is followed by an open-label extension for approximately 18 months. More information about the Phase 1/2 study can be found here . 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 . Reference SOURCE: Denali Therapeutics

Rolling submission of BLA initiated for tividenofusp alfa; preparations ongoing for potential U.S. commercial launch in late 2025 or early 2026Alignment through recent interactions with CDER on path to accelerated approval and conversion to full approval for tividenofusp alfaProductive collaboration continues under START for an accelerated development and approval path for DNL126 SOUTH SAN FRANCISCO, Calif., April 02, 2025 (GLOBE NEWSWIRE) -- Denali Therapeutics Inc. (NASDAQ: DNLI), today announced that the company’s initiation of a rolling submission of a biologics license application (BLA) for accelerated approval of tividenofusp alfa for the treatment of Hunter syndrome (MPS II) has been received by the Center for Drug Evaluation and Research (CDER) of the U.S. Food and Drug Administration (FDA). Denali continues to have regular, collaborative, and productive engagement with CDER and is aligned with CDER on the content of the BLA data package, including the use of cerebrospinal fluid heparan sulfate (CSF HS) as a surrogate endpoint to support an accelerated approval, as well as the full approval conversion path. Denali expects to complete the BLA submission in the first half of May 2025 and continues to prepare for a potential commercial launch in the U.S. in late 2025 or early 2026. “We are grateful to the FDA for their ongoing support of our BLA filing and continued dedication to advance new medicines,” said Carole Ho, M.D., Chief Medical Officer of Denali. “This regulatory milestone brings us closer to our goal of delivering a new treatment option to the Hunter syndrome community as we continue to listen, learn, and seek their advice in bringing tividenofusp alfa to patients. Our progress has broader positive implications supporting the expansion of our Enzyme TransportVehicle franchise of next-generation enzyme replacement therapies to treat the brain and body. In this context, we appreciate the ongoing and productive collaboration with CDER through the START program as we align on an accelerated development and approval path for DNL126 for the potential treatment of Sanfilippo syndrome.” About Hunter Syndrome (MPS II)Hunter syndrome (MPS II) is a rare genetic disease that affects over 2,000 individuals worldwide, 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 patients with Hunter syndrome are not addressed. Therapies that address the range of cognitive, behavioral, and physical manifestations of the disease are recognized as an unmet need for this patient community.1 About Tividenofusp AlfaTividenofusp 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. More information about the COMPASS study can be found here. Tividenofusp alfa is an investigational therapeutic and has not been approved for use by any Health Authority. About Sanfilippo Syndrome Type A (MPS IIIA)MPS III, also called Sanfilippo syndrome, is a rare, genetic lysosomal storage disease that causes neurodegeneration. There are four main types of MPS III, depending on the enzyme affected. Type A is caused by genetic defects that result in reduction in the activity of N-sulfoglucosamine sulfohydrolase (SGSH), an enzyme responsible for degrading heparan sulfate in the lysosome. There are no approved treatments for MPS IIIA. About DNL126 (ETV:SGSH)DNL126 (ETV:SGSH) is an intravenously administered, Enzyme TransportVehicle™ (ETV)-enabled SGSH replacement therapy designed to cross the BBB via receptor-mediated transcytosis into the brain and to enable broad delivery of SGSH into cells and tissues throughout the body with the goal of addressing the behavioral, cognitive, and physical manifestations of MPS IIIA. DNL126 is an investigational therapeutic and has not been approved for use by any Health Authority. About the Phase 1/2 study of DNL126Denali is conducting a multicenter, open-label, Phase 1/2 study to assess the safety, tolerability, pharmacokinetics, pharmacodynamics, and exploratory clinical efficacy of DNL126 in participants with MPS IIIA. The core study period is approximately 6 months and is followed by an open-label extension for approximately 18 months. More information about the Phase 1/2 study can be found here. 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. Cautionary Note Regarding Forward-Looking StatementsThis 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 plans, timelines, and expectations related to Denali's Enzyme TransportVehicle™ (TV) platform and its therapeutic and commercial potential; plans, timelines, and expectations relating to tividenofusp alfa (DNL310), including enrollment in the ongoing global Phase 2/3 COMPASS study, the timing of completion of its BLA submission, the likelihood of accelerated and full approval, and the timing and likelihood of commercial launch; expectations for ongoing communications with the FDA; plans, timelines, and expectations related to DNL126, including enrollment in and timing of the Phase 1/2 study; and statements made by Denali’s Chief Medical Officer. Actual results may differ materially from those expressed or implied by these forward-looking statements due to a variety of risks and uncertainties. These include, but are not limited to: risks arising from adverse economic conditions and their impact on Denali’s business and operations; the possibility of events or changes that could lead to the termination of Denali’s collaboration agreements; challenges associated with Denali’s transition to a late-stage clinical drug development company; the ability of Denali and its collaborators to complete the development and, if approved, the commercialization of product candidates; difficulties in patient enrollment for ongoing and future clinical trials; reliance on third-party manufacturers and suppliers for clinical trial materials; dependence on the successful development of Denali’s blood-brain barrier platform technology and related programs; potential delays or failures in meeting expected clinical trial timelines; the risk that promising preclinical profiles may not be replicated in clinical settings; discrepancies between preclinical, early-stage, or preliminary clinical results and outcomes from later-stage trials; the occurrence of significant adverse events or other undesirable side effects; and the uncertainty surrounding regulatory approvals required for commercialization; Denali’s ability to advance a pipeline of product candidates or develop commercially successful products; developments relating to Denali's competitors and its industry, including competing product candidates and therapies; Denali’s ability to obtain, maintain, or protect intellectual property rights related to its product candidates; implementation of Denali’s strategic plans for its business, product candidates, and blood-brain barrier platform technology; Denali's ability to obtain additional capital to finance its operations, as needed; Denali's ability to accurately forecast future financial results in the current environment; and other risks and uncertainties, including those described in Denali's most recent Annual Report on Form 10-K filed with the Securities and Exchange Commission (SEC) on February 27, 2025 and Denali’s future reports to be filed with the SEC. Denali's product candidates are investigational, and their safety and efficacy profiles have not yet been established. No Denali product candidates have been approved by any health authority for any use. 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. Reference Muenzer, J., et al. Community consensus for Heparan sulfate as a biomarker to support accelerated approval in Neuronopathic Mucopolysaccharidoses. Mol Genet Metab. 2024 Aug;142(4):108535 Investor ContactLaura Hansen, Ph.D.Vice President, Investor Relations(650) 452-2747hansen@dnli.comMedia ContactRich AllanFGS Global(503) 851-0807rich.allan@fgsglobal.com

iStock, Jorm Sangsorn After some high-pro the one-time biotech darling is inching toward success with its Hunter syndrome treatment, which today began a rolling BLA for accelerated approval. Denali Therapeutics has its wheels on the fast track. The company initiated a biologics license application Wednesday for accelerated approval for Hunter syndrome treatment tividenofusp alfa (DNL310). It’s been a long time coming for Denali, which launched in 2015 with what was then the largest first-round venture financing in biotech history, a whopping $215 million. But a decade later, Denali doesn’t yet have an approved product, and its stock has dipped from its 2020 peak of more than $85 to just over $12 today. “When we came out of stealth in 2015, we raised a significant amount of money,” Carole Ho, Denali’s chief medical officer and head of development, told BioSpace . “And there was a question: What were we doing differently?” The brand-new company trumpeted a lofty goal of deploying new approaches to tackle neurodegenerative diseases—by targeting newly discovered genes tied to degenerative brain diseases. A year after launching, Denali scored another $130 million in a series B round led by Genentech veterans and maintained all of its founding investors. The company signed a bevy of research agreements, including deals with Blaze Bioscience and the Fred Hutchinson Cancer Research Center, to work on one of neurology’s toughest problems: getting drugs across the blood-brain barrier (BBB). Now, Denali is eyeing the culmination of these approaches with DNL310, an enzyme-replacement therapy that rides a specialized transport vehicle across the blood-brain barrier. The therapy secured FDA Breakthrough Therapy Designation in January, adding to a list of honors already held by the drug, including Fast Track Designation, Orphan Drug Designation and Rare Pediatric Disease Designation. “All of this suggests the agency’s enthusiasm for the molecule,” Ho said. Stifel analysts responded to the BLA submission Wednesday morning, saying, “We’re potentially nearing the end of an up-and-down regulatory path for [DNL310], where DNLI was finally able to align with FDA’s CDER on leveraging CSF heparan-sulfate (HS) as a surrogate biomarker for the basis of accelerated approval.” Stifel also noted the turbulent times in which this application has been submitted. “Notably, this announcement comes amidst significant turnover at FDA, where several senior directors across both CBER/CDER have departed,” the analysts wrote. From Small to Large Molecules In tackling Hunter syndrome, Denali has tried to set itself up for success. The company wanted to pursue a disease that was relatively derisked, where the underlying biology was very clear, Ho said. Hunter syndrome, a rare, X-linked condition resulting from a loss in the iduronate 2-sulfatase (IDS) enzyme, primarily affects boys and causes damage affecting both physical and mental development. There is one missing gene, the cause is monogenic and the mechanics of how a drug might treat the condition are very clear, even if practically achieving a treatment is still difficult, Ho explained. “If you could just replace that enzyme, you should see benefit.” DNL310 does just that. It is currently being tested in Phase I/II and II/III trials for the disease. Denali recently reported primary results from the earlier-stage study, touting improvements in hearing, cognition and adaptive behavior and a “generally well-tolerated” safety pro to four years. Denali’s getting to the one-yard line on Hunter syndrome may be partly due to a little bit of good timing—piggybacking off of technical advancements in gene sequencing that occurred in the mid-2010s—and changing tactics when other clinical trials failed. “Our early years were focused on small molecules,” Ho said. That includes parts of Denali’s pipeline still in development today, like DNL151, a Biogen-partnered LRRK2-targetting small molecule being developed for Parkinson’s disease. Denali’s pipeline also includes small molecules for Alzheimer’s and amyotrophic lateral sclerosis (ALS), developed as part of a partnership with Sanofi that began in 2018, netting Denali $125 million up front. Those molecules—DNL747 and DNL758—flopped on multiple occasions in early- and mid-stage trials. In a Phase Ib trial testing the drug in Alzheimer’s and ALS, DNL747 had dangerous and difficult-to-manage side effects, and in a Phase II study, DNL788 simply “did not meet the primary endpoint of change” on the ALS Functional Rating Scale-Revised, according to a company statement. In response, Denali laid off staff and dropped not only the Sanofi partnership and molecules but the entire molecular class: no more new small molecules. Going forward, the focus would be almost entirely on large molecules, such as biologics and engineered enzymes. For now, though, the focus is on Hunter and Parkinson’s, Ho said, with ALS and Alzheimer’s having been moved to the back burner. Denali currently has no candidate molecules in the pipeline targeting either disease, according to Ho. “We have a wealth of data there, and we are still interested in ALS in general,” she said, adding that the company is still analyzing data from past trials. Crossing the Blood-Brain Barrier With DNL310 leading the way, Denali is going all-in on drugs that cross the blood-brain barrier. “In terms of therapeutic development, crossing the BBB has been the greatest challenge in neurology,” Ho said. Indeed, it’s a hurdle that has tripped up generations of scientists and pharma companies. To overcome this challenge, the company has a suite of what it calls transport vehicles—molecules engineered to bind to transferrin, a cell surface receptor enriched on the BBB. In the case of DNL310, this is a so-called enzyme transport vehicle, or ETV. “Denali was built on the ability to build a next-gen platform to enable molecules to cross the blood brain barrier,” Ho said. Other biomolecules in Denali’s pipeline have different types of transport vehicles. An oligo transport vehicle (OTV) targets alpha synuclein in Parkinson’s disease, for example, while a progranulin transport vehicle (PTV) delivers a key neuroprotective molecule to patients with frontotemporal dementia. For its now-canned Alzheimer’s program, Denali had developed an antibody transport vehicle (ATV) in partnership with Biogen to deliver anti-amyloid antibodies to the brain (a partnership Biogen walked away from last summer ). Ho emphasized the nuanced nature of this transferrin-based drug delivery system. “In the past, you would always hear that you want high specificity,” she said. “But you don’t want it to stick too much. With transferrin, you want the opposite. You want it to bind but then come off. . . . We’ve fine-tuned this affinity.” This, Ho said, is key to the success of DNL310, which according to Wednesday’s announcement, Denali hopes to launch in late 2025 or early 2026.