Rolling submission of BLA initiated for tividenofusp alfa; preparations ongoing for potential U.S. commercial launch in late 2025 or early 2026

Tividenofusp alfa的BLA滚动提交已启动；正为2025年底或2026年初可能的美国商业上市做准备。

Alignment through recent interactions with CDER on path to accelerated approval and conversion to full approval for tividenofusp alfa

通过最近与CDER的互动，tividenofusp alfa在加速批准和转为完全批准的路径上达成一致。

Productive collaboration continues under START for an accelerated development and approval path for DNL126

在START框架下，DNL126的加速开发和审批路径继续取得富有成效的合作。

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.

南旧金山，加利福尼亚州，2025年4月2日（环球新闻社）——Denali Therapeutics Inc.（纳斯达克股票代码：DNLI）今日宣布，公司已向美国药物评估与研究中心（CDER）提交了Tividenofusp Alfa用于治疗亨特综合征（MPS II）的生物制品许可申请（BLA），以寻求加速批准。

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.

美国食品药品监督管理局 (FDA)。Denali 与 CDER 保持着定期、协作且富有成效的互动，并在 BLA 数据包的内容上与 CDER 保持一致，包括使用脑脊液肝素硫酸盐 (CSF HS) 作为替代终点以支持加速批准，以及完全批准的转换路径。

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..

Denali预计将在2025年5月上半月完成BLA提交，并继续为在2025年底或2026年初可能的美国市场商业发布做准备。

“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.

“我们感谢FDA对我们BLA文件的持续支持以及推动新药发展的不懈努力，”Denali首席医疗官Carole Ho博士表示。“这一监管里程碑使我们更接近为亨特综合征患者群体提供新的治疗选择的目标，同时我们将继续倾听、学习，并寻求他们的建议，以期将tividenofusp alfa带给患者。”

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.”.

我们的进展具有更广泛的积极意义，支持我们下一代酶替代疗法的酶转运载体（Enzyme Transport Vehicle）系列产品扩展到治疗大脑和身体。在此背景下，我们非常感谢通过START计划与CDER保持持续且富有成效的合作，因为我们正在为DNL126的加速开发和审批路径达成一致，DNL126可能用于治疗Sanfilippo综合征。

About Hunter Syndrome (MPS II)

关于亨特综合征 (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.

亨特综合征（MPS II）是一种罕见的遗传病，全球范围内影响超过2000人，主要为男性，并导致身体、认知和行为症状。亨特综合征由艾杜糖醛酸-2-硫酸酯酶（IDS）基因突变引起，导致IDS酶缺乏。

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.

症状通常在两岁左右开始显现，包括身体并发症，如器官功能障碍、关节僵硬、听力丧失和生长受阻，以及神经认知症状和发育受损。该疾病的特点是糖胺聚糖 (GAGs) 在溶酶体中积累——溶酶体是细胞中分解包括 GAGs 在内的物质的部分。

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..

目前的标准治疗方案——酶替代疗法——只能部分缓解身体症状，但无法穿越血脑屏障，因此大多数亨特综合征患者的认知和行为症状仍未得到解决。能够涵盖该疾病认知、行为和身体表现的疗法被认为是这一患者群体未满足的需求。

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About Tividenofusp Alfa

关于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).

Tividenofusp alfa（或DNL310）由艾杜隆酸2-硫酸酯酶（IDS）与Denali专有的酶转运载体™（ETV）融合而成，该设计旨在将IDS递送至大脑和身体，以期解决亨特综合征（MPS II）的行为、认知和躯体症状。

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..

美国食品药品监督管理局（FDA）已授予tividenofusp alfa快速通道和突破性疗法认定，用于亨特综合征（MPS II）治疗的开发。欧洲药品管理局（EMA）已授予tividenofusp alfa优先药物认定。

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

第二/三期COMPASS研究正在北美、南美和欧洲招募MPS II患者，以支持全球批准。参与者按2:1的比例随机分配，分别接受tividenofusp alfa或idursulfase。有关COMPASS研究的更多信息，请访问

here

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Tividenofusp alfa is an investigational therapeutic and has not been approved for use by any Health Authority.

Tividenofusp alfa 是一种研究性治疗药物，尚未获得任何卫生部门的使用批准。

About Sanfilippo Syndrome Type A (MPS IIIA)

关于圣菲利波综合征A型（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.

MPS III，也称为Sanfilippo综合征，是一种罕见的遗传性溶酶体贮积病，会导致神经退行性病变。根据受影响的酶不同，MPS III可分为四种主要类型。A型是由基因缺陷引起的，这些缺陷导致溶酶体内负责降解硫酸肝素的N-磺基葡萄糖胺磺酰水解酶（SGSH）活性降低。

There are no approved treatments for MPS IIIA..

目前尚无获批的MPS IIIA治疗方法。

About DNL126 (ETV:SGSH)

关于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 (ETV:SGSH) 是一种静脉注射的、由酶运输载体™ (ETV) 辅助的 SGSH 替代疗法，旨在通过受体介导的转胞吞作用穿越血脑屏障进入大脑，并实现 SGSH 在全身细胞和组织中的广泛递送，以期解决 MPS IIIA 的行为、认知和身体症状。

DNL126 is an investigational therapeutic and has not been approved for use by any Health Authority.

DNL126 是一种研究性治疗药物，尚未获得任何卫生机构的使用批准。

About the Phase 1/2 study of DNL126

关于DNL126的1/2期研究

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.

Denali 正在进行一项多中心、开放标签的 1/2 期研究，以评估 DNL126 在 MPS IIIA 患者中的安全性、耐受性、药代动力学、药效学及探索性临床疗效。核心研究周期约为 6 个月，随后是为期约 18 个月的开放标签延长期。

More information about the Phase 1/2 study can be found .

有关第1/2阶段研究的更多信息，请参见。

here

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About Denali Therapeutics

关于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 Therapeutics是一家生物制药公司，致力于开发广泛的产品候选组合，这些产品经过工程设计以穿越血脑屏障，用于神经退行性疾病和溶酶体贮积症。Denali通过对基因验证靶点的严格评估、穿越血脑屏障的递送工程设计，并通过展示靶点和通路参与的生物标志物来指导开发，从而寻求新的治疗方法。

Denali is based in South San Francisco. For additional information, please visit .

Denali 总部位于南旧金山。欲了解更多信息，请访问 。

www.denalitherapeutics.com

www.denalitherapeutics.com

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Cautionary Note Regarding Forward-Looking Statements

关于前瞻性陈述的警告声明

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 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.

本新闻稿包含1995年《私人证券诉讼改革法案》所指的前瞻性声明。本新闻稿中明示或暗示的前瞻性声明包括但不限于关于Denali的酶运输载体™（TV）平台及其治疗和商业潜力的计划、时间表和预期；关于tividenofusp alfa（DNL310）的计划、时间表和预期，包括正在进行的全球2/3期COMPASS研究的入组情况、其BLA提交完成的时间、加速批准和完全批准的可能性以及商业上市的时间和可能性；与FDA持续沟通的预期；关于DNL126的计划、时间表和预期，包括1/2期研究的入组和时间安排；以及Denali首席医学官发表的声明。

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 rela.

由于各种风险和不确定性，实际结果可能与这些前瞻性陈述中明示或暗示的结果存在重大差异。这些风险和不确定性包括但不限于：不利经济状况及其对Denali业务和运营的影响所带来的风险；可能导致Denali合作协议终止的事件或变更的可能性；与Denali向晚期临床药物开发公司转型相关的挑战；Denali及其合作伙伴完成产品候选物的开发以及如果获批后的商业化能力；正在进行和未来临床试验中患者招募的困难；对第三方制造商和供应商提供临床试验材料的依赖；对Denali血脑屏障平台技术成功开发的依赖性及相关风险。

Reference

参考文献

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

Muenzer, J., 等。社区共识：硫酸乙酰肝素作为神经性粘多糖贮积症加速批准的支持生物标志物。《分子遗传学与代谢》。2024年8月；142(4):108535。

Investor Contact

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劳拉·汉森，博士

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投资者关系副总裁

(650) 452-2747

(650) 452-2747

hansen@dnli.com

汉森@dnli.com

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