Mucopolysaccharidosis III

Biologics License Application (BLA) Submission to U.S. FDA for Tralesinidase Alfa Enzyme Replacement Therapy (TA-ERT) Anticipated in 1H 2026 Spruce to Host Conference Call Today at 8:30 a.m. ET SOUTH SAN FRANCISCO, Calif.--(BUSINESS WIRE)--Apr. 15, 2025-- Spruce Biosciences, Inc. (Nasdaq: SPRB), a late-stage biopharmaceutical company focused on developing and commercializing novel therapies for neurological disorders with significant unmet medical need, today announced the company’s new corporate strategy and acquisition of tralesinidase alfa enzyme replacement therapy (TA-ERT) for the treatment of Sanfilippo Syndrome Type B (MPS IIIB). “This is truly a transformative moment for Spruce as we focus our expertise in rare disease on a potential near-term commercial opportunity with TA-ERT in MPS IIIB,” said Javier Szwarcberg, M.D., M.P.H., Chief Executive Officer of Spruce. “As a result of the strategic process initiated last year, Spruce acquired TA-ERT for the treatment of children with MPS IIIB, a neurodegenerative and ultimately fatal genetic disease. This new strategy opens a new chapter in our mission to provide transformative and life-changing therapies to patients affected by serious conditions with significant unmet medical need.” Dr. Szwarcberg continued, “In clinical studies, TA-ERT has been shown to significantly and durably normalize cerebral spinal fluid (CSF) heparan sulfate non-reducing end (HS-NRE) levels over a five-year period. Alignment has been achieved with the U.S. Food and Drug Administration (FDA) that HS-NRE could be used as a biomarker that may reasonably predict clinical benefit and serve as a basis for accelerated approval. Based on the existing clinical and non-clinical data, we anticipate submitting a BLA for TA-ERT to the FDA in the first half of 2026. We extend our gratitude to the patient and caregiver advocates, clinicians and industry leaders who have contributed to the TA-ERT program. With no FDA-approved treatments currently available, TA-ERT has the potential to be a groundbreaking advancement for patients and families impacted by MPS IIIB.” “The vision of the Spruce leadership team and their unrelenting commitment to serving patient communities with meaningful unmet need is on full display with the acquisition of TA-ERT,” said Mike Grey, Executive Chairman of Spruce. “The confidence and support shown by our Board underscore the immense potential of the company’s new portfolio and direction.” Corporate Strategy Seek regulatory approval and maximize the U.S. commercial potential of TA-ERT for the treatment of MPS IIIB. Spruce intends to seek U.S. accelerated approval of TA-ERT for MPS IIIB based on existing non-clinical and clinical data. As a condition of seeking such approval of a BLA from the FDA, Spruce will initiate a confirmatory trial. If the BLA is approved, Spruce intends to build a highly specialized commercial and medical affairs organization to support the commercialization of TA-ERT. Given that a relatively small number of clinicians and specialists treat most of the patients with MPS IIIB, the company believes this market can be effectively addressed with a modest-sized and targeted patient-centric field team, alongside various high-touch patient initiatives. Commercialize globally through a patient-focused organization. Spruce seeks to commercialize TA-ERT and its other investigational products throughout the developed world, including North America, the European Union (EU), the United Kingdom (U.K.), Latin America, Turkey, Asia, and other international markets. The company intends to establish its own commercial organization in the U.S., EU, and the U.K., and seek regional strategic collaborations and a network of third-party distributors in other international markets. Focus on serious diseases with significant unmet medical need and clear biology. Spruce focuses on diseases that have biology that is well understood. The company believes that developing drugs that directly impact known disease pathways will increase the probability of success of its development programs. TA-ERT for the Treatment of MPS IIIB Spruce entered into an Asset Purchase Agreement under which the company acquired an exclusive worldwide license agreement with BioMarin Pharmaceutical Inc. for TA-ERT and other enzyme replacement therapy products. TA-ERT is a fusion protein comprised of recombinant human alpha-N-acetylglucosaminidase (rhNAGLU) with modified human insulin-like growth factor 2 via an amino acid linker. TA-ERT is intended as an enzyme replacement therapy for the treatment of patients with MPS IIIB who lack rhNAGLU enzyme activity. In March 2024, in a Type C meeting with the FDA, the FDA confirmed that HS-NRE is deemed to be a surrogate biomarker reasonably likely to predict clinical benefit and could serve as a basis for accelerated approval. The FDA also confirmed that the completed clinical and non-clinical studies of TA-ERT were sufficient for a BLA submission and provided guidance around key design elements of a confirmatory trial, which must be initiated prior to potential accelerated approval of TA-ERT. TA-ERT has received fast-track designation, rare pediatric disease designation, and orphan drug designation in the U.S. and EU. Spruce intends to submit the BLA of TA-ERT for the treatment of MPS IIIB in the first half of 2026. Financial Update Spruce Biosciences also reported financial results for the year ended December 31, 2024. As of December 31, 2024, Spruce had cash and cash equivalents of $38.8 million. The company expects its cash runway to fund its current operating plan through the end of 2025. 42.2 million shares of common stock are issued and outstanding and 21.4 million shares of common stock are reserved for issuance of warrants and equity securities as of December 31, 2024. Please refer to Spruce’s 2024 Annual Report on Form 10-K filed with the U.S. Securities and Exchange Commission today for the company’s full annual 2024 financial results. Conference Call Details Spruce’s management team will host a conference call today at 8:30 a.m. ET to discuss the business update. Analysts and investors can participate in the conference call by registering here. An archived replay of the call will be available on the events section of the company’s investor relations website for approximately 90 days. About Spruce Biosciences Spruce Biosciences is a late-stage biopharmaceutical company focused on developing and commercializing novel therapies for neurological disorders with significant unmet medical need. To learn more, visit www.sprucebio.com and follow us on X, LinkedIn, Facebook and YouTube. Forward Looking Statements Statements contained in this press release regarding matters that are not historical facts are “forward-looking statements” within the meaning of the Private Securities Litigation Reform Act of 1995. Such forward-looking statements include statements regarding, among other things, the ability to seek accelerated approval of TA-ERT for MPS IIIB based on existing clinical data; the anticipated timing and conduct of our confirmatory trial for TA-ERT; the timing and likelihood of regulatory filings and approvals for TA-ERT, including our anticipated BLA Submission of TA-ERT for MPS IIIB in the first half of 2026; our ability to commercialize TA-ERT, if approved, in the United Sates and in international markets; the anticipated market opportunity and level of sales for TA-ERT for MPS IIIB, if approved; our ability to establish a commercial organization in the United States and leverage regional partnerships and a network of third-party distributors in international markets; our intended focus on serious diseases with significant unmet medical need and clear biology; and our expected future financing needs, are forward-looking statements. Because such statements are subject to risks and uncertainties, actual results may differ materially from those expressed or implied by such forward-looking statements. Words such as “anticipate”, “continue”, “will”, “potential”, “on track”, “can”, “intend”, “expect” and similar expressions are intended to identify forward-looking statements. These forward-looking statements are based upon Spruce’s current expectations and involve assumptions that may never materialize or may prove to be incorrect. Actual results could differ materially from those anticipated in such forward-looking statements as a result of various risks and uncertainties, which include, without limitation, risks and uncertainties associated with Spruce’s business in general, the impact of geopolitical and macroeconomic events, and the other risks described in Spruce’s filings with the U.S. Securities and Exchange Commission. All forward-looking statements contained in this press release speak only as of the date on which they were made and are based on management’s assumptions and estimates as of such date. Spruce undertakes no obligation to update such statements to reflect events that occur or circumstances that exist after the date on which they were made, except as required by law. View source version on businesswire.com: https://www.businesswire.com/news/home/20250415826256/en/ Media Katie Beach Oltsik Inizio Evoke Comms (937) 232-4889 katie.beach@inizioevoke.com media@sprucebio.com Investors Samir Gharib President and CFO Spruce Biosciences, Inc. investors@sprucebio.com Source: Spruce Biosciences, Inc.

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