SLC3A2

SOUTH SAN FRANCISCO, Calif., Nov. 06, 2024 (GLOBE NEWSWIRE) -- Denali Therapeutics Inc. (Nasdaq: DNLI) today reported financial results for the third quarter ended September 30, 2024, and provided business highlights. "As leaders in pioneering a new class of therapeutics that cross the blood-brain barrier, we are making significant progress across our Transport Vehicle (TV)-enabled portfolio,” said Ryan Watts, Ph.D., Chief Executive Officer of Denali Therapeutics. “Within our Enzyme TV (ETV) franchise, we are on track to file for accelerated approval of tividenofusp alfa in MPS II in early 2025 after a successful meeting with the FDA in the third quarter. Today, we are also pleased to share that preliminary data from our Phase 1/2 study of DNL126 in MPS IIIA demonstrate a robust reduction from baseline in CSF heparan sulfate levels, including normalization. Based on these data and a positive regulatory environment, we recently expanded the study to support a potential accelerated path. In addition, our recent preclinical publication on our oligonucleotide TV (OTV) technology in Science Translational Medicine, which describes broad and deep brain biodistribution of oligonucleotides following systemic administration of OTV, demonstrates the power and potential of our TV platform to transform the way we treat brain diseases.” Third Quarter 2024 and Recent Program Updates Late-stage and mid-stage clinical programs Tividenofusp alfa (DNL310): Enzyme Transport Vehicle (ETV)-enabled, iduronate-2-sulfatase (IDS) replacement therapy in development for MPS II (Hunter syndrome) In September, announced the outcome of a successful meeting with the Center for Drug Evaluation and Research (CDER) 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. 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. Denali intends to submit the BLA under the accelerated approval pathway in early 2025.In September, presented new interim data from the Phase 1/2 study at the Society for the Study of Inborn Errors of Metabolism (SSIEM 2024), including 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.COMPASS, the global Phase 2/3 study, is expected to complete enrollment in 2024. DNL343: eIF2B activator in development for the treatment of amyotrophic lateral sclerosis (ALS) DNL343 is being evaluated in Regimen G (DNL343) of the Phase 2/3 HEALEY ALS Platform Trial conducted by the Sean M. Healey & AMG Center for ALS at Massachusetts General Hospital (MGH) in collaboration with the Northeast ALS Consortium (NEALS). Enrollment in Regimen G is complete. SAR443820/DNL788: CNS-penetrant RIPK1 inhibitor In October, Denali was informed by its strategic partner Sanofi that the K2 Phase 2 study evaluating the safety and efficacy of oditrasertib (SAR443820/DNL788) on serum neurofilament light chain levels in participants with multiple sclerosis was discontinued based on not meeting the primary and key secondary endpoints. BIIB122/DNL151: LRRK2 inhibitor in development for the treatment of Parkinson’s disease (PD) Biogen is conducting the ongoing global Phase 2b LUMA study of BIIB122 in participants with early-stage Parkinson’s disease.Denali has initiated screening of participants for the global Phase 2a study to evaluate safety and biomarkers associated with BIIB122 in participants with Parkinson’s disease and confirmed pathogenic variants of LRRK2. This study is being funded under the Collaboration and Development Funding Agreement with a third party. Eclitasertib (SAR443122/DNL758): Peripheral RIPK1 inhibitor in development for the treatment of ulcerative colitis (UC) Sanofi is conducting the ongoing Phase 2 study of SAR443122/DNL758 in participants with UC. Early-stage clinical and preclinical programs DNL126: ETV-enabled N-sulfoglucosamine sulfohydrolase (SGSH) replacement therapy in development for the treatment of MPS IIIA (Sanfilippo syndrome Type A) Denali today announced that preliminary data from up to 25 weeks of dosing in the ongoing open-label Phase 1/2 study in MPS IIIA participants demonstrate a significant reduction in CSF HS levels from baseline, including normalization. The safety profile supports continued development. The most frequent treatment emergent adverse events were infusion related reactions of mild and moderate severity in all participants. There was one serious adverse event considered by the investigator not related to drug. Denali plans to present the data at a future medical meeting.Based on the preliminary Phase 1/2 results and a positive regulatory environment, Denali recently expanded the study and continues to assess the development plans including an accelerated approval path.DNL126 was selected in June 2024 for the FDA's Support for clinical Trials Advancing Rare disease Therapeutics (START) program to accelerate the development of rare disease therapeutics, and collaborative engagement has commenced to support progress to a pre-BLA meeting. TAK-594/DNL593: Protein Transport Vehicle (PTV)-enabled progranulin (PGRN) replacement therapy in development for the treatment of frontotemporal dementia-granulin (FTD-GRN) Screening of participants for Cohort B2 in the Phase 1/2 study is ongoing. Oligonucleotide Transport Vehicle (OTV) platform Denali is advancing OTV:MAPT, targeting tau for Alzheimer’s disease, and OTV:SNCA, targeting alpha-synuclein for Parkinson’s disease, in the investigational new drug (IND)-enabling stage of development.In August, announced publication of nonclinical data in the August 14, 2024 issue of Science Translational Medicine (link) demonstrating the ability of the OTV platform to achieve broad biodistribution of antisense oligonucleotides (ASOs) in the central nervous system and skeletal and cardiac muscle following intravenous administration. Antibody Transport Vehicle Amyloid beta (ATV:Abeta) program Denali is working to develop the next generation of anti-amyloid beta therapeutics with ATV:Abeta, which is designed to increase exposure of the therapeutic antibody and achieve broad biodistribution in the brain with the potential for improved efficacy and safety. Preclinical data demonstrated potential for a wider therapeutic window compared to a standard antibody, with superior plaque decoration and reduction and very low rates of amyloid related imaging abnormalities (ARIA). These data are included in a manuscript posted on bioRxiv (link).Denali plans to advance a TfR-targeting ATV:Abeta molecule as well as a CD98hc-targeting ATV:Abeta molecule into development for Alzheimer's disease. Discovery programs Denali applies its deep scientific expertise in neurodegeneration biology and the BBB to discover and develop medicines and platforms with the focus on programs enabled by the TV technology and targeting neurodegenerative disease, including Alzheimer’s and Parkinson’s, and lysosomal storage diseases. 2024 Guidance on Operating Expenses Cash, cash equivalents, and marketable securities were approximately $1.28 billion as of September 30, 2024. Denali is providing updated guidance on cash operating expenses for the full year 2024 and now anticipates an increase of approximately 5-10% compared to 2023, which is an increase from previous guidance of equal to or less than full year 2023 cash operating expenses. This updated guidance is associated with increased activities to support filing of a BLA in early 2025 and commercial readiness for tividenofusp alfa in MPS II, and to accelerate the development of additional therapeutic programs in Denali's TV platform portfolio. Participation in Upcoming Investor Conferences UBS Global Healthcare Conference, November 11-14B. Riley Securities’ Next-Gen Tissue Delivery Modalities Virtual Summit, November 14Stifel 2024 Healthcare Conference, November 18-19Jefferies London Healthcare Conference, November 19-217th Annual Evercore ISI HealthCONx Conference, December 3-5 Third Quarter 2024 Financial Results Net losses were $107.2 million and $99.4 million for the three months ended September 30, 2024 and 2023, respectively. There was no collaboration revenue for the quarter ended September 30, 2024, compared to $1.3 million for the quarter ended September 30, 2023. The decrease in collaboration revenue was primarily due to activities under the Biogen Collaboration Agreement. Total research and development expenses were $98.2 million for the quarter ended September 30, 2024, compared to $89.7 million for the quarter ended September 30, 2023. The increase of approximately $8.5 million for the quarter ended September 30, 2024 was primarily attributable to increases in costs in various clinical stage programs, including ETV:IDS, eIF2B, ETV:SGSH, and LRRK2 reflecting the continued progress of these programs in clinical trials, and increases in TV platform and other program external expenses, reflecting continued investment in TV-enabled product candidates. These increases were partially offset by a decrease in personnel and external expenses associated with the divestiture of Denali’s preclinical small molecule programs. General and administrative expenses were $24.9 million for the quarter ended September 30, 2024, and $25.3 million for the same period in 2023. About Denali Therapeutics Denali Therapeutics is a biopharmaceutical company developing a broad portfolio of product candidates engineered to cross the blood-brain barrier (BBB) for the treatment of neurodegenerative diseases and lysosomal storage diseases. Denali pursues new treatments by rigorously assessing genetically validated targets, engineering delivery across the BBB, 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 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 expectations regarding Denali’s TV technology platform; statements made by Denali’s Chief Executive Officer; plans, timelines, and expectations regarding DNL310 and the ongoing Phase 2/3 COMPASS and Phase 1/2 studies, the timing and likelihood of accelerated approval, and the timing and availability of program updates; plans and timelines regarding DNL343, including the timing and availability of data from the Phase 2/3 HEALEY ALS Platform Trial; plans, timelines, and expectations of both Denali and Sanofi regarding DNL788; plans, timelines, and expectations regarding DNL151, including with respect to the ongoing LUMA study as well as enrollment and timing of the proposed Phase 2a study in PD patients with LRRK2 mutations; expectations regarding DNL758, including the ongoing Phase 2 study in patients with UC; plans, timelines, and expectations related to DNL126, including the timing and availability of data in the ongoing Phase 1/2 study and the timing and likelihood of regulatory approval; plans, timelines, and expectations of both Denali and Takeda regarding DNL593 and the ongoing Phase 1/2 study; plans, timelines, and expectations regarding the advancement of OTV:MAPT and OTV:SNCA towards clinical development; plans, timelines, and expectations regarding the ATV:Abeta program, including its therapeutic potential and the clinical advancement of ATV:Abeta molecules; plans and expectations for Denali's preclinical programs; Denali's future operating expenses and anticipated cash runway; and Denali's participation in upcoming investor conferences. All drugs currently being developed by Denali are investigational and have not received regulatory approval for any indication. Actual results are subject to risks and uncertainties and may differ materially from those indicated by these forward-looking statements as a result of these risks and uncertainties, including but not limited to, risks related to: any and all risks to Denali’s business and operations caused by adverse economic conditions; risk of the occurrence of any event, change, or other circumstance that could give rise to the termination of Denali’s agreements with Sanofi, Takeda, or Biogen, or any of Denali’s other collaboration agreements; Denali’s transition to a late-stage clinical drug development company; Denali’s and its collaborators’ ability to complete the development and, if approved, commercialization of its product candidates; Denali’s and its collaborators’ ability to enroll patients in its ongoing and future clinical trials; Denali’s reliance on third parties for the manufacture and supply of its product candidates for clinical trials; Denali’s dependence on successful development of its blood-brain barrier platform technology and its programs and product candidates; Denali’s and its collaborators' ability to conduct or complete clinical trials on expected timelines; the risk that preclinical profiles of Denali’s product candidates may not translate in clinical trials; the potential for clinical trials to differ from preclinical, early clinical, preliminary or expected results; the risk of significant adverse events, toxicities or other undesirable side effects; the uncertainty that product candidates will receive regulatory approval necessary to be commercialized; Denali’s ability to continue to create 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 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. Denali Therapeutics Inc.Condensed Consolidated Statements of Operations(Unaudited)(In thousands, except share and per share amounts) Three Months Ended September 30, Nine Months Ended September 30, 2024 2023 2024 2023 Collaboration revenue: Collaboration revenue from customers(1)$— $1,267 $— $330,531 Other collaboration revenue — — — — Total collaboration revenue — 1,267 — 330,531 Operating expenses: Research and development(2) 98,238 89,737 296,653 316,073 General and administrative 24,949 25,325 75,379 78,585 Total operating expenses 123,187 115,062 372,032 394,658 Gain from divestiture of small molecule programs — — 14,537 — Loss from operations (123,187) (113,795) (357,495) (64,127)Interest and other income, net 15,995 14,442 49,475 38,376 Net loss$(107,192) $(99,353) $(308,020) $(25,751)Net loss per share, basic and diluted$(0.63) $(0.72) $(1.89) $(0.19)Weighted average number of shares outstanding, basic and diluted 169,456,988 137,644,534 162,589,325 137,076,199 __________________________________________________ (1) Includes related-party collaboration revenue from customers of $1.3 million and $295.5 million for the three and nine months ended September 30, 2023, respectively.(2) Includes expenses for cost sharing payments due to a related party of $3.4 million and $14.5 million for the three and nine months ended September 30, 2023, respectively. Denali Therapeutics Inc.Condensed Consolidated Balance Sheets(Unaudited)(In thousands) September 30, 2024 December 31, 2023Assets Current assets: Cash and cash equivalents$90,636 $127,106Short-term marketable securities 745,923 907,405Prepaid expenses and other current assets 32,280 29,626Total current assets 868,839 1,064,137Long-term marketable securities 445,463 —Property and equipment, net 50,822 45,589Operating lease right-of-use asset 23,717 26,048Finance lease right-of-use asset 38,685 —Other non-current assets 26,487 18,143Total assets$1,454,013 $1,153,917Liabilities and stockholders' equity Current liabilities: Accounts payable$9,594 $9,483Accrued clinical and other research & development costs 23,923 19,035Accrued manufacturing costs 9,568 15,462Accrued compensation 14,874 21,590Operating lease liability, current 8,036 7,260Deferred research and development funding liability, current 16,269 —Other accrued costs and current liabilities 4,829 5,152Total current liabilities 87,093 77,982Operating lease liability, less current portion 38,850 44,981Finance lease liability, less current portion 5,631 —Deferred research funding and development liability, less current portion 3,944 —Total liabilities 135,518 122,963Total stockholders' equity 1,318,495 1,030,954Total liabilities and stockholders’ equity$1,454,013 $1,153,917 Investor Contact:Laura Hansen, Ph.D.Vice President, Investor Relationshansen@dnli.com(650) 452-2747 Media Contact:Rich AllanFGS Global Rich.Allan@fgsglobal.com(503) 851-0807

Biogen has terminated a license to the ATV:Abeta program, which was developed by Denali’s TfR-targeting technology for amyloid beta. Biogen has handed back rights to an early Alzheimer’s disease program to Denali Therapeutics, leaving a large hole in the biotech’s collaboration revenue stream.Biogen has terminated a license to the ATV:Abeta program, which was developed by Denali’s TfR-targeting technology for amyloid beta. The companies had been working on potential Alzheimer’s treatments.Now, the rights will revert back to Denali, including all data generated during the collaboration, according to the biotech’s second-quarter earnings release issued Thursday.Denali looked to put a positive spin on the news. "Today, we are also pleased to share that we have regained the rights to our TfR-based ATV:Abeta program from Biogen, thereby expanding our opportunities for addressing Alzheimer's disease with a potential best-in-class approach,” said Denali CEO Ryan Watts, Ph.D.Denali noted that “Biogen’s decision was not related to any efficacy or safety concerns with the Transport Vehicle platform.” But the end of the partnership represents a big loss in future profits. Denali reported a net loss of $99 million for the second quarter, compared to income of $183.4 million for the same period a year prior. That’s because Denali took home $294.1 million in collaboration revenue for the quarter last year. Of that, $293.9 million was from Biogen.So with no money coming in from Biogen this quarter, Denali has clocked a loss in income.A spokesperson for Denali said the program had royalties remaining in the future, but the "full financial downstream upside" is now back in the biotech's hands. The ATV:Abeta program was licensed in April 2023 when Biogen exercised an existing option from a 2020 collaboration with Denali.With the program back, Denali hopes to advance a TfR-targeting ATV:Abeta molecule and a CD98hc-targeting ATV:Abeta molecule into development for Alzheimer’s, according to the release.The ATV:Abeta technology aims to increase exposure of therapeutic antibodies in the brain to improve efficacy and safety. This is not the first time Biogen has trimmed around the edges of the Denali collaboration. The biopharma cut work on a Parkinson’s disease clinical trial for BIIB122 (DNL151) just over a year ago as the test, which focused on patients with a certain gene mutation, was not expected to have a readout until 2031. The cut was part of Biogen's R&D prioritization. But the companies remain partnered on BIIB122, a selective LRRK2 inhibitor for Parkinson's disease, a spokesperson confirmed to Fierce Biotech in an email. A 640-patient phase 2b test is being conducted by Biogen for patients with early stage disease.

SOUTH SAN FRANCISCO, Calif., Aug. 01, 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 diseases and lysosomal storage diseases, today reported financial results for the second quarter ended June 30, 2024, and provided business highlights. "In the second quarter, our Enzyme Transport Vehicle franchise gained additional momentum with continued engagement with the FDA on an accelerated approval pathway for tividenofusp alfa (DNL310, ETV:IDS) in MPS II and the FDA's selection of DNL126 (ETV:SGSH) in MPS IIIA for the START program," said Ryan Watts, Ph.D., Chief Executive Officer of Denali Therapeutics. “Today, we are also pleased to share that we have regained the rights to our TfR-based ATV:Abeta program from Biogen, thereby expanding our opportunities for addressing Alzheimer's disease with a potential best-in-class approach. We look forward to continuing to make significant progress as leaders in the promising and growing field of BBB-crossing therapeutics." Second Quarter 2024 and Recent Program Updates Late-stage and mid-stage clinical programs Tividenofusp alfa (DNL310): Enzyme Transport Vehicle (ETV)-enabled, iduronate-2-sulfatase (IDS) replacement therapy in development for MPS II (Hunter syndrome) In April, completed enrollment of 47 participants with MPS II in the Phase 1/2 open-label study.COMPASS, the global Phase 2/3 study, is expected to complete enrollment in 2024.In July, Molecular Genetics and Metabolism published a review co-authored by Denali's Chief Medical Officer, Carole Ho, M.D., titled, "Community consensus for heparan sulfate as a biomarker to support accelerated approval in neuronopathic mucopolysaccharidoses", which summarizes many of the presentations at the Reagan-Udall Foundation workshop held in February 2024 and provides a perspective on the path forward for neuronopathic MPS disorders.Following the Reagan-Udall Foundation workshop, Denali received written communication from the Center for Drug Evaluation and Research (CDER) division of the FDA indicating openness to discussing an accelerated approval pathway for tividenofusp alfa in MPS II with cerebrospinal fluid heparan sulfate (CSF HS) as a surrogate biomarker. Denali looks forward to continued engagement with CDER regarding Denali’s intention to file for approval of tividenofusp alfa using the accelerated approval pathway. Denali will provide an update in 2H 2024. DNL343: eIF2B activator in development for the treatment of amyotrophic lateral sclerosis (ALS) In May, the Sean M. Healey & AMG Center for ALS at Massachusetts General Hospital (MGH) in collaboration with the Northeast ALS Consortium (NEALS) announced that enrollment is complete in Regimen G (DNL343) of the Phase 2/3 HEALEY ALS Platform Trial. SAR443820/DNL788: CNS-penetrant RIPK1 inhibitor in development for the treatment of multiple sclerosis (MS) Sanofi is evaluating SAR443820/DNL788 in a Phase 2 study in participants with MS, which is fully enrolled. BIIB122/DNL151: LRRK2 inhibitor in development for the treatment of Parkinson’s disease (PD) Biogen is conducting the ongoing global Phase 2b LUMA study of BIIB122 in participants with early-stage Parkinson’s disease.Denali plans to initiate a global Phase 2a study in 2024 to evaluate safety and biomarkers associated with BIIB122 in participants with Parkinson’s disease and confirmed pathogenic variants of LRRK2. This study is being funded under the Collaboration and Development Funding Agreement with a third party. Eclitasertib (SAR443122/DNL758): Peripheral RIPK1 inhibitor in development for the treatment of ulcerative colitis (UC) Sanofi is conducting the ongoing Phase 2 study of SAR443122/DNL758 in participants with UC. Early-stage clinical and preclinical programs DNL126: ETV-enabled N-sulfoglucosamine sulfohydrolase (SGSH) replacement therapy in development for the treatment of MPS IIIA (Sanfilippo syndrome Type A) In June, Denali announced that the CDER selected DNL126 for participation in the FDA's Support for clinical Trials Advancing Rare disease Therapeutics (START) Pilot Program to further accelerate the development of novel drug and biological products for rare diseases. Participation in START is expected to facilitate and accelerate development of DNL126.Phase 1/2 biomarker and safety data are expected by the end of 2024. TAK-594/DNL593: Protein Transport Vehicle (PTV)-enabled progranulin (PGRN) replacement therapy in development for the treatment of frontotemporal dementia-granulin (FTD-GRN) Denali has finalized the protocol amendment for the Phase 1/2 study and prescreening of participants for Cohort B2 is ongoing. Oligonucleotide Transport Vehicle (OTV) platform Denali is advancing OTV:MAPT, targeting tau for Alzheimer’s disease, and OTV:SNCA, targeting alpha-synuclein for Parkinson’s disease, in the investigational new drug (IND)-enabling stage of development. Antibody Transport Vehicle Amyloid beta (ATV:Abeta) program Today, Denali also announced that Biogen terminated its license to the ATV:Abeta program enabled by Denali’s TfR-targeting technology against amyloid beta for the potential treatment of Alzheimer's disease and granted Denali rights to data generated during the collaboration. As a result of the termination, all rights to develop, manufacture, perform medical affairs activities, and commercialize new TfR-targeting ATV:Abeta therapeutics reverted to Denali. Biogen licensed Denali's TfR-targeting ATV:Abeta program in April 2023 having exercised an option that was part of the 2020 collaboration agreement between the two companies. Biogen’s decision was not related to any efficacy or safety concerns with the Transport Vehicle platform.Denali is working to develop the next generation of anti-amyloid beta therapeutics with ATV:Abeta, which is designed to increase exposure of the therapeutic antibody and achieve broad biodistribution in the brain with the potential for improved efficacy and safety. Preclinical data demonstrated potential for a wider therapeutic window compared to a standard antibody, with superior plaque decoration and reduction and very low rates of amyloid related imaging abnormalities (ARIA). These data are included in a recent manuscript posted on bioRxiv.Denali plans to advance a TfR-targeting ATV:Abeta molecule as well as a CD98hc-targeting ATV:Abeta molecule into development for Alzheimer's disease. Discovery programs Denali applies its deep scientific expertise in neurodegeneration biology and the BBB to discover and develop medicines and platforms with the focus on programs enabled by the TV technology and targeting neurodegenerative disease, including Alzheimer’s and Parkinson’s, and lysosomal storage diseases. In July, Denali posted the manuscript titled, "Fc-engineered large molecules targeting the blood-brain barrier transferrin receptor and CD98hc have distinct central nervous system and peripheral biodistribution compared to standard antibodies" on bioRxiv. Using comprehensive and unbiased approaches, Denali scientists reveal distinct biodistribution of the TfR and CD98hc transport vehicle delivery platforms from the brain single-cell level all the way to the whole body. Participation in Upcoming Investor Conferences BTIG Virtual Biotechnology Conference, August 5-62024 Wedbush PacGrow Healthcare Conference, August 13-14Morgan Stanley 22nd Annual Global Healthcare Conference, September 4-6H.C. Wainwright 26th Annual Global Investment Conference, September 9-112024 Cantor Global Healthcare Conference, September 17-19 Second Quarter 2024 Financial Results Net loss was $99.0 million for the quarter ended June 30, 2024, compared to net income of $183.4 million for the quarter ended June 30, 2023. There was no collaboration revenue for the quarter ended June 30, 2024, compared to $294.1 million for the quarter ended June 30, 2023. The decrease in collaboration revenue was primarily due to $293.9 million of revenue recognized in the quarter ended June 30, 2023 as a result of Biogen exercising their option to license our ATV:Abeta program. Total research and development expenses were $91.4 million for the quarter ended June 30, 2024, compared to $97.5 million for the quarter ended June 30, 2023. The decrease of approximately $6.1 million for the quarter ended June 30, 2024 was primarily attributable to a decrease in personnel and external expenses associated with the divestiture of the Company's preclinical small molecule programs. There were also decreases in external expenses associated with the ATV:TREM2 and PTV:PGRN programs due to the discontinuation of clinical development of TAK-920/DNL919 (ATV:TREM2) in Alzheimer’s disease and voluntary pause of Part B in the TAK-594/DNL593 (PTV:PGRN) Phase 1/2 study, respectively. Additionally, the Company commenced recognition of research funding for the LRRK2 program from the Collaboration and Development Funding Agreement executed in January 2024. These decreases were partially offset by increases in costs in various clinical stage programs, including eIF2B, ETV:SGSH and ETV:IDS reflecting the continued progress of these programs in clinical trials. General and administrative expenses were $25.2 million for the quarter ended June 30, 2024, compared to $26.1 million for the quarter ended June 30, 2023. The decrease of $0.9 million for the quarter ended June 30, 2024 was primarily attributable to a decrease in personnel-related expenses consisting of employee compensation and stock-based compensation expense, partially offset by combined increases of $0.2 million in professional services, facilities and other corporate costs. Cash, cash equivalents, and marketable securities were approximately $1.35 billion as of June 30, 2024. About Denali Therapeutics Denali Therapeutics is a biopharmaceutical company developing a broad portfolio of product candidates engineered to cross the blood-brain barrier (BBB) for the treatment of neurodegenerative diseases and lysosomal storage diseases. Denali pursues new treatments by rigorously assessing genetically validated targets, engineering delivery across the BBB, 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 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 expectations regarding Denali’s TV technology platform; statements made by Denali’s Chief Executive Officer; plans, timelines, and expectations regarding DNL310 and the ongoing Phase 2/3 COMPASS and Phase 1/2 studies, the timing and likelihood of accelerated approval, and the timing and availability of program updates; plans and timelines regarding DNL343, including in Regimen G of the Phase 2/3 HEALEY ALS Platform Trial; plans, timelines, and expectations of both Denali and Sanofi regarding DNL788, including the Phase 2 study in MS; plans, timelines, and expectations regarding DNL151, including with respect to the ongoing LUMA study as well as enrollment and timing of the proposed Phase 2a study in PD patients with LRRK2 mutations; expectations regarding DNL758, including the ongoing Phase 2 study in patients with UC; plans, timelines, and expectations related to DNL126, including the timing and availability of data in the ongoing Phase 1/2 study and the impact on development of participation in START; plans, timelines, and expectations of both Denali and Takeda regarding DNL593 and the ongoing Phase 1/2 study; plans, timelines, and expectations regarding the advancement of OTV:MAPT and OTV:SNCA towards clinical development; plans, timelines, and expectations regarding the ATV:Abeta program, including its therapeutic potential and the clinical advancement of ATV:Abeta molecules; plans and expectations for Denali's preclinical programs; Denali's future operating expenses and anticipated cash runway; Denali's PIPE financing and its anticipated proceeds; and Denali's participation in upcoming investor conferences. Actual results are subject to risks and uncertainties and may differ materially from those indicated by these forward-looking statements as a result of these risks and uncertainties, including but not limited to, risks related to: any and all risks to Denali’s business and operations caused by adverse economic conditions; risk of the occurrence of any event, change, or other circumstance that could give rise to the termination of Denali’s agreements with Sanofi, Takeda, or Biogen, or any of Denali’s other collaboration agreements; Denali’s transition to a late-stage clinical drug development company; Denali’s and its collaborators’ ability to complete the development and, if approved, commercialization of its product candidates; Denali’s and its collaborators’ ability to enroll patients in its ongoing and future clinical trials; Denali’s reliance on third parties for the manufacture and supply of its product candidates for clinical trials; Denali’s dependence on successful development of its blood-brain barrier platform technology and its programs and product candidates; Denali’s and its collaborators' ability to conduct or complete clinical trials on expected timelines; the risk that preclinical profiles of Denali’s product candidates may not translate in clinical trials; the potential for clinical trials to differ from preclinical, early clinical, preliminary or expected results; the risk of significant adverse events, toxicities or other undesirable side effects; the uncertainty that product candidates will receive regulatory approval necessary to be commercialized; Denali’s ability to continue to create 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 and Quarterly Reports on Forms 10-K and 10-Q filed with the Securities and Exchange Commission (SEC) on February 28, 2024 and May 7, 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. Denali Therapeutics Inc.Condensed Consolidated Statements of Operations(Unaudited)(In thousands, except share and per share amounts) Three Months Ended June 30, Six Months Ended June 30, 2024 2023 2024 2023Collaboration revenue: Collaboration revenue from customers(1)$— $294,123 $— $329,264 Total collaboration revenue — 294,123 — 329,264 Operating expenses: Research and development(2) 91,399 97,520 198,415 226,336 General and administrative 25,194 26,120 50,430 53,260 Total operating expenses 116,593 123,640 248,845 279,596 Gain from divestiture of small molecule programs — — 14,537 — Income (loss) from operations (116,593) 170,483 (234,308) 49,668 Interest and other income, net 17,567 12,900 33,480 23,934 Net income (loss)$(99,026) $183,383 $(200,828) $73,602 Net income (loss) per share: Net income (loss) per share, basic$(0.59) $1.34 $(1.26) $0.54 Net income (loss) per share, diluted$(0.59) $1.30 $(1.26) $0.52 Weighted-average shares used in calculating: Net income (loss) per share, diluted 168,831,329 137,047,227 159,117,759 136,787,321 Weighted average number of shares outstanding, basic and diluted 168,831,329 140,930,625 159,117,759 140,550,226 __________________________________________________(1) Includes related-party collaboration revenue from customers of $294.1 million and $294.3 million for the three and six months ended June 30, 2023, respectively.(2) Includes expenses for cost sharing payments due to a related party of $7.0 million and $11.1 million for the three and six months ended June 30, 2023, respectively. Denali Therapeutics Inc.Condensed Consolidated Balance Sheets(Unaudited)(In thousands) June 30, 2024 December 31, 2023Assets Current assets: Cash and cash equivalents$74,679 $127,106 Short-term marketable securities 821,365 907,405 Prepaid expenses and other current assets 32,339 29,626 Total current assets 928,383 1,064,137 Long-term marketable securities 450,994 — Property and equipment, net 48,077 45,589 Operating lease right-of-use asset 24,533 26,048 Other non-current assets 50,578 18,143 Total assets$1,502,565 $1,153,917 Liabilities and stockholders' equity Current liabilities: Accounts payable$13,936 $9,483 Accrued clinical and other research & development costs 19,915 19,035 Accrued manufacturing costs 7,111 15,462 Other accrued costs and current liabilities 6,013 5,152 Accrued compensation 9,555 21,590 Operating lease liability, current 7,771 7,260 Deferred research funding liability 10,232 — Total current liabilities 74,533 77,982 Operating lease liability, less current portion 40,981 44,981 Total liabilities 115,514 122,963 Total stockholders' equity 1,387,051 1,030,954 Total liabilities and stockholders’ equity$1,502,565 $1,153,917 Investor and Media Contact: Laura Hansen, Ph.D.Vice President, Investor Relations(650) 452-2747hansen@dnli.com