Core Viewpoint - Many South Korean workers were sent to the U.S. on questionable documents, raising concerns about compliance with U.S. immigration laws and the potential implications for companies involved in such practices [1] Group 1: Company Implications - The situation highlights the risks companies face regarding immigration enforcement, particularly in light of recent raids [1] - Companies may need to reassess their hiring practices and ensure compliance with immigration regulations to avoid legal repercussions [1] Group 2: Industry Context - The incident reflects broader issues within the labor market, particularly in industries reliant on foreign workers [1] - Stricter U.S. immigration enforcement could lead to labor shortages in certain sectors, impacting overall productivity and operational efficiency [1]

Denali Therapeutics FY Conference Summary Company Overview - Denali Therapeutics focuses on developing therapies that can cross the blood-brain barrier, targeting large molecules such as enzymes and antibodies for neurodegenerative diseases [3][4] Core Industry Insights - The biotech sector is experiencing significant innovation, particularly in the neurodegeneration space, which has seen renewed interest after a period of companies exiting the field [4] - Denali's proprietary technology for crossing the blood-brain barrier is positioned uniquely compared to conventional methods, which enhances its competitive edge [7] Competitive Landscape - The rise of biotech innovation in China is acknowledged, with Denali maintaining a competitive stance through collaborations and a focus on proprietary technology [6] - Denali's approach to blood-brain barrier technologies is distinct, utilizing engineered Fc regions of antibodies, which allows for broader therapeutic applications [7] Regulatory Environment - Denali has filed its first Biologics License Application (BLA) for accelerated approval, with significant engagement with the FDA regarding clinical and manufacturing aspects [12][17] - Recent FDA guidance on rare disease evidence principles is seen as potentially beneficial for Denali's approval processes, particularly for monogenic diseases like Hunter syndrome [14][15] Clinical Development - Denali is running the COMPASS trial, which is expected to provide data for converting accelerated approval to full approval [21] - The company is also preparing for the launch of therapies for Sanfilippo syndrome, leveraging insights gained from the Hunter syndrome program to expedite development [37][41] Product Pipeline - Denali's lead product targets Hunter syndrome, a rare disease affecting approximately 500 patients in the US, with a focus on normalizing biomarkers and improving patient outcomes [24][25] - The company is also advancing programs for Sanfilippo syndrome and Parkinson's disease, with plans to accelerate clinical trials for multiple programs in the coming years [55][60] Financial Position - Denali reported a cash position of $977 million, expected to last into 2028, allowing for continued investment in multiple programs without significant increases in spending per program [62][63] Future Outlook - Denali aims to leverage its unique platform to develop a portfolio of best-in-class therapies, with a focus on capitalizing on its commercial launches to fund future growth [66][69] - The company is positioned to execute on its transport vehicle technology, with expectations to announce new clinical programs by the end of the year [60][62] Key Takeaways - Denali's innovative approach to crossing the blood-brain barrier and its focus on rare diseases positions it well in the competitive biotech landscape [4][7] - Regulatory changes and guidance from the FDA are seen as favorable for Denali's future approvals and market entry [14][15] - The company is strategically expanding its pipeline while maintaining a strong financial position to support its growth initiatives [62][63]

Denali Therapeutics (DNLI) Conference Call Summary Company Overview - Denali Therapeutics focuses on engineering brain delivery technologies for treating neurological diseases, particularly through enzyme replacement therapies [6][7] Key Product: Tividendifusp Alfa (TIVI) - TIVI is an enzyme replacement therapy targeting Hunter syndrome and Sanfilippo syndrome, with a Biologics License Application (BLA) submitted and a priority review granted by the FDA [7][8] - The PDUFA date for TIVI is set for January 5, 2026, indicating a significant milestone for the company [8] Regulatory Engagement - Denali has established a continuous engagement with the FDA, meeting quarterly to discuss trial designs and regulatory pathways [9][10] - Recent FDA guidance on rare diseases supports the use of single-arm trials for conditions with fewer than 1,000 patients, which aligns with Denali's approach for its programs [11][14] Market Dynamics and Patient Population - Approximately 400 to 500 Hunter syndrome patients are estimated in the U.S., with around 2,000 worldwide [15][16] - The majority of patients are currently on Elipraze, which has a three-hour infusion time, while TIVI has an average infusion time of four hours [19][20] - Denali aims to transition patients to at-home infusions, enhancing convenience and patient experience [20][21] Pricing Strategy - Denali is considering a pricing strategy that balances access for both neuropathic and attenuated patient populations, with potential for premium pricing based on clinical data superiority [24][25] Manufacturing and Cost of Goods - Denali expects a cost of goods sold (COGS) of about 20% due to manufacturing efficiencies from using Fc fusions for enzyme production [28][29] Competitive Landscape - Denali anticipates competition from gene therapies in the market, particularly for Sanfilippo syndrome, but believes that enzyme replacement therapy will remain necessary for comprehensive treatment [33][48] - The company is focused on building a franchise around enzyme replacement therapies, with plans to expand into other conditions like Pompe disease [50][54] Future Programs and Milestones - Denali is preparing for a Phase III trial for Sanfilippo syndrome, with an estimated patient population of 300 to 400 in the U.S. [41][43] - The company aims to launch TIVI in the U.S. in 2026 and is working on additional enzyme replacement therapies, including for Pompe disease [36][50][79] Conclusion - Denali Therapeutics is positioned to make significant advancements in the treatment of rare neurological diseases through innovative therapies and strategic regulatory engagement, with a focus on patient-centric solutions and robust clinical data to support its market entry and pricing strategies [6][7][8][9][10][11][14][24][25][28][29][50][54][79]

Core Insights - Denali Therapeutics reported a second-quarter 2025 loss of $0.72 per share, which was narrower than the Zacks Consensus Estimate of a loss of $0.74, but wider than the loss of $0.59 in the same quarter last year [1][8] - The company did not generate any collaboration revenues in the reported quarter, missing the Zacks Consensus Estimate of $25 million [2] - Year-to-date, shares of Denali have declined by 31.7%, while the industry has only seen a 0.6% decline [2] Financial Performance - Research and development expenses increased by 12.4% to $102.7 million, primarily due to higher spending on multiple preclinical programs and increased costs for consultants and general facilities [4] - General and administrative expenses rose by 28% to $32.3 million, driven by preparations for the potential launch of tividenofusp alfa [4] - As of June 30, 2025, the company had cash, cash equivalents, and marketable securities totaling approximately $977.4 million [5] Pipeline Developments - The FDA accepted Denali's biologics license application (BLA) for tividenofusp alfa for priority review, with a target action date set for January 5, 2026 [6][8] - The BLA seeks accelerated approval based on data from a phase I/II study in individuals with Hunter syndrome, with previous designations from the FDA including Breakthrough Therapy and Fast Track [7] - Denali is also advancing DNL126 for Sanfilippo syndrome type A, with alignment from the FDA on using cerebrospinal fluid heparan sulfate as a surrogate endpoint for accelerated approval [10] Ongoing Studies - Data from the ongoing phase I/II study of DNL126 shows a significant reduction in cerebrospinal fluid heparan sulfate levels, supporting continued development [11] - Denali is conducting a phase I/II study of DNL593 for frontotemporal dementia, in collaboration with Takeda [12] - The company is also evaluating BIIB122/DNL151 in partnership with Biogen for Parkinson's disease, with a global phase IIb study fully enrolled [13][14] Future Plans - Denali plans to submit regulatory applications for one to two TV-enabled programs each year over the next three years across its various franchises [15] - The most advanced programs include DNL952 for Pompe disease and DNL111 for Parkinson's/Gaucher disease, among others [15] Overall Assessment - Denali's recent pipeline progress is viewed positively, with potential approval of tividenofusp alfa expected to significantly boost the company [16] - The strong cash position is seen as a positive factor for funding ongoing programs [16]

PART I. FINANCIAL INFORMATION [Item 1. Financial Statements](index=3&type=section&id=Item%201.%20Financial%20Statements) The unaudited condensed consolidated financial statements for Denali Therapeutics Inc. as of June 30, 2025, show a decrease in total assets to $1.17 billion from $1.37 billion at year-end 2024, primarily due to cash used in operations [Condensed Consolidated Balance Sheets](index=3&type=section&id=Condensed%20Consolidated%20Balance%20Sheets) As of June 30, 2025, the company's total assets were $1.17 billion, a decrease from $1.37 billion at December 31, 2024, driven by a reduction in cash and long-term marketable securities Condensed Consolidated Balance Sheet Highlights (in thousands) | Account | June 30, 2025 | December 31, 2024 | | :--- | :--- | :--- | | Cash and cash equivalents | $141,207 | $174,960 | | Total current assets | $934,706 | $864,436 | | **Total assets** | **$1,166,241** | **$1,374,180** | | Total current liabilities | $91,057 | $102,208 | | **Total liabilities** | **$139,188** | **$144,496** | | **Total stockholders' equity** | **$1,027,053** | **$1,229,684** | [Condensed Consolidated Statements of Operations and Comprehensive Loss](index=4&type=section&id=Condensed%20Consolidated%20Statements%20of%20Operations%20and%20Comprehensive%20Loss) For the three months ended June 30, 2025, Denali reported a net loss of $124.1 million, compared to a $99.0 million loss in the same period of 2024, primarily due to increased research and development expenses Statement of Operations Highlights (in thousands, except per share data) | Metric | Three Months Ended June 30, 2025 | Three Months Ended June 30, 2024 | Six Months Ended June 30, 2025 | Six Months Ended June 30, 2024 | | :--- | :--- | :--- | :--- | :--- | | Research and development | $102,696 | $91,399 | $218,923 | $198,415 | | General and administrative | $32,267 | $25,194 | $61,620 | $50,430 | | Loss from operations | $(134,963) | $(116,593) | $(280,543) | $(234,308) | | **Net loss** | **$(124,119)** | **$(99,026)** | **$(257,089)** | **$(200,828)** | | Net loss per share | $(0.72) | $(0.59) | $(1.50) | $(1.26) | [Condensed Consolidated Statements of Stockholders' Equity](index=5&type=section&id=Condensed%20Consolidated%20Statements%20of%20Stockholders'%20Equity) Total stockholders' equity decreased from $1.23 billion at the end of 2024 to $1.03 billion as of June 30, 2025, primarily driven by the net loss for the six-month period - Total stockholders' equity declined by approximately **$202.6 million** in the first six months of 2025, from **$1,229,684 thousand** to **$1,027,053 thousand**[15](index=15&type=chunk) - The primary driver of the decrease in equity was the net loss of **$257,089 thousand** for the six months ended June 30, 2025[15](index=15&type=chunk) [Condensed Consolidated Statements of Cash Flows](index=6&type=section&id=Condensed%20Consolidated%20Statements%20of%20Cash%20Flows) For the six months ended June 30, 2025, net cash used in operating activities was $206.8 million, while net cash provided by investing activities was $176.7 million, resulting in a net decrease in cash of $32.2 million Cash Flow Summary (in thousands) | Activity | Six Months Ended June 30, 2025 | Six Months Ended June 30, 2024 | | :--- | :--- | :--- | | Net cash used in operating activities | $(206,766) | $(204,840) | | Net cash provided by (used in) investing activities | $176,683 | $(354,618) | | Net cash (used in) provided by financing activities | $(2,139) | $507,031 | | **Net decrease in cash, cash equivalents and restricted cash** | **$(32,222)** | **$(52,427)** | [Notes to Condensed Consolidated Financial Statements](index=7&type=section&id=Notes%20to%20Condensed%20Consolidated%20Financial%20Statements) The notes detail significant accounting policies, fair value measurements, collaboration agreements, and commitments, including the termination of several collaboration programs and a research and development funding agreement - In July 2024, Biogen terminated its license to the ATV:Abeta program for Alzheimer's disease, ending future milestone or royalty payments for this program[51](index=51&type=chunk) - In February 2025, Sanofi terminated its license to the CNS Products program (SAR443820/DNL788), and Takeda terminated the ATV:TREM2 collaboration program[54](index=54&type=chunk)[58](index=58&type=chunk) - The company entered into an R&D funding agreement in January 2024, receiving **$25.0 million** in 2024 and another **$25.0 million** in Q1 2025 to support a Phase 2a study of BIIB122/DNL151 in Parkinson's disease[48](index=48&type=chunk)[49](index=49&type=chunk) - In March 2024, the company divested certain preclinical small molecule programs to Tenvie Therapeutics, Inc. in exchange for **$15.0 million** in equity, recognizing a gain of approximately **$14.5 million**[80](index=80&type=chunk)[81](index=81&type=chunk)[82](index=82&type=chunk) [Item 2. Management's Discussion and Analysis of Financial Condition and Results of Operations](index=22&type=section&id=Item%202.%20Management's%20Discussion%20and%20Analysis%20of%20Financial%20Condition%20and%20Results%20of%20Operations) Management discusses the company's financial results, highlighting an increase in operating expenses driven by advancing clinical programs and operating a new manufacturing facility, with sufficient cash to fund operations for at least the next twelve months [Overview and Key Milestones](index=23&type=section&id=Overview%20and%20Key%20Milestones) The company highlights its strategy focused on its Transport Vehicle (TV) platform and key operational milestones in 2025, including BLA submission for tividenofusp alfa and alignment with the FDA on an accelerated approval pathway for DNL126 - Completed a rolling Biologics License Application (BLA) submission for tividenofusp alfa (DNL310) for MPS II under the accelerated approval pathway in May 2025[94](index=94&type=chunk) - The FDA accepted the BLA for tividenofusp alfa for priority review, with a PDUFA target action date of January 5, 2026[94](index=94&type=chunk) - Reached alignment with the FDA that cerebrospinal fluid heparan sulfate (CSF HS) may be used as a surrogate endpoint to support accelerated approval of DNL126 for MPS IIIA[94](index=94&type=chunk) - Opened a new clinical biomanufacturing facility in Salt Lake City, Utah, in March 2025 to expand manufacturing capabilities[94](index=94&type=chunk) [Results of Operations](index=29&type=section&id=Results%20of%20Operations) For the six months ended June 30, 2025, R&D expenses increased by $20.5 million (10%) and G&A expenses rose by $11.2 million (22%), primarily due to TV programs, the new manufacturing facility, and commercial launch preparations Change in Operating Expenses (Six Months Ended June 30, in thousands) | Expense Category | 2025 | 2024 | Change ($) | Change (%) | | :--- | :--- | :--- | :--- | :--- | | Research and development | $218,923 | $198,415 | $20,508 | 10% | | General and administrative | $61,620 | $50,430 | $11,190 | 22% | | **Total operating expenses** | **$280,543** | **$248,845** | **$31,698** | **13%** | - The increase in R&D expenses was primarily due to an **$18.1 million** increase in TV program external costs and a **$12.3 million** increase in other R&D expenses related to the new Salt Lake City facility[113](index=113&type=chunk) - The increase in G&A expenses was primarily driven by activities related to preparations for a potential commercial launch for tividenofusp alfa[114](index=114&type=chunk) [Liquidity and Capital Resources](index=31&type=section&id=Liquidity%20and%20Capital%20Resources) As of June 30, 2025, the company had $977.4 million in cash, cash equivalents, and marketable securities, which management believes is sufficient to support projected operations for at least the next twelve months - The company held **$977.4 million** in cash, cash equivalents, and marketable securities as of June 30, 2025[116](index=116&type=chunk) - In February 2024, the company received net proceeds of approximately **$499.3 million** from a private placement of common stock and pre-funded warrants[118](index=118&type=chunk) - Management believes existing cash is sufficient to fund operations for at least the next twelve months from the filing date of this report[124](index=124&type=chunk) [Item 3. Quantitative and Qualitative Disclosures About Market Risk](index=35&type=section&id=Item%203.%20Quantitative%20and%20Qualitative%20Disclosures%20About%20Market%20Risk) The company is exposed to market risks primarily from interest rate and foreign currency sensitivities on its $977.4 million investment portfolio, though a hypothetical 10% change in interest rates is not expected to have a material impact - The company's primary market risk exposures are interest rate sensitivity on its **$977.4 million** portfolio of cash and marketable securities and foreign currency risk[135](index=135&type=chunk)[136](index=136&type=chunk) - The investment portfolio is designed to preserve capital and consists of high-credit-quality, short-term duration securities. A hypothetical **10%** change in interest rates is not expected to have a material impact[137](index=137&type=chunk) - Foreign currency risk arises from transactions denominated in the Euro, Swiss Franc, and British Pound related to preclinical, clinical, and manufacturing activities[138](index=138&type=chunk) [Item 4. Controls and Procedures](index=36&type=section&id=Item%204.%20Controls%20and%20Procedures) Management concluded that the company's disclosure controls and procedures were effective as of June 30, 2025, with no material changes to internal control over financial reporting during the quarter - The CEO and CFO concluded that as of June 30, 2025, the company's disclosure controls and procedures were effective at a reasonable assurance level[141](index=141&type=chunk) - No changes in internal control over financial reporting occurred during the quarter ended June 30, 2025, that have materially affected, or are reasonably likely to materially affect, internal controls[142](index=142&type=chunk) PART II. OTHER INFORMATION [Item 1. Legal Proceedings](index=37&type=section&id=Item%201.%20Legal%20Proceedings) The company is not currently a party to any litigation or legal proceedings that management believes are likely to have a material adverse effect on its business - Denali is not currently involved in any legal proceedings expected to have a material adverse effect on the business[144](index=144&type=chunk) [Item 1A. Risk Factors](index=37&type=section&id=Item%201A.%20Risk%20Factors) This section details significant risks that could harm the company's business, financial condition, and growth prospects, including its history of net losses, dependence on its TV platform, drug development uncertainty, regulatory hurdles, reliance on third parties, and intellectual property challenges [Risks Related to Business, Financial Condition and Capital Requirements](index=40&type=section&id=Risks%20Related%20to%20Our%20Business,%20Financial%20Condition%20and%20Capital%20Requirements) The company has a limited operating history, no approved products, and a history of significant net losses, with future profitability uncertain and potential need for additional dilutive capital - The company has incurred significant net losses since inception, with an accumulated deficit of **$1.80 billion** as of June 30, 2025, and expects to continue incurring losses[154](index=154&type=chunk) - As a clinical-stage company with no approved products, its business is difficult to evaluate and subject to the high risks of drug development[153](index=153&type=chunk) - The company may require additional financing to complete development and commercialization, and failure to obtain it could force delays or discontinuation of programs[164](index=164&type=chunk)[167](index=167&type=chunk) [Risks Related to Discovery, Development, and Commercialization](index=43&type=section&id=Risks%20Related%20to%20the%20Discovery,%20Development%20and%20Commercialization%20of%20Our%20Product%20Candidates) The company's success is heavily dependent on its TV platform and clinical-stage candidates, facing high failure rates in neurodegenerative diseases, risks of clinical trial delays, and challenges in manufacturing, competition, and market acceptance - The company is heavily dependent on the success of its TV technology and its pipeline candidates, which are still in development and may not receive regulatory approval[169](index=169&type=chunk) - The company's focus on neurodegenerative and lysosomal storage diseases is a high-risk field with a history of limited drug development success[175](index=175&type=chunk) - Clinical trials may be substantially delayed or fail, as exemplified by the Phase 2/3 HEALEY ALS Platform Trial for DNL343, which did not meet its primary endpoints[171](index=171&type=chunk)[177](index=177&type=chunk) [Risks Related to Regulatory Approval and Legal Compliance](index=57&type=section&id=Risks%20Related%20to%20Regulatory%20Approval%20and%20Other%20Legal%20Compliance%20Matters) The regulatory approval process is lengthy, costly, and unpredictable, with no guarantee of success, and products will be subject to extensive ongoing scrutiny and compliance with complex healthcare and data privacy laws - The regulatory approval process is lengthy and unpredictable, and there is no guarantee that any product candidates will be approved[224](index=224&type=chunk) - Even if accelerated approval is granted for DNL310, the FDA will require a confirmatory study, and failure of this study could lead to withdrawal of the approval[235](index=235&type=chunk) - The business is subject to complex and evolving U.S. and foreign laws regarding data privacy (GDPR, CCPA) and healthcare fraud and abuse, with non-compliance risking significant penalties[243](index=243&type=chunk)[245](index=245&type=chunk) [Risks Related to Reliance on Third Parties](index=66&type=section&id=Risks%20Related%20to%20Our%20Reliance%20on%20Third%20Parties) Denali depends heavily on collaborations with partners for development and commercialization, and on third-party CROs and CDMOs for clinical trials and manufacturing, introducing risks related to performance, regulatory compliance, and supply chain continuity - The company depends on collaborations with third parties (e.g., Biogen, Sanofi, Takeda) for R&D and commercialization, and the success of these programs depends on the collaborators' performance[257](index=257&type=chunk) - Denali relies on third-party CROs to conduct clinical trials and third-party manufacturers for most of its materials, creating risks related to quality, timeliness, and regulatory compliance[262](index=262&type=chunk)[267](index=267&type=chunk) [Risks Related to Intellectual Property](index=70&type=section&id=Risks%20Related%20to%20Our%20Intellectual%20Property) The company's success depends on obtaining and maintaining patent protection for its TV platform and product candidates, which is challenging and subject to risks of invalidation, non-compliance with license agreements, and third-party infringement claims - The company's ability to commercialize its products depends on obtaining and maintaining patent protection for its TV platform and candidates, which is uncertain[275](index=275&type=chunk)[277](index=277&type=chunk) - The company relies on licenses from third parties (e.g., Genentech, F-star) and could lose important rights if it fails to comply with its obligations under these agreements[285](index=285&type=chunk)[289](index=289&type=chunk) - The company may face third-party claims of intellectual property infringement, which could be expensive to defend and could prevent or delay the commercialization of its products[318](index=318&type=chunk)[322](index=322&type=chunk) [Risks Related to Operations](index=84&type=section&id=Risks%20Related%20to%20Our%20Operations) The company is highly dependent on key personnel and faces challenges in managing growth, with internal computer systems vulnerable to cyberattacks and operations subject to disruption from external events - Denali is highly dependent on its key managerial and scientific personnel, and the inability to attract and retain them could harm the business[328](index=328&type=chunk)[329](index=329&type=chunk) - Internal computer systems are vulnerable to security breaches and cyberattacks, which could lead to data loss, disruption of development programs, and liability[338](index=338&type=chunk)[340](index=340&type=chunk) - Business operations are subject to risks from international operations, economic instability, and disruptions like natural disasters or public health crises[343](index=343&type=chunk)[345](index=345&type=chunk) [Risks Related to Ownership of Common Stock](index=90&type=section&id=Risks%20Related%20to%20Ownership%20of%20Our%20Common%20Stock) The market price of the company's common stock is highly volatile, future capital raises may cause significant dilution, and principal stockholders and management can exercise substantial influence - The trading price of the company's common stock is highly volatile and subject to wide fluctuations[350](index=350&type=chunk) - Raising additional capital may cause dilution to existing stockholders or require relinquishing rights to technologies or product candidates[356](index=356&type=chunk)[358](index=358&type=chunk) - Principal stockholders and management own a significant percentage of stock, enabling them to exercise significant influence over matters requiring stockholder approval[360](index=360&type=chunk) [Item 2. Unregistered Sales of Equity Securities and Use of Proceeds](index=95&type=section&id=Item%202.%20Unregistered%20Sales%20of%20Equity%20Securities%20and%20Use%20of%20Proceeds) In February 2024, the company completed a private placement of common stock and pre-funded warrants, raising approximately $499.3 million for R&D, TV technology expansion, and general corporate purposes - On February 29, 2024, the company closed a private placement of **3,244,689** shares of common stock and pre-funded warrants to purchase **26,046,065** shares, receiving net proceeds of approximately **$499.3 million**[375](index=375&type=chunk) - The proceeds will be used to support R&D, accelerate the BBB-crossing TV technology, and for general corporate purposes[375](index=375&type=chunk) [Item 5. Other Information](index=95&type=section&id=Item%205.%20Other%20Information) Co-founder Marc Tessier-Lavigne will step down from the Board effective September 1, 2025, and no officers or directors adopted or terminated a Rule 10b5-1 trading plan during the second quarter of 2025 - Co-founder and Board member Marc Tessier-Lavigne will step down from the Board effective September 1, 2025[383](index=383&type=chunk) - No officers or directors adopted or terminated a Rule 10b5-1 trading arrangement during the second quarter ended June 30, 2025[384](index=384&type=chunk)

[Business Highlights and Program Updates](index=1&type=section&id=Business%20Highlights%20and%20Program%20Updates) Denali Therapeutics achieved significant regulatory milestones for its Transport Vehicle (TV) platform, advancing multiple clinical and preclinical programs [Overview](index=1&type=section&id=Overview) Denali Therapeutics made significant regulatory progress for its Transport Vehicle (TV) platform, including FDA priority review for tividenofusp alfa and an accelerated approval pathway for DNL126 - The CEO highlighted the potential of the company's **Transport Vehicle (TV) platform** to create a new class of therapeutics that can cross the blood-brain barrier, positioning Denali to deliver treatments for lysosomal, neurodegenerative, and other serious diseases[3](index=3&type=chunk) - The FDA accepted the Biologics License Application (BLA) for tividenofusp alfa for Hunter syndrome for **priority review**, with a PDUFA target action date of **January 5, 2026**[4](index=4&type=chunk)[6](index=6&type=chunk) - An **accelerated approval pathway** for DNL126 for Sanfilippo syndrome Type A was aligned with the FDA[5](index=5&type=chunk)[6](index=6&type=chunk) - The company is on track to submit regulatory applications in 2025 to begin clinical testing for **one to two additional TV-enabled programs**[6](index=6&type=chunk) - Preclinical research on the **ATV:Abeta program** for Alzheimer's disease was published in the journal ***Science***, demonstrating potential advantages in crossing the blood-brain barrier and reducing ARIA risk[6](index=6&type=chunk)[10](index=10&type=chunk) [Clinical Programs](index=1&type=section&id=Clinical%20Programs) Denali's clinical pipeline advanced significantly with tividenofusp alfa under FDA priority review and DNL126 on an accelerated approval pathway [Tividenofusp alfa (DNL310) for Hunter syndrome (MPS II)](index=1&type=section&id=Tividenofusp%20alfa%20(DNL310)%20for%20Hunter%20syndrome%20(MPS%20II)) The FDA accepted the Biologics License Application (BLA) for tividenofusp alfa for priority review, setting a PDUFA target action date of January 5, 2026 - The FDA accepted the BLA for tividenofusp alfa for **priority review** and assigned a PDUFA target action date of **January 5, 2026**[4](index=4&type=chunk) - The BLA seeks **accelerated approval** based on data from the Phase 1/2 study[4](index=4&type=chunk) - The company is preparing for **commercial launch** and conducting the **Phase 2/3 COMPASS study** to support global regulatory submissions[4](index=4&type=chunk) [DNL126 (ETV:SGSH) for Sanfilippo syndrome type A (MPS IIIA)](index=1&type=section&id=DNL126%20(ETV%3ASGSH)%20for%20Sanfilippo%20syndrome%20type%20A%20(MPS%20IIIA)) Denali has aligned with the FDA that cerebrospinal fluid heparan sulfate (CSF HS) can be used as a surrogate endpoint to support an accelerated approval for DNL126 - Reached alignment with the FDA that **CSF heparan sulfate (CSF HS)** may be used as a surrogate endpoint to support **accelerated approval**[5](index=5&type=chunk) - Ongoing open-label Phase 1/2 study data demonstrated a **significant reduction in CSF HS** from baseline, supporting continued development[5](index=5&type=chunk) - Enrollment in the Phase 1/2 study is **nearly complete**, and planning for a confirmatory **global Phase 3 study** is underway[5](index=5&type=chunk) [TAK-594/DNL593 (PTV:PGRN) for GRN-related frontotemporal dementia](index=2&type=section&id=TAK-594%2FDNL593%20(PTV%3APGRN)%20for%20GRN-related%20frontotemporal%20dementia) The collaboration with Takeda to develop DNL593, a therapeutic designed to cross the blood-brain barrier for the treatment of FTD-GRN, is progressing with a Phase 1/2 study currently ongoing - Denali and Takeda are collaborating on the development of **DNL593** for FTD-GRN, with a **Phase 1/2 study** currently ongoing[7](index=7&type=chunk) [BIIB122/DNL151 (small molecule LRRK2 inhibitor) for Parkinson's disease (PD)](index=2&type=section&id=BIIB122%2FDNL151%20(small%20molecule%20LRRK2%20inhibitor)%20for%20Parkinson's%20disease%20(PD)) In partnership with Biogen, the Phase 2b LUMA study of LRRK2 inhibitor BIIB122 has completed enrollment, with results expected in 2026 - The **Phase 2b LUMA study** of BIIB122, co-developed with Biogen, has completed enrollment with a readout expected in **2026**[8](index=8&type=chunk) - Denali is also conducting the **Phase 2a BEACON study**, which focuses on LRRK2-associated Parkinson's disease[8](index=8&type=chunk) [IND-Enabling Stage Programs](index=2&type=section&id=IND-Enabling%20Stage%20Programs) Denali plans to advance one to two new TV-enabled programs into clinical testing annually, with preclinical data for ATV:Abeta showing improved brain distribution and reduced ARIA risk - The company expects to submit regulatory applications to begin clinical testing of **one to two TV-enabled programs each year** for the next three years[9](index=9&type=chunk) - Advanced preclinical programs include candidates for **Pompe disease (DNL952)**, **Parkinson's/Gaucher disease (DNL111)**, **MPS I (DNL622)**, and **Alzheimer's disease (DNL921, DNL628)**[9](index=9&type=chunk) - Preclinical data published in ***Science*** for the **ATV:Abeta program** demonstrated **improved brain distribution** and **reduced ARIA risk** in a mouse model compared to conventional antibody treatment[10](index=10&type=chunk) [Second Quarter 2025 Financial Results](index=3&type=section&id=Second%20Quarter%202025%20Financial%20Results) Denali reported an increased net loss in Q2 2025 due to higher R&D and G&A expenses, while maintaining a strong cash position [Financial Performance Summary](index=3&type=section&id=Financial%20Performance%20Summary) For the second quarter of 2025, Denali reported a net loss of $124.1 million, an increase from $99.0 million in the same period of 2024 | Financial Metric | Q2 2025 | Q2 2024 | | :--- | :--- | :--- | | Net Loss | $124.1 million | $99.0 million | | Research & Development Expenses | $102.7 million | $91.4 million | | General & Administrative Expenses | $32.3 million | $25.2 million | | Cash, Cash Equivalents, & Marketable Securities | $977.4 million | N/A | - The **$11.3 million increase in R&D expenses** was primarily driven by increased spending on preclinical TV programs and costs associated with the commencement of operations at the Salt Lake City manufacturing facility[13](index=13&type=chunk) - The **$7.1 million increase in G&A expenses** was mainly due to activities related to preparations for a potential commercial launch of tividenofusp alfa[14](index=14&type=chunk) [Condensed Consolidated Statements of Operations](index=5&type=section&id=Condensed%20Consolidated%20Statements%20of%20Operations) The statement of operations shows a net loss of $124.1 million for Q2 2025, compared to a net loss of $99.0 million for the same period in 2024 | (In thousands, except per share amounts) | Three Months Ended June 30, 2025 | Three Months Ended June 30, 2024 | | :--- | :--- | :--- | | Research and development | $102,696 | $91,399 | | General and administrative | $32,267 | $25,194 | | **Total operating expenses** | **$134,963** | **$116,593** | | Loss from operations | ($134,963) | ($116,593) | | Interest and other income, net | $10,844 | $17,567 | | **Net loss** | **($124,119)** | **($99,026)** | | Net loss per share, basic and diluted | ($0.72) | ($0.59) | [Condensed Consolidated Balance Sheets](index=6&type=section&id=Condensed%20Consolidated%20Balance%20Sheets) As of June 30, 2025, Denali had total assets of $1.17 billion, compared to $1.37 billion at the end of 2024 | (In thousands) | June 30, 2025 | December 31, 2024 | | :--- | :--- | :--- | | **Assets** | | | | Cash, cash equivalents, and marketable securities | $977,415 | $1,191,704 | | Total current assets | $934,706 | $864,436 | | **Total assets** | **$1,166,241** | **$1,374,180** | | **Liabilities and Stockholders' Equity** | | | | Total current liabilities | $91,057 | $102,208 | | **Total liabilities** | **$139,188** | **$144,496** | | **Total stockholders' equity** | **$1,027,053** | **$1,229,684** | [Corporate Information](index=2&type=section&id=Corporate%20Information) Denali Therapeutics will participate in upcoming investor conferences and continues its focus on developing therapies to cross the blood-brain barrier [Upcoming Investor Conferences](index=2&type=section&id=Upcoming%20Investor%20Conferences) Denali is scheduled to participate in seven investor conferences between September and November 2025, including events hosted by Cantor, Morgan Stanley, Baird, H.C. Wainwright, Deutsche Bank, Stifel, and Jefferies - The company will participate in **seven investor conferences** in the fall of 2025, providing opportunities to engage with the investment community[11](index=11&type=chunk) [About Denali Therapeutics](index=3&type=section&id=About%20Denali%20Therapeutics) Denali Therapeutics is a biopharmaceutical company based in South San Francisco, focused on 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's core strategy involves developing therapies engineered to cross the **blood-brain barrier (BBB)** to treat neurodegenerative and lysosomal storage diseases[16](index=16&type=chunk) - The company's approach includes assessing genetically validated targets and using biomarkers to guide development[16](index=16&type=chunk)

Core Insights - Denali Therapeutics reported financial results for Q2 2025, highlighting significant advancements in its clinical programs and financial performance [1][12]. Clinical Programs - The FDA accepted Denali's Biologics License Application (BLA) for tividenofusp alfa for Hunter syndrome, with a PDUFA target action date of January 5, 2026, indicating a potential accelerated approval path [3][8]. - DNL126 for Sanfilippo syndrome type A has reached alignment with the FDA on using cerebrospinal fluid heparan sulfate as a surrogate endpoint for accelerated approval, with ongoing Phase 1/2 study data showing significant reductions in CSF HS [4][8]. - Denali is collaborating with Takeda on DNL593 for frontotemporal dementia, with a Phase 1/2 study currently in progress [5]. - The company is co-developing BIIB122 with Biogen for Parkinson's disease, with the Phase 2b LUMA study completed enrollment and results expected in 2026 [6]. Financial Performance - Denali reported a net loss of $124.1 million for Q2 2025, compared to a net loss of $99.0 million in Q2 2024 [12][19]. - Research and development expenses increased to $102.7 million in Q2 2025 from $91.4 million in Q2 2024, driven by external R&D expenses and personnel-related costs [13][19]. - General and administrative expenses rose to $32.3 million in Q2 2025 from $25.2 million in Q2 2024, primarily due to preparations for the potential commercial launch of tividenofusp alfa [14][19]. - As of June 30, 2025, Denali had approximately $977.4 million in cash, cash equivalents, and marketable securities [14]. Research and Development Pipeline - Denali plans to submit regulatory applications for one to two additional TV-enabled programs each year over the next three years, with advanced programs including DNL952 for Pompe disease and DNL111 for Parkinson's/Gaucher disease [9]. - Preclinical research on the ATV:Abeta program for Alzheimer's disease was published, demonstrating improved brain distribution and reduced ARIA risk compared to conventional treatments [10].

Core Viewpoint - Alzheimer's disease (AD) is a severe neurodegenerative disorder with significant impacts on individuals and society, yet drug development has faced numerous failures despite substantial investments from major pharmaceutical companies [2][3]. Drug Development and FDA Approvals - In June 2021, the FDA accelerated the approval of Aducanumab, developed by Eisai and Biogen, marking the first new drug for Alzheimer's since 2003, although its approval was controversial due to associated risks like ARIA (Amyloid-related Imaging Abnormalities) [3][6]. - Following Aducanumab, the FDA approved two additional antibody drugs targeting Aβ: Donanemab by Eli Lilly and Lecanemab by Eisai and Biogen, both of which also present ARIA-related side effects [3][6]. Denali Therapeutics' Research - Denali Therapeutics published a study in August 2025 on a new antibody transport carrier, ATV cisLALA, which utilizes transferrin receptor (TfR) to enhance brain delivery of anti-Aβ antibodies while mitigating ARIA risks [4][9]. - The ATV cisLALA carrier shows improved distribution in brain tissue compared to traditional Aβ antibodies, which tend to accumulate around blood vessels, potentially triggering inflammatory responses and ARIA [9][11]. Mechanism of Action - Traditional Aβ antibodies enter the brain through cerebrospinal fluid and perivascular spaces, where amyloid deposits are located, leading to inflammation and ARIA. In contrast, the ATV carrier enhances delivery through capillaries, reducing ARIA side effects [11][12]. - Denali's TfR-based approach is not limited to Aβ; the company is also developing therapies targeting tau protein using the same delivery mechanism, aiming to address two key toxic proteins in Alzheimer's simultaneously [11].

Core Insights - Denali Therapeutics, Inc. (DNLI) has received FDA acceptance for its biologics license application (BLA) for tividenofusp alfa, aimed at treating Hunter syndrome, with a target action date set for January 5, 2026 [1][7] - The acceptance of the BLA marks a significant step for DNLI towards becoming a commercial-stage biotech company, especially as its shares have declined by 30.1% year to date [2] Drug Development and Clinical Trials - Tividenofusp alfa has received Breakthrough Therapy Designation from the FDA for Hunter syndrome, a rare genetic disorder caused by a deficiency in the iduronate 2-sulfatase (IDS) enzyme [3] - The drug is designed to cross the blood-brain barrier, addressing both cognitive and physical symptoms of MPS II, unlike traditional enzyme replacement therapies [4] - The BLA submission is supported by data from a phase I/II study involving 47 participants, and an ongoing phase II/III COMPASS study is expected to provide pivotal data for global regulatory filings [5] Pipeline and Collaborations - Denali is also evaluating DNL126 for Sanfilippo syndrome type A and has engaged in discussions with the FDA for an accelerated development path [9] - Another candidate, DNL593, is being co-developed with Takeda for frontotemporal dementia, with an ongoing phase I/II study [10] - Denali and Biogen are jointly developing a LRRK2 inhibitor for Parkinson's disease, with a global phase IIb study fully enrolled and results expected in 2026 [11] - Denali is also conducting a phase IIa study for LRRK2-associated Parkinson's disease and evaluating DNL343 for amyotrophic lateral sclerosis (ALS), although a primary endpoint was not met in a recent trial [12] - The company has multiple early-stage clinical and preclinical programs and maintains a sound cash position to fund ongoing initiatives [13]

Core Insights - Denali Therapeutics Inc. announced that the FDA has accepted the Biologics License Application (BLA) for tividenofusp alfa, seeking accelerated approval for the treatment of Hunter syndrome, with a target action date of January 5, 2026 [1][7]. Company Overview - Denali Therapeutics is a biotechnology company focused on developing therapies that can cross the blood-brain barrier (BBB) for neurodegenerative and lysosomal storage diseases [9]. - The company utilizes a proprietary TransportVehicle™ platform designed to deliver large therapeutic molecules across the BBB, enhancing drug efficacy [8]. Product Details - Tividenofusp alfa is an investigational enzyme replacement therapy designed to address both neurological and physical symptoms of Hunter syndrome by delivering the iduronate 2-sulfatase (IDS) enzyme into the brain and body [2][4]. - The therapy has received Fast Track and Breakthrough Therapy designations from the FDA, as well as Priority Medicines designation from the European Medicines Agency [4]. Clinical Studies - The BLA submission is supported by data from a Phase 1/2 study involving 47 participants with Hunter syndrome [3]. - Denali is conducting an ongoing Phase 2/3 COMPASS study to support global regulatory approvals, with participants randomized to receive either tividenofusp alfa or idursulfase [5]. Disease Context - Hunter syndrome (MPS II) is a rare genetic disorder caused by a deficiency in the IDS enzyme, leading to the accumulation of glycosaminoglycans and resulting in cognitive decline, behavioral issues, and physical complications [6]. - Current therapies do not effectively address neurological symptoms due to their inability to cross the BBB, highlighting the unmet need for new treatments [6].