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]

CROSSING BARRIERS AND DEFEATING DEGENERATION MAY 2025 ©2025 Denali Therapeutics Inc. DISCLAIMERS Forward-Looking Statements. This presentation contains forward-looking statements within the meaning of the Private Securities Litigation Reform Act of 1995. These forward-looking statements do not relate strictly to historical or current facts and they may be accompanied by such words as "anticipate," "believe," "could," "estimate," "expected," "forecast," "intend," "may," "plan," "potential," "possible," "futu ...

Summary of Denali Therapeutics Conference Call Company Overview - **Company**: Denali Therapeutics - **Industry**: Biotechnology - **Focus**: Development of therapies targeting the blood-brain barrier (BBB) for rare diseases, particularly enzyme replacement therapies (ERTs) for conditions like Hunter syndrome and Sanfilippo syndrome Key Points and Arguments Pipeline Progress and Upcoming Milestones - Denali is in the process of filing a Biologics License Application (BLA) for its lead program targeting Hunter syndrome, with a PDUFA date pending [4][18] - The company has developed a novel blood-brain barrier technology, which has garnered significant interest in the industry [5][4] - Denali has three transport vehicle molecules currently in clinical testing and plans to introduce at least three more within the next year [7][8] Commercial Strategy - The company is preparing for the launch of its lead product, DNL310, which is positioned as a next-generation ERT [21][22] - Denali is building a commercial team to ensure a successful launch and has engaged with all prescribers of existing treatments in the U.S. [22][23] - Education for healthcare providers and patients is a core focus, emphasizing the advantages of their therapy over standard care [25][23] Regulatory Engagement - Denali has had consistent and productive dialogue with the FDA regarding its BLA submission and the accelerated approval pathway for its programs [17][19] - The company is also engaging with European regulators to align on the approval process for its therapies [26][28] Manufacturing Capabilities - Denali is utilizing Lonza for the manufacturing of its lead product, with plans to transition to a U.S. facility for larger volumes [31][32] - The company has established its own manufacturing capabilities to enhance efficiency and reduce costs [8][31] Competitive Landscape - Denali is aware of the competitive dynamics with gene therapies and other ERTs in the market, particularly for Hunter and Sanfilippo syndromes [39][37] - The company believes that its therapies may complement existing gene therapies rather than compete directly [40][39] Strategic Prioritization - Denali is focusing on high-probability success programs within its enzyme replacement therapy portfolio, which has a multibillion-dollar market opportunity [45][46] - The company aims to balance its resources between smaller indications and larger opportunities, ensuring efficient capital allocation [42][44] Future Directions - Denali is exploring additional therapeutic areas beyond the brain, including potential applications in tumors and muscle diseases [59][58] - The company is committed to maintaining a strong business development strategy to partner its assets effectively while managing capital efficiency [60][61] Additional Important Insights - Denali's approach to the blood-brain barrier delivery is seen as a significant advancement in the field, with a growing number of companies now pursuing similar technologies [58][59] - The company is focused on reducing the cost of bringing programs from idea to clinical proof of concept, which is crucial given the high cost of capital in the biotech industry [59][58]

Core Viewpoint - Denali Therapeutics Inc. has seen a slight increase in share price of about 0.7% over the past month, underperforming the S&P 500, raising questions about the sustainability of this trend leading up to the next earnings release [1] Group 1: Earnings and Estimates - Estimates for Denali Therapeutics have trended upward over the past month, indicating positive revisions [2] - The stock has a Zacks Rank of 3 (Hold), suggesting an expectation of in-line returns in the coming months [4] Group 2: VGM Scores - Denali Therapeutics has a poor Growth Score of F, a Momentum Score of C, and a Value Score of F, resulting in an overall aggregate VGM Score of F, placing it in the lowest quintile for investment strategies [3] Group 3: Industry Comparison - Denali Therapeutics operates within the Zacks Medical - Biomedical and Genetics industry, where Moderna has experienced a gain of 13.3% over the past month [5] - Moderna reported revenues of $108 million for the last quarter, reflecting a year-over-year decline of 35.3%, with an EPS of -$2.52 compared to -$3.07 a year ago [5] - Moderna is projected to post a loss of $2.97 per share for the current quarter, with a year-over-year change of +10.8% and a Zacks Rank of 3 (Hold) [6]

Summary of Denali Therapeutics Conference Call Company Overview - **Company**: Denali Therapeutics - **Industry**: Biotechnology, specifically focusing on rare diseases and blood-brain barrier technology Key Points and Arguments 1. **FDA Approval Process**: Denali is currently on file with the FDA for a potential first approval, indicating a significant milestone for the company and its transition to a commercial entity [1][2] 2. **Transport Vehicle Technology**: The company has developed a novel technology to facilitate the crossing of large molecules through the blood-brain barrier, which has shown promise in treating diseases like Hunter syndrome [4][5] 3. **Clinical Trials**: Denali completed a Phase 1/2 study with 47 patients, all of whom reached at least six months of treatment. The data from this study has matured and is being presented to the FDA [6][7] 4. **Regulatory Engagement**: The company has had consistent and timely interactions with the FDA, even during periods of uncertainty within the agency, which has been beneficial for their accelerated approval path [7][9] 5. **Competing Therapies**: There is increasing competition in the field, particularly with other companies developing transferrin receptor-enabled therapies for similar conditions [5][20] 6. **Gene Therapy Considerations**: Denali is aware of competing gene therapy products targeting Hunter syndrome, which are under different FDA divisions. The company believes its data package is robust and differentiates its product from competitors [20][29] 7. **Accelerated Approval Path**: Denali expects to receive accelerated approval based on its data package, with a confirmatory study (COMPASS) planned for the future [37][41] 8. **Sanfilippo Program**: The company is also advancing a program for Sanfilippo syndrome, with plans to utilize natural history data for regulatory approval due to the lack of standard care options [50][52] 9. **Future Pipeline**: Denali is preparing to enter multiple new programs targeting Alzheimer's disease, with a focus on leveraging its blood-brain barrier technology for broader applications beyond rare diseases [74][86] 10. **Market Potential**: The company sees significant potential in the Alzheimer's market, especially with the development of therapies that can reduce safety concerns associated with existing treatments [86][90] Additional Important Content - **Breakthrough Therapy Designation**: Denali's product for Hunter syndrome has received breakthrough therapy designation, which may facilitate a faster review process [40][41] - **Patient Access**: The company is expanding its studies to allow more patients access to the drug while under accelerated approval [37][49] - **Data Strategy**: Denali is cautious about releasing data too early and is focused on ensuring a robust data package before making announcements [56][57] - **Investment in Technology**: The company has heavily invested in proving its transport vehicle technology, which is expected to benefit future programs across various diseases [61][63] This summary encapsulates the key discussions and insights from the conference call, highlighting Denali Therapeutics' strategic direction, regulatory interactions, and competitive landscape in the biotechnology sector.

Denali Therapeutics Conference Call Summary Company Overview - **Company**: Denali Therapeutics (DNLI) - **Event**: Bank of America Healthcare Conference - **Date**: May 13, 2025 Key Industry Insights - **FDA Interactions**: Denali has had numerous interactions with the FDA, particularly regarding their Biologics License Application (BLA) filing for TIVI, which received breakthrough therapy designation. This designation is significant as it is the first for a blood-brain barrier-enabled technology in the context of MPS (Mucopolysaccharidoses) [4][5][6] - **Enzyme Replacement Therapy**: The probability of success for enzyme replacement therapies reaching the market is between 85% and 90%, which is notably high compared to other drug development areas. Denali's TIVI aims to address neurological symptoms in lysosomal storage disease patients, a significant unmet need [7][8] Product Development - **TIVI Overview**: TIVI (tividendifusp alfa) is engineered to cross the blood-brain barrier and aims to normalize substrate levels in the brain, showing downstream biomarker benefits such as NfL (neurofilament light chain) [8][9] - **Target Population**: Approximately 500 patients in the U.S. and 2,000 patients worldwide are affected by Hunter syndrome, the primary indication for TIVI [10] - **Commercial Readiness**: Denali has been building a commercial foundation for TIVI over the past three years, focusing on medical education and awareness among healthcare providers [11][12] Market Dynamics - **Switching from Standard of Care**: Most patients currently on Allopraze (the standard of care) are expected to switch to TIVI, with a strong clinical data package supporting this transition [13][16] - **Physician Education**: The company emphasizes the importance of educating physicians about the benefits of TIVI, particularly in achieving normalization of substrate levels [14][15] Future Indications and Expansion - **Next Steps**: Denali plans to expand into other indications such as Sanfilippo syndrome, Pompe disease, and Gaucher disease, leveraging the same biomarkers used for TIVI [32][34] - **Alzheimer's and Parkinson's**: Denali is also developing programs targeting Alzheimer's and Parkinson's diseases, focusing on amyloid beta and tau pathologies. They have two IND-enabling programs in this area [48][49] Financial Outlook - **Cash Position**: Denali reported $1.05 billion in cash, guiding towards cash sustainability into 2028. The company plans to increase spending by 10% to 15% this year to support portfolio expansion [60][61] Strategic Partnerships - **Business Development**: Denali has entered over 40 partnerships to share risk and enhance its portfolio. The company is open to strategic partnerships that can accelerate its development efforts, particularly in blood-brain barrier technologies [63][64] Conclusion Denali Therapeutics is positioned to make significant strides in the treatment of rare neurological diseases through its innovative transport vehicle technology. The company is focused on building a strong commercial foundation while exploring new therapeutic areas, backed by a robust financial position and strategic partnerships.

Core Viewpoint - Denali Therapeutics reported a wider-than-expected loss in Q1 2025, primarily due to increased operating expenses, and did not generate collaboration revenues during the quarter [1][2]. Financial Performance - The company reported a loss of 78 cents per share, compared to the Zacks Consensus Estimate of a loss of 71 cents and a loss of 68 cents in the same quarter last year [1]. - Research and development expenses rose by 8.6% to $116.3 million, driven by increased spending on clinical and preclinical programs [5]. - General and administrative expenses increased by 16.4% to $29.4 million, attributed to activities related to the submission of a biologics license application for tividenofusp alfa [6]. - As of May 31, 2025, the company had approximately $1.05 billion in cash, cash equivalents, and marketable securities [6]. Pipeline Developments - Denali completed the submission of a biologics license application for tividenofusp alfa under the FDA's accelerated approval pathway, based on phase I/II study data for Hunter syndrome [7]. - The FDA granted Breakthrough Therapy Designation for tividenofusp alfa in January 2025 [8]. - Denali is conducting a global phase II/III COMPASS study to support regulatory approvals for tividenofusp alfa [8]. - The company is evaluating DNL126 for Sanfilippo syndrome type A and has had productive discussions with the FDA regarding its accelerated development [9]. - Denali is collaborating with Takeda on DNL593 for frontotemporal dementia and is conducting a phase I/II study [10]. - Denali and Biogen are jointly evaluating BIIB122/DNL151 for Parkinson's disease, with the LUMA study fully enrolled [11]. - The company is also conducting the phase IIa BEACON study for LRRK2-associated Parkinson's disease and evaluating DNL343 in a phase II/III study for ALS [12]. - Denali's partner Sanofi discontinued the development of SAR443820/DNL788 for ALS due to unmet primary endpoints in the phase II study [14]. Market Performance - Shares of Denali Therapeutics have declined by 31.4% year-to-date, while the industry has seen a smaller decline of 2.2% [4]. Overall Assessment - The progress in Denali's pipeline is viewed as encouraging, with potential approval of tividenofusp alfa expected to significantly benefit the company [15].

Financial Performance - The company reported net losses of $133.0 million and $101.8 million for the three months ended March 31, 2025, and 2024, respectively, with an accumulated deficit of $1.67 billion as of March 31, 2025[96]. - The net loss for the three months ended March 31, 2025, was $132.97 million, a 31% increase from the net loss of $101.80 million in the same period of 2024[108]. - The company has incurred significant operating losses and expects to continue doing so as it expands its research and development efforts and hires additional personnel[96]. - The company expects to incur significant losses for the foreseeable future as it expands research and development activities and seeks regulatory approvals[120]. - Net cash used in operating activities was $131.5 million for the three months ended March 31, 2025, compared to $113.6 million in the same period of 2024[126]. Revenue Generation - The company has not generated any product revenue since inception and has funded operations primarily through the issuance of convertible preferred stock and collaboration agreements with Takeda, Sanofi, and Biogen[95]. - The company received approximately $754.4 million from public offerings and $575.0 million from collaboration agreements through March 31, 2025[115][118]. Research and Development - Research and development expenses are expected to increase as the company advances its clinical programs and seeks regulatory approvals for product candidates[103]. - Research and development expenses increased by 9% to $116.2 million for the three months ended March 31, 2025, compared to $107.0 million in the same period of 2024[109]. - The company is developing multiple product candidates targeting rare lysosomal storage diseases and neurodegenerative conditions, including tividenofusp alfa and DNL126[94]. - The company announced that the primary endpoint was not met in the Phase 2/3 HEALEY ALS Platform Trial evaluating DNL343, leading to the discontinuation of the active treatment extension[97]. Regulatory and Clinical Developments - The FDA granted Breakthrough Therapy Designation for tividenofusp alfa (DNL310) for the treatment of MPS II, with a rolling submission of a Biologics License Application (BLA) completed in May 2025[97]. - General and administrative expenses rose by 16% to $29.4 million for the three months ended March 31, 2025, driven by activities related to the submission of the BLA for tividenofusp alfa[112]. Cash and Investments - Cash, cash equivalents, and marketable securities totaled $1.05 billion as of March 31, 2025[114]. - As of March 31, 2025, the company had cash, cash equivalents, and marketable securities totaling $1.05 billion, primarily in money market funds and investment-grade fixed income securities[133]. - The company anticipates needing substantial additional funding to support ongoing operations and future commitments[121]. - The company aims to preserve capital while maximizing income from investments, maintaining a portfolio of high credit quality and short-term duration securities[134]. - The company’s investment activities are primarily focused on preserving capital to fund operations while avoiding significant risk[134]. Market and Operational Risks - The company has experienced challenges in predicting the costs and timing of drug development due to external factors such as global pandemics and geopolitical uncertainties[100]. - The company is exposed to interest rate risk, but a hypothetical 10% relative change in interest rates would not have a material impact on its financial statements[134]. - The majority of the company's transactions are conducted in U.S. dollars, but it is also subject to foreign exchange risk due to transactions in Euro, Swiss Franc, and British Pound[135]. - The company is exposed to market risks related to interest rates and foreign currency sensitivities in the ordinary course of business[132]. - The company’s investments are largely composed of short to intermediate-term fixed income securities, which are subject to interest rate fluctuations[134]. Accounting and Estimates - There have been no material changes to critical accounting estimates during the three months ended March 31, 2025[130]. - No new accounting pronouncements or changes have occurred during the three months ended March 31, 2025, that are significant to the company[131]. - The company’s financial condition and results of operations are based on estimates and assumptions that may differ from actual results under different conditions[130].

Financial Performance - Denali Therapeutics reported a net loss of $133.0 million for Q1 2025, compared to a net loss of $101.8 million in Q1 2024, reflecting an increase of approximately 30.5% year-over-year[13] - Total research and development expenses for Q1 2025 were $116.2 million, up from $107.0 million in Q1 2024, marking an increase of about 8.6%[14] - General and administrative expenses rose to $29.4 million in Q1 2025, compared to $25.2 million in Q1 2024, an increase of approximately 16.5%[15] - Denali's total operating expenses for Q1 2025 were $145.6 million, compared to $132.3 million in Q1 2024, reflecting an increase of approximately 10%[21] Cash and Assets - Cash, cash equivalents, and marketable securities totaled approximately $1.05 billion as of March 31, 2025[16] Regulatory Developments - Denali completed the Biologics License Application (BLA) submission for tividenofusp alfa for Hunter syndrome, initiating the FDA's 60-day filing review process[3] - The FDA granted Breakthrough Therapy Designation for tividenofusp alfa in January 2025, which is also designated as Fast Track, Orphan Drug, and Rare Pediatric Disease[3] - Denali is conducting the ongoing global Phase 2/3 COMPASS study to support global regulatory approvals for tividenofusp alfa[3] - The company is collaborating with the FDA under the START program for accelerated development of DNL126 for Sanfilippo syndrome Type A[4] Operational Developments - Denali's clinical biomanufacturing facility in Salt Lake City commenced operations, enhancing U.S. manufacturing capabilities and supply chain control[9] Contact Information - Investor Relations contact is Laura Hansen, Ph.D., Vice President, reachable at hansen@dnli.com[23] - Media contact is Rich Allan from FGS Global, reachable at Rich.Allan@fgsglobal.com[23]

Core Insights - Denali Therapeutics has completed the Biologics License Application (BLA) submission for tividenofusp alfa, marking a significant milestone in its development as a late-stage commercial organization focused on treating Hunter syndrome [2][3] - The company is preparing for the commercial launch of tividenofusp alfa, expected in late 2025 or early 2026, which would be the first FDA-approved enzyme replacement therapy designed to cross the blood-brain barrier [2][3] - Denali's clinical pipeline includes ongoing programs for Sanfilippo syndrome Type A and frontotemporal dementia, with collaborations with the FDA and Takeda, respectively [4][5] Financial Performance - For Q1 2025, Denali reported a net loss of $133.0 million, an increase from a net loss of $101.8 million in Q1 2024 [10] - Research and development expenses rose to $116.2 million in Q1 2025 from $107.0 million in Q1 2024, primarily due to increased spending on clinical and preclinical programs [11] - General and administrative expenses increased to $29.4 million in Q1 2025 from $25.2 million in Q1 2024, driven by activities related to the BLA submission for tividenofusp alfa [14] Clinical Program Updates - The BLA submission for tividenofusp alfa is based on data from a Phase 1/2 study involving 47 participants, with the FDA's review process now initiated [3] - Denali is conducting a global Phase 2/3 COMPASS study to support regulatory approvals for tividenofusp alfa [3] - The company is also advancing DNL126 for Sanfilippo syndrome Type A, with ongoing discussions with the FDA for an accelerated development path [4] Corporate Developments - Denali has launched a clinical biomanufacturing facility in Salt Lake City, enhancing its manufacturing capabilities and supply chain control [9] - The company is actively participating in several upcoming investor conferences to engage with stakeholders and present its developments [13]