Denali Therapeutics Conference Call Summary Company Overview - **Company**: Denali Therapeutics (NasdaqGS:DNLI) - **Focus**: Development of therapies targeting the blood-brain barrier and neurodegenerative diseases, particularly using transferrin receptor technology for drug delivery [4][5][6] Key Points and Arguments Product Pipeline and Milestones - **Hunter Program**: First program utilizing transferrin receptor technology, showing substantial benefits in hearing, cognition, and behavior after four to five years of treatment [5] - **Tividenofusp Alpha (DNL-310)**: First BLA submitted using transferrin receptor technology, currently under review [5][10] - **Alzheimer's Portfolio**: Recent regulatory filing for an Alzheimer's medicine using oligonucleotide technology to cross the blood-brain barrier [5][6] - **ETV Franchise**: Expanding beyond Hunter and Sanfilippo, with plans for regulatory filings for Pompe disease [6] Market Opportunity - **Hunter Syndrome Market**: Benchmarking against EloPrase, which has annual sales of $650 million to $700 million, with a global distribution of one-third in the U.S., Europe, and the rest of the world [10] - **Pricing Strategy**: EloPrase costs approximately $500,000 per patient per year, and Denali anticipates a premium price for Tivi based on its clinical profile [16] Launch Strategy - **Launch Expectations**: Modest revenues expected in the first year post-launch, with a focus on patient treatment initiation as a key metric [15][20] - **Sales Force**: A small, focused sales team will be in place, leveraging existing relationships with physicians already treating Hunter syndrome patients [20][21] Sanfilippo Program - **Clinical Development**: Enrollment of 20 patients completed, with plans to file for accelerated approval based on biomarker data [22][23] - **Market Potential**: Sanfilippo is expected to have a similar market size to Hunter syndrome, with no existing standard of care, potentially allowing for flexible pricing [25] Regulatory and Manufacturing Updates - **FDA Engagement**: Ongoing discussions with the FDA regarding labeling and manufacturing issues, with a clerical error identified as a minor administrative issue [17][19] - **Manufacturing Capabilities**: Denali is transitioning to in-house manufacturing for Sanfilippo, which is expected to reduce costs [24] Other Programs - **LRRK2 Program for Parkinson's**: A phase IIb study is ongoing, with a focus on lysosomal function improvement through LRRK2 inhibition [34] - **Alzheimer's Research**: IND filed for a new oligonucleotide therapy targeting tau pathology, with a focus on achieving broad distribution in the CNS [37][38] Additional Insights - **Market Strategy**: Denali plans to leverage U.S. approval for global market access, targeting approximately 60% to two-thirds of the global market based on phase one/two data [30] - **Clinical Differentiation**: Denali's approach to FTD dementia involves a unique delivery mechanism for progranulin, contrasting with other therapies that block natural receptors [44] This summary encapsulates the key discussions and insights from the Denali Therapeutics conference call, highlighting the company's strategic direction, product pipeline, and market opportunities.

Denali Therapeutics Conference Call Summary Company Overview - **Company**: Denali Therapeutics (NasdaqGS:DNLI) - **Focus**: Development of technologies to cross the blood-brain barrier and address neurodegeneration Key Points Industry and Technology - Denali aims to develop medicines that can effectively cross the blood-brain barrier using transport vehicle technology, specifically targeting the transferrin receptor [3][4] - The company has three main franchises: enzyme transport vehicle, oligonucleotide molecules, and a progranulin program for frontotemporal dementia (FTD) [4][5] Pipeline Progress - Denali has made significant progress in its pipeline, with multiple programs in late-stage development and new modalities entering clinical trials [3][4] - The lead program for Hunter syndrome has a Biologics License Application (BLA) under review, with plans for accelerated approval for the Sanfilippo program [4][5] - The company is also preparing to file for a second Alzheimer's program targeting amyloid beta [7] Regulatory Updates - A recent clerical error led to a major amendment in the regulatory review process, shifting the PDUFA date from January 5 to April 5 [10][11] - Despite the delay, Denali reports positive engagement with the FDA and is optimistic about the review process [13][14] Market Access and Launch Strategy - Denali's market strategy divides the potential market into thirds: one-third in the U.S., one-third accessible with accelerated approval, and one-third in Europe [17][18] - The company has a small but prepared team for launching its products, with plans to expand as needed [15][16] Clinical Data and Trials - Denali has completed enrollment for the Phase 1/2 study for the Sanfilippo program, aiming for a faster and smaller data package compared to previous trials [19][20] - The company is focusing on both proximal and distal biomarkers for its programs, with plans for data presentations at upcoming medical conferences [22][40] Safety and Efficacy Considerations - Denali is aware of safety concerns related to transferrin receptor targeting and has been actively working to mitigate these risks through engineering [52][54] - The company emphasizes the importance of understanding the mechanisms behind any observed safety events and differentiates its approach from other programs in the space [56][59] Alzheimer's Programs - Denali is developing two clinical candidates for Alzheimer's, with plans to advance them independently before potentially seeking partnerships [64][65] - The company is focused on achieving a better safety profile and efficacy through its unique delivery mechanism, which aims to reduce the risk of amyloid-related imaging abnormalities (ARIA) [77][81] Future Outlook - Denali plans to provide more insights into its strategy and pipeline during an upcoming Analyst Day on December 4 [35][48] - The company is optimistic about its ability to address unmet needs in rare diseases and neurodegenerative conditions through its innovative technologies [34][36] Additional Insights - Denali's approach to using natural history as a comparator in trials for Sanfilippo reflects a shift in regulatory perspectives, allowing for more flexible trial designs [30][31] - The company is committed to onshoring manufacturing capabilities, which will enhance its control over the production process for its therapies [21][22]

Core Insights - Denali Therapeutics (DNLI) reported a narrower loss of 74 cents per share for Q3 2025, compared to the Zacks Consensus Estimate of a loss of 76 cents and a loss of 63 cents 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 $14 million [2] - DNLI's stock has declined by 29.3% year-to-date, while the industry has grown by 11.5% [2] Financial Performance - Research and development expenses increased by 3.8% to $101.9 million, primarily due to the start of operations at Denali's large molecule manufacturing facility in Salt Lake City, UT [4] - General and administrative expenses rose by 42.2% to $35.5 million, driven by preparations for a potential launch of tividenofusp alfa [4] - As of September 30, 2025, the company had cash, cash equivalents, and marketable securities totaling approximately $872.9 million [5] Regulatory and Pipeline Updates - The FDA extended the review timeline for the biologics license application (BLA) for tividenofusp alfa to April 5, 2026, from January 5, 2026, following the submission of updated clinical pharmacology information [6][9] - The extension was classified as a major amendment, but the FDA did not request additional data [9] - Denali is advancing programs for Sanfilippo syndrome, Alzheimer’s disease, Parkinson’s disease, and Pompe disease [8][10] Pipeline Developments - Denali is evaluating DNL126 for Sanfilippo syndrome type A, with a phase I/II study completed [10][11] - The company is also developing DNL593 in collaboration with Takeda for frontotemporal dementia and has submitted a clinical trial application for DNL628 for Alzheimer's disease [12][14] - Denali and Biogen are co-developing BIIB122, with a phase IIb study fully enrolled and results expected in 2026 [13] Overall Assessment - The delay in the approval of tividenofusp alfa is disappointing, as it is the lead candidate in Denali's pipeline, but progress with DNL126 is encouraging [15] - The company's strong cash position is a positive factor for funding ongoing programs [15]

Financial Performance - The company reported net losses of $126.9 million and $384.0 million for the three and nine months ended September 30, 2025, respectively, compared to $107.2 million and $308.0 million for the same periods in 2024[95]. - As of September 30, 2025, the company had an accumulated deficit of $1.92 billion[95]. - The net loss for the three months ended September 30, 2025, was $126.90 million, an 18% increase compared to a net loss of $107.19 million in 2024[107]. - The company expects to continue incurring significant losses as it expands research and development activities and seeks regulatory approvals for product candidates[123]. - The company has not generated any product revenue to date and does not expect to until regulatory approval and commercialization of product candidates occur[122]. - For the nine months ended September 30, 2025, net cash used in operating activities was $314.1 million, driven by a net loss of $384.0 million[130]. - Cash, cash equivalents, and marketable securities amounted to $872.9 million as of September 30, 2025[117]. - The company had cash, cash equivalents, and marketable securities totaling $872.9 million as of September 30, 2025[136]. Research and Development - The company incurred significant research and development expenses, which are a major component of its operating expenses[97]. - Research and development expenses increased to $101.95 million for the three months ended September 30, 2025, up 4% from $98.24 million in the same period of 2024[108]. - Research and development expenses for the nine months ended September 30, 2025, totaled $320.87 million, an 8% increase from $296.65 million in 2024[112]. - The company is developing multiple product candidates, including tividenofusp alfa for MPS II and DNL126 for Sanfilippo syndrome, with ongoing clinical trials[91]. - The company plans to continue incurring significant expenses and operating losses as it advances its clinical programs and develops its TV platform[95]. Regulatory and Collaboration Efforts - The FDA granted Breakthrough Therapy Designation for tividenofusp alfa (DNL310) for the treatment of MPS II in January 2025, with a rolling submission of a Biologics License Application (BLA) completed in May 2025[93]. - The company announced that the FDA accepted the BLA for tividenofusp alfa for priority review, with a target action date of January 5, 2026, later extended to April 5, 2026[96]. - The company is actively pursuing collaborations with third parties, including Takeda and Biogen, to enhance its development and commercialization efforts[90]. - The company anticipates needing substantial additional resources to fund operations and meet future commitments[125]. Operating Expenses - General and administrative expenses rose to $35.48 million for the three months ended September 30, 2025, a 42% increase from $24.95 million in 2024[115]. - Total operating expenses for the three months ended September 30, 2025, were $137.43 million, reflecting a 12% increase from $123.19 million in 2024[107]. - The company anticipates an increase in general and administrative expenses due to preparations for the potential commercialization of Tividenofusp alfa[115]. Cash Flow and Financial Position - Net cash provided by investing activities was $234.5 million, primarily from $431.0 million in proceeds from marketable securities maturities[131]. - Cash used in financing activities was $2.9 million, consisting of $8.2 million in finance lease payments, partially offset by $5.2 million from stock option exercises[132]. - The company has raised approximately $754.4 million from public offerings of common stock through September 30, 2025[118]. Risks and Future Outlook - The company is exposed to interest rate risk, but a hypothetical 10% change in interest rates would not have a material impact on its financial statements[137]. - The company is also subject to foreign exchange risk due to transactions in currencies other than the U.S. dollar, primarily the Euro, Swiss Franc, and British Pound[138]. - Future funding requirements will depend on various factors, including regulatory approvals and the progress of clinical development activities[127]. - The company expects to incur substantial additional losses in the future due to ongoing research and development activities[125]. - Total undiscounted lease payment obligations amount to $57.4 million, with non-refundable purchase commitments of $39.4 million as of September 30, 2025[126].

Financial Performance - Net loss for Q3 2025 was $126.9 million, compared to a net loss of $107.2 million in Q3 2024, representing an increase of approximately 18%[14] - Total research and development expenses were $102.0 million for Q3 2025, up from $98.2 million in Q3 2024, reflecting a rise of about 2%[15] - General and administrative expenses increased to $35.5 million in Q3 2025 from $24.9 million in Q3 2024, marking a significant increase of approximately 42.5%[16] Cash and Assets - Cash, cash equivalents, and marketable securities totaled approximately $872.9 million as of September 30, 2025[17] - Total current assets decreased to $882,598,000 from $864,436,000, a decline of approximately 2%[22] - Cash and cash equivalents dropped significantly to $90,963,000 from $174,960,000, a decrease of about 48%[22] - Short-term marketable securities increased to $757,241,000 from $657,371,000, reflecting a growth of approximately 15%[22] - Total assets decreased to $1,055,621,000 from $1,374,180,000, a decline of around 23%[22] - Total stockholders' equity decreased to $926,197,000 from $1,229,684,000, a decline of approximately 25%[22] Liabilities and Equity - Total current liabilities decreased to $90,146,000 from $102,208,000, a reduction of about 12%[22] - Accounts payable decreased to $6,745,000 from $11,137,000, a reduction of about 39%[22] - Accrued compensation decreased to $18,358,000 from $24,728,000, a decline of approximately 26%[22] - Operating lease liability, less current portion decreased to $29,686,000 from $36,673,000, a reduction of about 19%[22] - Deferred research funding and development liability, less current portion increased to $4,038,000 from $0, indicating new funding commitments[22] Regulatory and Development Updates - The FDA extended the review timeline for the BLA of tividenofusp alfa from January 5, 2026, to April 5, 2026, due to a Major Amendment submission[4] - Enrollment in the Phase 1/2 study of DNL126 for Sanfilippo syndrome type A was completed, supporting an accelerated approval path[5] - Two new regulatory applications were submitted for DNL628 for Alzheimer's disease and DNL952 for Pompe disease, expanding the TransportVehicle platform[6] - Denali plans to continue expanding its TV-enabled pipeline, aiming to bring forward one to two new programs annually[10] - Denali's Investor Day is scheduled for December 4, 2025, to discuss progress and strategic priorities, including the launch of tividenofusp alfa[12] Share Information - The weighted average number of shares outstanding was 172,421,492 for Q3 2025, compared to 169,456,988 for Q3 2024[21]

Core Insights - Denali Therapeutics is preparing for the launch of tividenofusp alfa and has submitted regulatory applications for two additional programs targeting Alzheimer's and Pompe diseases [2][3][8] Clinical Programs - Tividenofusp alfa (DNL310) for Hunter syndrome: The FDA has extended the review timeline for the Biologics License Application (BLA) from January 5, 2026, to April 5, 2026, due to a Major Amendment submission [3][8] - DNL126 for Sanfilippo syndrome type A: Enrollment in the Phase 1/2 study has been completed, showing significant reduction in cerebrospinal fluid heparan sulfate levels [4][8] - DNL628 for Alzheimer's disease: A Clinical Trial Application has been submitted to initiate studies, marking a key milestone for the Oligonucleotide TransportVehicle platform [6][8] - DNL952 for Pompe disease: An Investigational New Drug application has been submitted to begin clinical studies [9][8] - DNL151 for Parkinson's disease: Co-development with Biogen continues, with a Phase 2b study expected to read out data in 2026 [10] Financial Results - For Q3 2025, the net loss was $126.9 million, compared to a net loss of $107.2 million in Q3 2024 [14] - Research and development expenses totaled $102.0 million, up from $98.2 million in the same quarter last year, driven by increased operational costs [15] - General and administrative expenses rose to $35.5 million from $24.9 million, primarily due to preparations for the commercial launch of tividenofusp alfa [16] Corporate Updates - Tim Van Hauwermeiren has been appointed to the Board of Directors, while Carole Ho, M.D., is departing the company [12] - Peter Chin, M.D., will serve as Acting Chief Medical Officer [12] - Denali will host an Investor Day on December 4, 2025, to discuss progress and strategic priorities [13] Cash Position - As of September 30, 2025, Denali had approximately $872.9 million in cash, cash equivalents, and marketable securities [18]

Core Viewpoint - The U.S. FDA has extended the review timeline for Denali Therapeutics Inc.'s Biologics License Application for tividenofusp alfa, delaying the PDUFA target date from January 5, 2026, to April 5, 2026 [2][6]. Group 1: FDA Review Process - The extension is due to Denali's submission of updated clinical pharmacology information in response to an FDA request, and it is not related to efficacy, safety, or biomarkers [3][5]. - The FDA did not request any additional data, indicating that the extension is procedural rather than indicative of concerns regarding the drug's safety or efficacy [3][5]. Group 2: Clinical Trials and Studies - The Phase 2/3 COMPASS study is currently enrolling participants with MPS II across North America, South America, and Europe to support global approval [4]. - Denali believes that the updated information submitted does not affect the clinical pharmacology or benefit-risk conclusions of the BLA [4]. Group 3: Market Reaction and Analyst Opinions - Denali Therapeutics' stock is down 0.87%, trading at $14.85 at the time of publication [6]. - Analyst Myles Minter expressed disappointment over the PDUFA extension but remains confident in the approvability of tividenofusp alfa based on current clinical datasets, citing regulatory precedence from a prior approval in Hunter syndrome [6].

Core Insights - Denali Therapeutics Inc. (DNLI) announced that the FDA has extended the review timeline for its Biologics License Application (BLA) for tividenofusp alfa, a treatment for mucopolysaccharidosis type II (MPS II) [1][3][7] - The new target date for the BLA review is now April 5, 2026, pushed back from January 5, 2026, due to the submission of updated clinical pharmacology information [3][7] - The extension is classified as a major amendment and is not related to the drug's efficacy, safety, or biomarkers [3][4][7] Company Performance - Denali's stock experienced a decline of 26.5% year to date, contrasting with the industry average gain of 9.2% [2] Drug Development Details - Tividenofusp alfa is designed to deliver the iduronate 2-sulfatase (IDS) enzyme to address symptoms of Hunter syndrome [4][5] - The FDA has previously granted Fast Track and Breakthrough Therapy designations to tividenofusp alfa, and the European Medicines Agency has given it Priority Medicines designation [8] Other Pipeline Candidates - Denali is also developing DNL126 for Sanfilippo syndrome type A (MPS IIIA), with the FDA considering cerebrospinal fluid heparan sulfate as a potential surrogate endpoint for accelerated approval [9] - Another candidate, TAK-594/DNL593, is in collaboration with Takeda for treating frontotemporal dementia (FTD) [10] - Denali and Biogen are jointly evaluating BIIB122/DNL151 for Parkinson's disease, with a global phase IIb study currently ongoing [11][12] Market Position - Denali currently holds a Zacks Rank 3 (Hold), while competitors Amicus Therapeutics and CorMedix have higher rankings of 1 (Strong Buy) and 2 (Buy) respectively [13]

Core Points - Denali Therapeutics Inc. announced an extension of the FDA review timeline for the Biologics License Application (BLA) for tividenofusp alfa from January 5, 2026, to April 5, 2026 [1][2] - The extension is due to Denali's submission of updated clinical pharmacology information, classified as a Major Amendment, and does not relate to efficacy, safety, or biomarkers [2] - Denali is preparing for the potential approval and commercial launch of tividenofusp alfa, emphasizing the urgency to deliver this therapy to the MPS community [3] Product Information - Tividenofusp alfa (DNL310) is designed to deliver the iduronate 2-sulfatase (IDS) enzyme to address symptoms of Hunter syndrome, including behavioral, cognitive, and physical symptoms [4] - The FDA has granted Fast Track and Breakthrough Therapy designations to tividenofusp alfa, and the European Medicines Agency has granted Priority Medicines designation [4] - The Phase 2/3 COMPASS study is currently enrolling participants in North America, South America, and Europe to support global approval [5] Disease Background - Hunter syndrome (MPS II) is a rare genetic lysosomal storage disease caused by mutations in the IDS gene, leading to a deficiency of the IDS enzyme [6] - Symptoms include developmental delays, cognitive decline, and physical complications, with current therapies not addressing neurological symptoms due to their inability to cross the blood-brain barrier [6] - There is a significant unmet need for therapies that can address both central nervous system and peripheral manifestations of Hunter syndrome [6] Company Overview - Denali Therapeutics is focused on developing therapies that can cross the blood-brain barrier for neurodegenerative and lysosomal storage diseases [7] - The company employs a rigorous approach to assess genetically validated targets and develop treatments guided by biomarkers [7]

Core Viewpoint - Denali Therapeutics Inc. has shown a positive stock performance, gaining approximately 16.2% since the last earnings report, outperforming the S&P 500, but questions remain about the sustainability of this trend leading up to the next earnings release [1] Financial Performance - Denali reported a second-quarter 2025 loss of 72 cents per share, which was narrower than the Zacks Consensus Estimate of a loss of 74 cents, but worse than the loss of 59 cents in the same quarter last year [2] - The company did not generate any collaboration revenues in the reported quarter, despite a Zacks Consensus Estimate for revenues set at $25 million [3] - Research and development expenses increased by 12.4% to $102.7 million, primarily due to heightened spending on multiple preclinical programs, while general and administrative expenses rose by 28% to $32.3 million due to preparations for a potential product launch [4] Cash Position - As of June 30, 2025, Denali 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 tividenofuspalfa for priority review, with a target action date set for January 5, 2026 [6] - The BLA seeks accelerated approval based on data from a phase I/II study for Hunter syndrome, with tividenofuspalfa having received multiple designations from the FDA [7] - Denali is preparing for the commercial launch of tividenofuspalfa and is conducting a phase II/III COMPASS study to support global regulatory submissions [8] Additional Pipeline Candidates - Denali is evaluating DNL126 for Sanfilippo syndrome type A and has aligned with the FDA on using cerebrospinal fluid heparan sulfate as a potential surrogate endpoint for accelerated approval [9] - Data from an ongoing phase I/II study for DNL126 shows significant reductions in CSF HS and a favorable safety profile [10] - Denali is also collaborating with Takeda on DNL593 for frontotemporal dementia and with Biogen on BIIB122/DNL151 for Parkinson's disease [12][13] Future Outlook - Denali plans to submit regulatory applications for one to two TV-enabled programs each year over the next three years across various therapeutic franchises [14] - Estimates for Denali's stock have been trending upward, with a Zacks Rank of 3 (Hold), indicating expectations for an in-line return in the coming months [15][17] Industry Comparison - Denali operates within the Zacks Medical - Biomedical and Genetics industry, where another player, MannKind, has seen a 50.6% increase in stock price over the past month [18] - MannKind reported revenues of $76.53 million, reflecting a year-over-year increase of 5.7%, but is expected to post a significant decline in earnings for the current quarter [19]