[Executive Summary & Business Highlights](index=1&type=section&id=Executive%20Summary%20%26%20Business%20Highlights) This section summarizes Denali's 2023 achievements, 2024 outlook, pipeline updates, corporate strategy, and financial guidance [CEO Statement & 2024 Outlook](index=1&type=section&id=CEO%20Statement%20%26%202024%20Outlook) CEO highlighted 2023 portfolio progress and TV platform validation, with 2024 goals for trial completion and commercial readiness - 2023 achievements include significant progress across the broad therapeutic portfolio and further clinical validation of the BBB-crossing Transport Vehicle (TV) platform[2](index=2&type=chunk) - 2024 goals include completing enrollment of late-stage trials in MPS II and ALS, establishing commercial readiness for initial programs, and expanding the TV-enabled portfolio to address large neurodegenerative diseases with enzymes, antibodies, and oligonucleotides[2](index=2&type=chunk) [Program Updates](index=1&type=section&id=Program%20Updates) Denali updated its clinical and preclinical pipeline, detailing late-stage trial progress, new funding, and TV platform advancements [Late-stage and Mid-stage Clinical Programs](index=1&type=section&id=Late-stage%20and%20Mid-stage%20Clinical%20Programs) Updates on Denali's late-stage and mid-stage clinical programs for MPS II, ALS, MS, Parkinson's, and UC are presented - **Tividenofusp alfa (DNL310) for MPS II (Hunter syndrome):** Presented additional interim data from the open-label, single-arm Phase 1/2 study at 2024 WORLDSymposium, showing improvement and stabilization in adaptive behavior, cognition, hearing, and growth trajectory out to 104 weeks. Robust and sustained responses in neuronal health and peripheral activity biomarkers were observed[3](index=3&type=chunk)[4](index=4&type=chunk) - Enrollment continues in the global Phase 2/3 COMPASS study and is expected to be completed in 2024[3](index=3&type=chunk) - **DNL343 for ALS:** Enrollment continues in Regimen G of the Phase 2/3 HEALEY ALS Platform Trial and is expected to be completed in 2024[3](index=3&type=chunk) - **SAR443820/DNL788 (CNS-penetrant RIPK1 inhibitor) for MS/ALS:** The Phase 2 HIMALAYA study in ALS did not meet the primary endpoint of change in ALS Functional Rating Scale-Revised (ALSFRS-R)[3](index=3&type=chunk)[4](index=4&type=chunk) - Sanofi is evaluating SAR443820/DNL788 in another Phase 2 clinical trial in participants with MS, and the outcome of the HIMALAYA study has no impact on the ongoing MS study[3](index=3&type=chunk)[4](index=4&type=chunk) - **BIIB122/DNL151 (LRRK2 inhibitor) for Parkinson's disease (PD):** Executed a Collaboration and Development Funding Agreement in January 2024 with a third party for a global Phase 2a study, with committed funding of **$75.0 million** (**$12.5 million** received in January 2024)[5](index=5&type=chunk) - Denali plans to solely operationalize the Phase 2a study to evaluate safety and biomarkers in PD participants with confirmed pathogenic variants of LRRK2[5](index=5&type=chunk) - Biogen will continue to conduct the ongoing global Phase 2b LUMA study in early-stage PD; Denali and Biogen will co-commercialize upon regulatory approval[5](index=5&type=chunk) - **Eclitasertib (SAR443122/DNL758) (Peripheral RIPK1 inhibitor) for Ulcerative Colitis (UC):** Sanofi is conducting the Phase 2 trial[5](index=5&type=chunk) [Early-stage Clinical and Preclinical Programs](index=2&type=section&id=Early-stage%20Clinical%20and%20Preclinical%20Programs) Updates on Denali's early-stage clinical and preclinical programs for MPS IIIA and FTD-GRN are presented - **DNL126 (ETV-enabled SGSH replacement therapy) for MPS IIIA (Sanfilippo syndrome Type A):** Initiated dosing in the Phase 1/2 study; biomarker proof of concept and safety data are expected by the end of 2024[6](index=6&type=chunk)[9](index=9&type=chunk) - Preclinical data demonstrated DNL126 improves lysosomal and microglial morphology, neurodegeneration, and cognitive function in adult MPS IIIA mice[6](index=6&type=chunk)[9](index=9&type=chunk) - **TAK-594/DNL593 (PTV-enabled progranulin replacement therapy) for FTD-GRN:** Part B has been voluntarily paused in the Phase 1/2 study to implement protocol modifications, and is expected to resume this year[6](index=6&type=chunk) [Transport Vehicle (TV) Platform & Discovery Programs](index=2&type=section&id=Transport%20Vehicle%20%28TV%29%20Platform%20%26%20Discovery%20Programs) Advancements in Denali's TV platforms, including OTV, ATV:Abeta, and the novel CD98hc-targeting TV platform, are presented - **Oligonucleotide Transport Vehicle (OTV) platform:** Announced two lead OTV programs in the IND-enabling stage: OTV:MAPT targeting tau for Alzheimer's disease and OTV:SNCA targeting alpha-synuclein for Parkinson's disease[7](index=7&type=chunk) - **Antibody Transport Vehicle Amyloid beta (ATV:Abeta) program:** Licensed by Biogen and is in the IND-enabling stage of development[8](index=8&type=chunk)[10](index=10&type=chunk) - Preclinical data showed superior amyloid plaque binding and reduction compared to a conventional Abeta antibody and the potential to reduce the risk of amyloid-related imaging abnormalities (ARIA)[8](index=8&type=chunk)[10](index=10&type=chunk) - **CD98hc-targeting TV platform:** Announced as a second TV platform, targeting CD98 heavy chain, an amino acid transporter expressed at the BBB, offering distinct properties from Denali's TfR-targeting TV platform[8](index=8&type=chunk) [Corporate Updates & Strategic Initiatives](index=2&type=section&id=Corporate%20Updates%20%26%20Strategic%20Initiatives) Denali completed a **$500 million** PIPE financing to extend its cash runway and plans to spin out its preclinical small molecule portfolio - **PIPE Financing:** Entered into a securities purchase agreement for a private investment in public equity (PIPE) financing, issuing 3,244,689 shares of common stock and 26,046,065 pre-funded warrants at **$17.07** and **$17.06** per share/warrant, respectively[9](index=9&type=chunk) - Anticipates gross proceeds of approximately **$500 million**[9](index=9&type=chunk) - **Preclinical Small Molecule Portfolio Spin-out:** Announced the intention to spin out the company's preclinical small molecule portfolio[11](index=11&type=chunk) - Decision based on clinical validation and prioritization of Denali's TV-enabled platforms for brain delivery of large molecules, while maintaining current clinical stage small molecule programs[11](index=11&type=chunk) [2024 Financial Guidance & Cash Runway](index=3&type=section&id=2024%20Financial%20Guidance%20%26%20Cash%20Runway) Denali anticipates 2024 operating expenses to be less than or equal to 2023, with PIPE financing extending its cash runway into 2028 - Cash, cash equivalents, and marketable securities were approximately **$1.03 billion** as of December 31, 2023[12](index=12&type=chunk) - For the full year 2024, operating expenses are anticipated to be less than or equal to those in 2023, based on portfolio prioritization[12](index=12&type=chunk) - With anticipated proceeds from the PIPE financing, the company's cash runway is expected to extend into 2028[12](index=12&type=chunk) [Investor Conferences](index=3&type=section&id=Investor%20Conferences) Denali announced participation in several investor conferences in March 2024, including Cowen, Leerink, Jefferies, and Stifel events - Upcoming participation in investor conferences: Cowen 44th Annual Health Care Conference (March 4-6), Leerink Global Biopharma Conference (March 11-13), Jefferies Biotech on the Bay Summit (March 12-13), and Stifel 2023 CNS Days (March 19-20)[15](index=15&type=chunk) [Financial Performance (Q4 and Full Year 2023)](index=3&type=section&id=Financial%20Performance%20%28Q4%20and%20Full%20Year%202023%29) Denali's Q4 and full year 2023 financial performance is reviewed, covering net loss, collaboration revenue, operating expenses, and liquidity [Overview of Net Loss](index=3&type=section&id=Overview%20of%20Net%20Loss) Denali reported an increased net loss for Q4 2023 but a significant reduction for full year 2023, driven by higher collaboration revenue Net Loss (in millions) | Metric | Q4 2023 | Q4 2022 | YoY Change (Q4) | FY 2023 | FY 2022 | YoY Change (FY) | | :----------------- | :------ | :------ | :---------------- | :------ | :------ | :---------------- | | Net Loss | $(119.5) | $(98.7) | $(20.8) | $(145.2) | $(326.0) | $180.8 | [Collaboration Revenue](index=3&type=section&id=Collaboration%20Revenue) Q4 2023 collaboration revenue was zero due to milestone timing, while full-year 2023 revenue significantly increased, driven by a Biogen payment Collaboration Revenue (in millions) | Metric | Q4 2023 | Q4 2022 | YoY Change (Q4) | FY 2023 | FY 2022 | YoY Change (FY) | | :------------------- | :------ | :------ | :---------------- | :------ | :------ | :---------------- | | Collaboration Revenue | $0 | $10.3 | $(10.3) | $330.5 | $108.5 | $222.0 | - The Q4 2023 decrease was primarily due to a **$10.0 million** decrease in revenue earned under the Sanofi Collaboration for a milestone triggered in December 2022[14](index=14&type=chunk) - The FY 2023 increase was primarily due to **$293.9 million** in revenue recognized in April 2023 under the Biogen Collaboration Agreement as a result of Biogen exercising its option to license the ATV:Abeta program, partially offset by decreases from Takeda (**$41.9 million**) and Sanofi (**$28.4 million**) due to timing of activities and milestones[14](index=14&type=chunk) [Operating Expenses](index=3&type=section&id=Operating%20Expenses) Total operating expenses increased in Q4 and full year 2023, driven by higher R&D costs from clinical trial progress and increased headcount, and rising G&A expenses [Research and Development Expenses](index=3&type=section&id=Research%20and%20Development%20Expenses) R&D expenses increased in Q4 and full year 2023, primarily due to clinical trial progress, higher headcount, and a shift in net cost sharing Research and Development Expenses (in millions) | Metric | Q4 2023 | Q4 2022 | YoY Change (Q4) | FY 2023 | FY 2022 | YoY Change (FY) | | :----------------------- | :------ | :------ | :---------------- | :------ | :------ | :---------------- | | Research and Development | $107.8 | $92.1 | $15.7 | $423.9 | $358.7 | $65.2 | - Increases were primarily attributable to: increases in ETV:IDS and eIF2B program external expenses reflecting continued clinical trial progress; an increase in personnel-related expenses due to higher headcount; and a shift in net cost sharing from reimbursements to payments[15](index=15&type=chunk) - These increases were partially offset by decreases in TV platform and other program external expenses, PTV:PGRN program external expenses, and LRRK2 program external expenses due to timing and transition of activities to Biogen[15](index=15&type=chunk) [General and Administrative Expenses](index=4&type=section&id=General%20and%20Administrative%20Expenses) G&A expenses increased in Q4 and full year 2023, primarily due to higher personnel-related expenses and new facility costs General and Administrative Expenses (in millions) | Metric | Q4 2023 | Q4 2022 | YoY Change (Q4) | FY 2023 | FY 2022 | YoY Change (FY) | | :-------------------------- | :------ | :------ | :---------------- | :------ | :------ | :---------------- | | General and Administrative | $24.8 | $23.5 | $1.3 | $103.4 | $90.5 | $12.9 | - Increases were primarily attributable to an increase in personnel-related expenses, including employee compensation and stock-based compensation expenses, driven by higher headcount and equity award grants. Additionally, there was an increase in facility and other corporate costs associated with the new Salt Lake City manufacturing facility[16](index=16&type=chunk) [Liquidity and Capital Resources](index=4&type=section&id=Liquidity%20and%20Capital%20Resources) As of December 31, 2023, Denali maintained a strong liquidity position with approximately **$1.03 billion** in cash, cash equivalents, and marketable securities - Cash, cash equivalents, and marketable securities were approximately **$1.03 billion** as of December 31, 2023[17](index=17&type=chunk) [Additional Information](index=4&type=section&id=Additional%20Information) Background information on Denali Therapeutics and a cautionary note regarding forward-looking statements are provided [About Denali Therapeutics](index=4&type=section&id=About%20Denali%20Therapeutics) Denali Therapeutics is a biopharmaceutical company developing BBB-crossing product candidates for neurodegenerative and lysosomal storage diseases, focusing on validated targets and biomarker-guided development - Denali Therapeutics is a biopharmaceutical company developing a broad portfolio of product candidates engineered to cross the blood-brain barrier (BBB) for the treatment of neurodegenerative diseases and lysosomal storage diseases[18](index=18&type=chunk) - The company's strategy involves rigorously assessing genetically validated targets, engineering delivery across the BBB, and guiding development through biomarkers that demonstrate target and pathway engagement[18](index=18&type=chunk) [Cautionary Note Regarding Forward-Looking Statements](index=5&type=section&id=Cautionary%20Note%20Regarding%20Forward-Looking%20Statements) This disclaimer indicates the press release contains forward-looking statements subject to risks and uncertainties, which could cause actual results to differ materially, and Denali does not undertake to update them - The press release contains forward-looking statements subject to risks and uncertainties, and actual results may differ materially from those indicated[20](index=20&type=chunk) - Risks include those related to clinical development, regulatory approval, collaborations, manufacturing, intellectual property rights, financing, and the ability to enroll patients or complete trials on expected timelines[20](index=20&type=chunk) - Denali does not undertake any obligation to update or revise any forward-looking statements, except as required by law[20](index=20&type=chunk) [Condensed Consolidated Financial Statements](index=6&type=section&id=Condensed%20Consolidated%20Financial%20Statements) This section presents the unaudited condensed consolidated statements of operations and balance sheets for the specified periods [Statements of Operations](index=6&type=section&id=Statements%20of%20Operations) This section presents the unaudited condensed consolidated statements of operations, detailing collaboration revenue, operating expenses, loss from operations, and net loss for Q4 and full year 2023 and 2022 Condensed Consolidated Statements of Operations (Unaudited, in thousands) | Metric | Three Months Ended Dec 31, 2023 | Three Months Ended Dec 31, 2022 | Twelve Months Ended Dec 31, 2023 | Twelve Months Ended Dec 31, 2022 | | :---------------------------------- | :------------------------------ | :------------------------------ | :------------------------------- | :------------------------------- | | Total collaboration revenue | $— | $10,283 | $330,531 | $108,463 | | Research and development | $107,803 | $92,111 | $423,876 | $358,732 | | General and administrative | $24,769 | $23,516 | $103,354 | $90,475 | | Total operating expenses | $132,572 | $115,627 | $527,230 | $449,207 | | Loss from operations | $(132,572) | $(105,344) | $(196,699) | $(340,744) | | Interest and other income, net | $13,129 | $6,660 | $51,505 | $14,774 | | Net loss | $(119,473) | $(98,678) | $(145,224) | $(325,991) | | Net loss per share, basic and diluted | $(0.86) | $(0.75) | $(1.06) | $(2.60) | [Balance Sheets](index=7&type=section&id=Balance%20Sheets) This section provides the unaudited condensed consolidated balance sheets, outlining Denali's assets, liabilities, and stockholders' equity as of December 31, 2023, and 2022 Condensed Consolidated Balance Sheets (Unaudited, in thousands) | Metric | December 31, 2023 | December 31, 2022 | | :-------------------------------------- | :------------------ | :------------------ | | Cash and cash equivalents | $127,106 | $218,044 | | Short-term marketable securities | $907,405 | $1,118,171 | | Total current assets | $1,064,137 | $1,372,319 | | Total assets | $1,153,917 | $1,460,242 | | Total current liabilities | $77,982 | $363,922 | | Total liabilities | $122,963 | $417,812 | | Total stockholders' equity | $1,030,954 | $1,042,430 |

SOUTH SAN FRANCISCO, Calif., Feb. 01, 2024 (GLOBE NEWSWIRE) -- Denali Therapeutics Inc. (NASDAQ:DNLI), a biopharmaceutical company developing a broad portfolio of product candidates engineered to cross the blood-brain barrier (BBB) for the treatment of neurodegenerative diseases and lysosomal storage diseases, today announced upcoming presentations from its Enzyme Transport Vehicle (ETV) development programs, tividenofusp alfa (DNL310) and DNL126 (ETV:SGSH), to be given at the 20th Annual WORLDSymposium™, w ...

Denali Therapeutics Inc. (DNLI) develops therapies targeting neurodegenerative diseases. The company owns an impressive pipeline of targeted therapeutic candidates for neurodegenerative diseases. Its recent pipeline progress has been encouraging.Denali’s strategic partnerships with bigwigs like Biogen (BIIB) and Sanofi (SNY) provide funds for pipeline development.Denali and Biogen are developing BIIB122/DNL151, a small-molecule inhibitor, of LRRK2 for Parkinson’s disease (“PD”).Earlier this month, Denali ou ...

Table of Contents UNITED STATES SECURITIES AND EXCHANGE COMMISSION Washington, D.C. 20549 FORM 10-Q (Mark One) ☒ QUARTERLY REPORT PURSUANT TO SECTION 13 OR 15(d) OF THE SECURITIES EXCHANGE ACT OF 1934 For the quarterly period ended September 30, 2023 OR ☐ TRANSITION REPORT PURSUANT TO SECTION 13 OR 15(d) OF THE SECURITIES EXCHANGE ACT OF 1934 For the transition period from to Commission File Number: 001-38311 Denali Therapeutics Inc. (Exact name of registrant as specified in its charter) (State or other jur ...

☒ QUARTERLY REPORT PURSUANT TO SECTION 13 OR 15(d) OF THE SECURITIES EXCHANGE ACT OF 1934 For the quarterly period ended June 30, 2023 OR Table of Contents UNITED STATES SECURITIES AND EXCHANGE COMMISSION Washington, D.C. 20549 FORM 10-Q (Mark One) ☐ TRANSITION REPORT PURSUANT TO SECTION 13 OR 15(d) OF THE SECURITIES EXCHANGE ACT OF 1934 For the transition period from to Commission File Number: 001-38311 Denali Therapeutics Inc. (Exact name of registrant as specified in its charter) (State or other jurisdic ...

Table of Contents UNITED STATES SECURITIES AND EXCHANGE COMMISSION Washington, D.C. 20549 FORM 10-Q (Mark One) ☒ QUARTERLY REPORT PURSUANT TO SECTION 13 OR 15(d) OF THE SECURITIES EXCHANGE ACT OF 1934 For the quarterly period ended March 31, 2023 OR ☐ TRANSITION REPORT PURSUANT TO SECTION 13 OR 15(d) OF THE SECURITIES EXCHANGE ACT OF 1934 161 Oyster Point Blvd. South San Francisco, CA, 94080 (Address of principal executive offices and zip code) (650) 866-8548 (Registrant's telephone number, including area c ...

Pipeline and Programs - Denali has 10 INDs across 6 indications, with 7 programs in clinical development and 3 in late-stage[11] - Denali's discovery engine has yielded >14 programs in the discovery stage, 20+ publications in top-tier journals, and 90+ patents granted worldwide[3] - DNL310 (ETV:IDS) for MPS II (Hunter syndrome) is in Phase 2/3 development, with additional interim Phase 1/2 data expected in Early/Mid 2023[94] - DNL126 (ETV:SGSH) for MPS IIIA (Sanfilippo) is planned for IND submission in 1H:23, with recruitment activities in 2H:23[32, 135] - BIIB122 (LRRK2 inhibitor) for Parkinson's Disease is in Phase 3 for LRRK2+ PD and Phase 2b for Idiopathic PD, with recruitment ongoing[34, 199] - DNL593 (PTV:PGRN) for FTD-GRN is in Phase 1/2, with final Phase 1/2 Part A (HV) data expected Mid 2023 and recruitment for Part B ongoing[155] - DNL919 (ATV:TREM2) for Alzheimer's Disease is in Phase 1, with Phase 1 HV data expected YE 2023[34, 60] - SAR443820 (RIPK1 inhibitor) for ALS is in Phase 2, with complete recruitment expected in 2023[19, 210] - DNL343 (eIF2B activator) for ALS is in Phase 1b, with final 28-day Phase 1b data expected Mid 2023 and initiation of Phase 2/3 HEALEY study Mid 2023[19, 200] Strategic Partnerships - Denali has strategic partnerships with Biogen, Sanofi, and Takeda totaling $1.3 billion in upfront payments and >$3 billion in milestones[30, 171] - The LRRK2 inhibitor partnership with Biogen includes $1.025 billion upfront (cash/equity) and $2 billion in milestones, with a 50/50 profit share in the US and 40/60 in China[30] - The RIPK1 inhibitor partnership with Sanofi includes $125 million upfront and $1.1 billion in milestones, with ~50% profit sharing in key geographies[30] - Multiple TV-Platform Programs with Takeda including PTV:PGRN and ATV:TREM2 include $150 million upfront (cash/equity) and $1 billion in milestones, with 50/50 profit share worldwide[30] Technology and Platforms - Denali is focused on solving the blood-brain barrier (BBB) challenge for a broad range of therapeutics and indications[11] - Denali's Transport Vehicle (TV) platform includes Enzyme Transport Vehicle (ETV), Antibody Transport Vehicle (ATV), Protein Transport Vehicle (PTV), and Oligonucleotide Transport Vehicle (OTV) technologies[54] - OTV provides uniform ASO deposition across the CNS with IV delivery[38]

Collaboration Agreements - Biogen made a $400.0 million upfront payment in October 2020 under the LRRK2 Agreement, with potential milestone payments up to approximately $1.125 billion[107]. - Sanofi paid an upfront payment of $125.0 million when the Sanofi Collaboration Agreement became effective in November 2018, with potential milestone payments up to approximately $1.1 billion[132]. - Cumulative earned and potential milestones from Sanofi include $120.0 million in clinical milestone payments and $175.0 million in regulatory milestone payments for CNS Products[132]. - The company will share profits and losses equally with Sanofi for CNS Products sold in the United States and China[133]. - Sanofi is responsible for 70% of the costs for Phase 3 and later stage development trials for CNS Products, while the company funds 30%[135]. - Takeda paid a $40 million upfront payment and an additional $110 million under a share purchase agreement as part of the Takeda Collaboration Agreement[147]. - Takeda may pay up to $280 million upon achieving certain clinical milestones and up to $200 million for regulatory milestones related to product approvals[152]. - The company retains rights to lead clinical activities for each indication up to the first trial with a clinical outcomes-based efficacy endpoint in collaboration with Takeda[154]. - The F-star Collaboration Agreement aims to develop antibody domains to enhance therapeutic delivery across the blood-brain barrier[161]. - The company exercised a buy-out option for F-star Gamma, acquiring all outstanding shares in May 2018[162]. - The acquisition of F-star Gamma resulted in an initial payment of $18.0 million, with contingent payments up to $243.0 million based on achieving specific milestones[163]. - Under the Genentech agreement, the company made an upfront payment of $8.5 million and may owe up to $315.0 million in milestone payments[167]. - In 2022, the company paid Genentech $12.5 million in milestone payments related to the LRRK2 program, with total milestones of $15.0 million earned through the end of 2022[167]. Financial Performance - Denali Therapeutics reported total collaboration revenue of $108.463 million for the year ended December 31, 2022, a significant increase from $48.661 million in 2021, representing a growth of approximately 123%[655]. - Research and development expenses for 2022 were $358.732 million, up from $265.353 million in 2021, indicating a year-over-year increase of about 35%[655]. - The net loss for 2022 was $325.991 million, compared to a net loss of $290.581 million in 2021, reflecting a decline of approximately 12% in net income[655]. - As of December 31, 2022, Denali Therapeutics had cash, cash equivalents, and marketable securities totaling $1.3 billion, a decrease from $1.3 billion in 2021[635]. - The company's total assets increased to $1.460 billion as of December 31, 2022, compared to $1.404 billion in 2021, marking a growth of about 4%[652]. - Denali Therapeutics' interest and other income for 2022 was $14.774 million, compared to $4.595 million in 2021, indicating an increase of about 221%[655]. - The weighted-average shares used in calculating basic net income (loss) per share increased to 125.531 million in 2022 from 121.525 million in 2021[655]. - The company had total stockholders' equity of $1.042 billion as of December 31, 2022, an increase from $962.291 million in 2021, representing a growth of approximately 8%[652]. Regulatory Environment - The FDA regulates drug approvals, requiring extensive data demonstrating quality, safety, and efficacy before marketing[194]. - The clinical development process involves three phases, with each phase requiring compliance with Good Clinical Practice (GCP) regulations[201]. - Post-approval trials may be mandated by the FDA to gain additional experience from treatment in the intended therapeutic indication[203]. - The FDA's user fee for an NDA or BLA requiring clinical data is $3,242,026, with an annual program fee of $393,933 for each marketed human drug or biologic[210]. - The FDA has ten months to complete its initial review of a new molecular-entity NDA or original BLA, and six months for priority review[212]. - Orphan drug designation must be requested before submitting an NDA or BLA, and grants exclusivity for seven years if the product receives FDA approval for the designated condition[216]. - The FDA's fast track program expedites the review process for drugs intended to treat serious conditions with unmet medical needs[218]. - A product may qualify for accelerated approval if it provides a meaningful advantage over existing therapies based on surrogate endpoints[222]. - The FDA may require post-marketing studies to confirm clinical benefits for drugs receiving accelerated approval, with the risk of revocation if not confirmed[222]. - The BPCIA created an abbreviated approval pathway for biosimilars, aiming to reduce development costs and increase patient access[224]. - Biosimilar products must demonstrate high similarity to reference products, with no clinically meaningful differences in safety, purity, and potency[226]. - The FDA has discretion over the scientific evidence required to demonstrate biosimilarity, which poses challenges for implementation[227]. - The FDA requires a stepwise approach for biosimilar product development, and may refuse approval if there is insufficient information regarding safety, purity, or potency[228]. - A biosimilar application may be deemed incomplete if applicable user fees under the Biosimilar User Fee Act have not been paid[229]. - The FDA grants a twelve-year exclusivity period for reference biological products, during which no biosimilar applications can be accepted until four years after the reference product's first licensure[246]. - The first interchangeable biological product is entitled to exclusivity, which lasts until one year after its commercial marketing or 18 months after resolution of patent infringement[232]. - The FDA may impose post-approval requirements, including monitoring and reporting adverse experiences, and compliance with promotion and advertising regulations[233]. - Non-compliance with regulatory standards can lead to withdrawal of product approvals or significant penalties[242]. Patent and Intellectual Property - The company currently has over 1,400 patents and patent applications, with a focus on protecting its proprietary technology and product candidates[181]. - The BBB platform technology includes ten patent families, with key patents expected to expire in 2038[182]. - The ETV platform and related products have seven patent families, with an issued U.S. patent expected to expire in 2038[183]. - The PTV:PGRN program includes four patent families, with key patents expected to expire in 2039 and 2040[184]. - The ATV:TREM2 program includes five patent families, with a granted U.S. patent expected to expire in 2041, and the other four families expected to expire between 2038 and 2040[185]. - The Oligonucleotide Transport Vehicle (OTV) platform has two patent families expected to expire in 2042 and 2043[186]. - The LRRK2 program is under a collaboration with Biogen, with multiple patent families expected to expire in 2031 and additional families projected to expire in 2038 or later[187]. - The RIPK1 inhibitor program includes five patent families, with one U.S. patent expected to expire in 2038 and another family with two U.S. patents expected to expire in 2037[188]. - The eIF2B activator program consists of seven patent families, with expiration dates ranging from 2038 to 2040[189]. - The company cannot guarantee that pending patent applications will result in issued patents, and the scope of claims may be significantly reduced before issuance[190]. - The patent term for drugs in the U.S. can be extended by up to five years under the Hatch-Waxman Act, and similar provisions exist in Europe[192]. Workforce and Employee Management - The company had approximately 427 full-time employees as of December 31, 2022, with a majority based in South San Francisco, CA[264]. - The company aims to enhance employee retention and attraction through professional development and stock-based compensation awards[265]. - As of December 31, 2022, approximately 53% of the workforce and 51% of managers were female, while ethnic or racial minorities represented about 53% of the workforce and 47% of managers[268]. - The company has maintained zero reportable regulatory safety incidents since its operations began in 2015[266]. - The company has implemented flexible work options to enhance productivity and collaboration in a hybrid work environment[270]. Market and Legislative Impact - The company is subject to various legislative changes that may impact its profitability, including the elimination of the statutory cap on Medicaid Drug Rebate Program rebates effective January 1, 2024[259]. - The company faces potential increased rebate liabilities due to changes in the Medicaid Drug Rebate Program, raising the minimum basic rebate from 15.1% to 23.1% of average manufacturer price[255]. - The company is impacted by the Inflation Reduction Act of 2022, which allows the federal government to negotiate maximum fair prices for certain high-priced Medicare drugs[259]. - The company’s marketability may suffer if adequate coverage and reimbursement are not provided by government and third-party payors[261]. - The company’s operations are managed as a single reportable segment for performance assessment and decision-making[263].

Table of Contents UNITED STATES SECURITIES AND EXCHANGE COMMISSION Washington, D.C. 20549 FORM 10-Q (Mark One) ☒ QUARTERLY REPORT PURSUANT TO SECTION 13 OR 15(d) OF THE SECURITIES EXCHANGE ACT OF 1934 For the quarterly period ended September 30, 2022 OR ☐ TRANSITION REPORT PURSUANT TO SECTION 13 OR 15(d) OF THE SECURITIES EXCHANGE ACT OF 1934 For the transition period from to Commission File Number: 001-38311 Denali Therapeutics Inc. (Exact name of registrant as specified in its charter) Delaware 46-3872213 ...

[PART I. FINANCIAL INFORMATION](index=3&type=section&id=PART%20I.%20FINANCIAL%20INFORMATION) [Item 1. Financial Statements (Unaudited)](index=3&type=section&id=Item%201.%20Financial%20Statements%20(Unaudited)) This section presents Denali Therapeutics Inc.'s unaudited condensed consolidated financial statements as of June 30, 2022, showing total collaboration revenue of **$94.6 million** and a net loss of **$124.0 million** for the six months ended June 30, 2022, with total assets decreasing to **$1.29 billion** from **$1.40 billion** [Condensed Consolidated Balance Sheets](index=3&type=section&id=Condensed%20Consolidated%20Balance%20Sheets) Total assets decreased to **$1.29 billion** as of June 30, 2022, from **$1.40 billion** at December 31, 2021, primarily due to reduced cash and marketable securities, while total liabilities decreased to **$408.0 million** from **$441.9 million** Condensed Consolidated Balance Sheet Highlights (in thousands) | Account | June 30, 2022 | December 31, 2021 | | :--- | :--- | :--- | | **Assets** | | | | Cash and cash equivalents | $155,088 | $293,477 | | Total current assets | $1,114,600 | $897,234 | | Total assets | $1,292,462 | $1,404,162 | | **Liabilities & Stockholders' Equity** | | | | Total current liabilities | $348,160 | $378,245 | | Total liabilities | $408,014 | $441,871 | | Total stockholders' equity | $884,448 | $962,291 | [Condensed Consolidated Statements of Operations and Comprehensive Loss](index=4&type=section&id=Condensed%20Consolidated%20Statements%20of%20Operations%20and%20Comprehensive%20Loss) For Q2 2022, Denali reported a net loss of **$58.8 million** or **($0.48) per share**, a slight decrease from **$60.7 million** or **($0.50) per share** in Q2 2021, driven by increased collaboration revenue offsetting a **41%** rise in R&D expenses Statement of Operations Summary (in thousands, except per share data) | Metric | Three Months Ended June 30, 2022 | Three Months Ended June 30, 2021 | Six Months Ended June 30, 2022 | Six Months Ended June 30, 2021 | | :--- | :--- | :--- | :--- | :--- | | Total collaboration revenue | $52,480 | $22,939 | $94,621 | $30,862 | | Research and development | $92,737 | $65,711 | $178,835 | $125,918 | | General and administrative | $21,159 | $19,045 | $43,700 | $37,981 | | Loss from operations | ($61,416) | ($61,817) | ($127,914) | ($133,037) | | Net loss | ($58,794) | ($60,691) | ($124,014) | ($130,732) | | Net loss per share | ($0.48) | ($0.50) | ($1.01) | ($1.08) | [Condensed Consolidated Statements of Stockholders' Equity](index=5&type=section&id=Condensed%20Consolidated%20Statements%20of%20Stockholders'%20Equity) Total stockholders' equity decreased from **$962.3 million** at December 31, 2021, to **$884.4 million** at June 30, 2022, primarily due to a **$124.0 million** net loss, partially offset by stock-based compensation and equity incentive plan proceeds Changes in Stockholders' Equity (in thousands) | Description | Amount | | :--- | :--- | | Balance at December 31, 2021 | $962,291 | | Net loss (Six months ended June 30, 2022) | ($124,014) | | Stock-based compensation | $50,081 | | Issuances under equity incentive plans | $5,865 | | Other comprehensive loss | ($9,775) | | Balance at June 30, 2022 | $884,448 | [Condensed Consolidated Statements of Cash Flows](index=6&type=section&id=Condensed%20Consolidated%20Statements%20of%20Cash%20Flows) Net cash used in operating activities increased to **$115.0 million** for the six months ended June 30, 2022, while investing activities shifted from providing **$72.1 million** to using **$29.2 million**, resulting in a **$138.4 million** decrease in cash, cash equivalents, and restricted cash Cash Flow Summary (in thousands) | Activity | Six Months Ended June 30, 2022 | Six Months Ended June 30, 2021 | | :--- | :--- | :--- | | Net cash used in operating activities | ($115,007) | ($104,461) | | Net cash (used in) provided by investing activities | ($29,247) | $72,132 | | Net cash provided by financing activities | $5,865 | $10,865 | | Net decrease in cash, cash equivalents and restricted cash | ($138,389) | ($21,464) | [Notes to Condensed Consolidated Financial Statements](index=7&type=section&id=Notes%20to%20Condensed%20Consolidated%20Financial%20Statements) The notes detail significant accounting policies and financial statement items, highlighting **$40.0 million** and **$24.0 million** in collaboration milestones from Sanofi and Takeda respectively, a **$7.5 million** milestone payment to Genentech, and **$25.2 million** in non-cancellable purchase commitments with Lonza - The company recognized a **$40.0 million** milestone from Sanofi in April 2022 upon the first patient dosing in a Phase 2 study of SAR443820/DNL788 for ALS[66](index=66&type=chunk) - Two preclinical milestones from Takeda totaling **$24.0 million** were recognized in the first six months of 2022 upon CTA approvals for TAK-594/DNL593 and TAK-920/DNL919[72](index=72&type=chunk) - In June 2022, the company paid a **$7.5 million** clinical milestone to Genentech triggered by the start of dosing in the Phase 2b LUMA study for BIIB122/DNL151, with Biogen responsible for **50%** of this payment[81](index=81&type=chunk) - As of June 30, 2022, the company had **$25.2 million** in non-cancellable purchase commitments with Lonza for the development and manufacturing of biologic products[92](index=92&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 performance, noting increased collaboration revenue from Sanofi and Takeda milestones, offset by rising R&D expenses for clinical programs, with **$1.16 billion** in cash, cash equivalents, and marketable securities deemed sufficient for at least the next 12 months [Overview](index=24&type=section&id=Overview) Denali's strategy targets neurodegenerative diseases using genetically validated pathways, proprietary BBB platform for brain delivery, and biomarkers, with key 2022 milestones including a **$40.0 million** Sanofi milestone and two **$12.0 million** Takeda milestones from clinical advancements - The company's strategy is guided by three principles: targeting genetically validated pathways (degenogenes), engineering brain delivery across the blood-brain barrier (BBB), and using biomarkers to drive development[109](index=109&type=chunk)[111](index=111&type=chunk) - Key 2022 milestones include the initiation of a Phase 2 ALS study by Sanofi for SAR443820/DNL788, triggering a **$40.0 million** milestone payment[118](index=118&type=chunk) - Collaboration partner Biogen commenced dosing in the global Phase 2b LUMA study for BIIB122/DNL151 in Parkinson's disease, triggering a milestone payment to Genentech[120](index=120&type=chunk) - The company's IND application for TAK-920/DNL919 (ATV:TREM2) was placed on clinical hold by the FDA in January 2022, but a Phase 1 study has commenced in the Netherlands[120](index=120&type=chunk) [Results of Operations](index=31&type=section&id=Results%20of%20Operations) Q2 2022 collaboration revenue increased by **$29.6 million** to **$52.5 million** due to Sanofi and Takeda milestones, while R&D expenses rose by **$27.0 million** to **$92.7 million** driven by program advancements and personnel costs, and G&A expenses increased by **$2.2 million** to **$21.2 million** Comparison of Operating Results (in thousands) | Item | Three Months Ended June 30, 2022 | Three Months Ended June 30, 2021 | Change ($) | Change (%) | | :--- | :--- | :--- | :--- | :--- | | Total collaboration revenue | $52,480 | $22,939 | $29,541 | 128.8% | | Research and development | $92,737 | $65,711 | $27,026 | 41.1% | | General and administrative | $21,159 | $19,045 | $2,114 | 11.1% | | Net loss | ($58,794) | ($60,691) | $1,897 | 3.1% | - The increase in R&D expenses for Q2 2022 was primarily driven by a **$10.4 million** increase in ETV:IDS program external expenses as it progresses towards a Phase 2/3 study, and a **$6.3 million** increase in LRRK2 program external expenses, which included a **$7.5 million** milestone payment to Genentech[143](index=143&type=chunk)[145](index=145&type=chunk) [Liquidity and Capital Resources](index=34&type=section&id=Liquidity%20and%20Capital%20Resources) As of June 30, 2022, Denali held **$1.16 billion** in cash, cash equivalents, and marketable securities, with management asserting sufficiency for at least the next 12 months, having cumulatively received **$843.0 million** from collaboration agreements and establishing a **$400.0 million** 'at-the-market' facility - The company had cash, cash equivalents, and marketable securities of **$1.16 billion** as of June 30, 2022[157](index=157&type=chunk) - Management believes existing cash resources are sufficient to fund projected operations for at least the 12 months following the filing date of the Form 10-Q[161](index=161&type=chunk) - Through June 30, 2022, the company has received a total of **$843.0 million** in upfront, option, and milestone payments from its collaboration agreements with Takeda (**$93.0 million**), Sanofi (**$190.0 million**), and Biogen (**$560.0 million**)[155](index=155&type=chunk) [Item 3. Quantitative and Qualitative Disclosures About Market Risk](index=38&type=section&id=Item%203.%20Quantitative%20and%20Qualitative%20Disclosures%20About%20Market%20Risk) The company's primary market risks are interest rate sensitivity on its **$1.16 billion** investment portfolio and foreign currency sensitivity from transactions in Euro, Swiss francs, and British Pound, with a hypothetical **10%** interest rate change not expected to have a material impact - The company is exposed to market risk from changes in interest rates on its **$1.16 billion** portfolio of cash, cash equivalents, and marketable securities[175](index=175&type=chunk) - Foreign currency sensitivity is a risk due to transactions denominated in the Euro, Swiss francs, and British Pound for preclinical, clinical, and manufacturing activities[177](index=177&type=chunk) [Item 4. Controls and Procedures](index=39&type=section&id=Item%204.%20Controls%20and%20Procedures) As of June 30, 2022, management concluded that the company's disclosure controls and procedures were effective, with no material changes to internal control over financial reporting during the quarter - Management concluded that the company's disclosure controls and procedures were effective as of June 30, 2022[180](index=180&type=chunk) - There were no material changes to the company's internal control over financial reporting during the second quarter of 2022[181](index=181&type=chunk) [PART II. OTHER INFORMATION](index=40&type=section&id=PART%20II.%20OTHER%20INFORMATION) [Item 1. Legal Proceedings](index=40&type=section&id=Item%201.%20Legal%20Proceedings) The company is not currently a party to any litigation or legal proceedings expected to have a material adverse effect on its business - Denali is not currently a party to any legal proceedings expected to have a material adverse effect on its business[184](index=184&type=chunk) [Item 1A. Risk Factors](index=40&type=section&id=Item%201A.%20Risk%20Factors) This section details significant risks, substantially similar to those in the 2021 Annual Report, including the company's early development stage, history of net losses, dependence on its BBB platform, high failure rates in neurodegenerative drug development, reliance on third-party collaborations and manufacturing, and intellectual property protection challenges - The company is in the early stages of clinical drug development with a limited operating history, has incurred significant net losses since inception, and has no products approved for commercial sale[188](index=188&type=chunk)[197](index=197&type=chunk)[199](index=199&type=chunk) - The business is heavily dependent on the successful development of its blood-brain barrier (BBB) technology and its early-stage pipeline, with no assurance of regulatory approval for any product candidates[189](index=189&type=chunk)[231](index=231&type=chunk) - The company depends on collaborations with third parties like Biogen, Sanofi, and Takeda for research, development, and commercialization, and relies on third parties for clinical trial conduct and manufacturing[192](index=192&type=chunk)[384](index=384&type=chunk)[393](index=393&type=chunk) - There is a significant risk of being unable to obtain and maintain patent protection for its product candidates and BBB technology, which is critical for its competitive position[193](index=193&type=chunk)[410](index=410&type=chunk) [Item 2. Unregistered Sales of Equity Securities and Use of Proceeds](index=111&type=section&id=Item%202.%20Unregistered%20Sales%20of%20Equity%20Securities%20and%20Use%20of%20Proceeds) The company reported no unregistered sales of equity securities during the quarter and confirmed no material change in the planned use of **$193.9 million** net proceeds from its January 2020 public offering - There were no unregistered sales of equity securities during the period[541](index=541&type=chunk) - The company confirmed no material change in the planned use of proceeds from its January 2020 public offering of **$193.9 million**[542](index=542&type=chunk) [Other Information (Items 3-6)](index=111&type=section&id=Item%203-6) This section addresses standard disclosure items, reporting no defaults upon senior securities, no mine safety disclosures, and no other material information, while Item 6 provides an index of filed exhibits - Items 3 (Defaults Upon Senior Securities), 4 (Mine Safety Disclosures), and 5 (Other Information) are noted as not applicable or having no information to report[544](index=544&type=chunk)[545](index=545&type=chunk)[546](index=546&type=chunk) - Item 6 lists the exhibits filed with the quarterly report, including officer certifications and XBRL data files[550](index=550&type=chunk)[551](index=551&type=chunk)