Disclaimers BUILDING DENALI TO DEFEAT DEGENERATION Discovery engine with >14 programs in discovery stage, 20+ publications in toptier journals, and 90+ patents granted WW Complete 3 - 4 late-stage clinical studies and establish commercial launch readiness Defeating Degeneration Partner of choice in neurodegeneration OUR FOCUS AND STRATEGIC PRINCIPLES 4 Brain delivery of therapeutic proteins using an Fc fragment blood-brain barrier transport vehicle in mice and monkeys c CellPress TREM2 Regulates Microglial ...

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 ...

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 June 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 (Sta ...

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, 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 (St ...

Corporate Overview Ryan Watts Ph.D., Chief Executive Officer 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," "future," "will" and other wor ...

Table of Contents Securities registered pursuant to Section 12(b) of the Act: Title of each class Trading Symbol Name of each exchange on which registered Common Stock, par value $0.01 per share DNLI The NASDAQ Global Select Market Securities registered pursuant to Section 12(g) of the Act: None UNITED STATES SECURITIES AND EXCHANGE COMMISSION Washington, D.C. 20549 FORM 10-K (Mark One) ☒ ANNUAL REPORT PURSUANT TO SECTION 13 OR 15(d) OF THE SECURITIES EXCHANGE ACT OF 1934 For the fiscal year ended December ...

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, 2021 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 ...

DETACK Company Overview Alexander Schuth, Chief Operating Officer H.C. Wainwright 23rd Annual Global Investment Conference September 13-15, 2021 Disclaimers Forward Looking Statements This presentation contains forward-looking statements within the meaning of the Private Securities Litigation Reform Act of 1995. All statements other than statements of historical facts contained in this presentation, including, without limitation, statements regarding future results of operations and financial position of De ...

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 June 30, 2021 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 (Sta ...