Denali Therapeutics to Highlight Progress Across Broad Biotherapeutics Portfolio for Neurodegeneration Enabled by Its Blood-Brain Barrier (BBB) TV…

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SOUTH SAN FRANCISCO, CA, USA I October 15, 2020 I Denali Therapeutics Inc. (NASDAQ: DNLI), a biopharmaceutical company developing a broad portfolio of product candidates engineered to cross the blood-brain barrier (BBB) for neurodegenerative diseases, will host a virtual R&D Day webinar today highlighting progress across the Companys broad and diverse biotherapeutics portfolio enabled by its BBB transport vehicle (TV) platform. The webinar will begin at 1:00 p.m. Eastern Time and can be accessed here.

Delivering biotherapeutics to the brain has historically been a significant challenge in the field, hindering efforts to develop medicines for neurodegenerative diseases, said Ryan Watts, Ph.D., Denalis chief executive officer. Addressing this challenge is a core scientific principle in our multi-pronged strategy to defeat degeneration. We have designed our BBB-crossing TV technology to access the brain for biotherapeutics. In addition to our small molecule therapeutic programs, we believe that our TV-enabled biotherapeutics portfolio has the potential to yield effective new medicines for patients.

We are pleased to share recent progress in our portfolio of TV-enabled biotherapeutic programs, said Carole Ho, M.D., Denalis chief medical officer. We are especially excited to highlight new preclinical data for our Enzyme Transport Vehicle: iduronate 2-sulfatase (ETV:IDS) program, which supports best-in-class potential to replace standard-of-care therapy and address current unmet patient need in Hunter syndrome (MPS II). We are on track to announce earlybiomarker data from an ongoingPhase 1/2 study of ETV:IDS (DNL310) in Hunter syndrome by year end; positive data would provide biomarker proof-of-concept for our TV technology for Hunter patients and unlock large platform potential in neurodegeneration and other therapeutic areas.

R&D Day Highlights Related to TV-Enabled Biotherapeutic Programs

Denalis TV technology is engineered to significantly increase brain access for multiple therapeutic modalities: enzyme/protein replacement therapy via ETV/PTV, antibody delivery via ATV, and oligonucleotide delivery via OTV, enhancing and unlocking brain targets for biotherapeutics. The Company will share new preclinical data from select TV-enabled biotherapeutic programs in its portfolio including:

Enzyme TV (ETV) and Protein TV (PTV) Platform

Antibody TV (ATV) Platform

Oligonucleotide TV (OTV) Platform

R&D Day Summary of ETV:IDS Flagship Program DNL310 Denalis flagship ETV program is ETV:IDS for Hunter syndrome (MPS II), a rare neurodegenerative lysosomal storage disorder caused by a mutation in the gene that encodes for the enzyme IDS. Existing enzyme replacement therapies (ERTs) do not effectively cross the BBB and do not address neurodegeneration in patients. Intravenous administration of ETV:IDS is designed to take advantage of a highly vascularized CNS, and the nearly 400 miles of capillaries in the human brain, to actively transport biotherapeutics through receptor mediated transcytosis into the brain. Denali has engineered aspects of its TV technology for accessing all brain regions and brain cell types to enable and enhance therapeutic benefit. Throughintravenous administration, Denalis investigational ETV:IDS (DNL310)aims to treat the behavioral and cognitive aspectsof Hunter syndrome while maintaining benefit for the entire body.

Previously, Denali published research showing for the first time that in patients with Hunter syndrome, abnormalities in GAGs, the substrate of IDS enzymatic activity, are correlated with biomarkers of secondary lysosomal dysfunction (gangliosides, BMP, GluCer), axonal injury (Nf-L), and inflammation.1 The Company will share published and new biomarker data from multiple studies of a mouse model of Hunter syndrome demonstrating that systemically administered ETV:IDS (1) achieved high concentration and broad distribution of IDS enzymes in the brain, (2) led to reduction in GAGs, (3) corrected the abnormal accumulation of lysosomal lipids (gangliosides, BMP, GluCer), and (4) slowed neuroaxonal injury, as evidenced by a reduction in Nf-L.

In addition, new preclinical data will be presented showing that systemic administration of ETV:IDS was associated with improvements in neurobehavioral deficits (spatial learning and memory deficits) and motor function (locomotor performance and agility) as well as correction of skeletal disease manifestations (abnormal increased trabecular and cortical bone mass in the femur).

Denali will also share additional details on the status and design of the ongoing Phase 1/2 trial of DNL310, which began enrolling pediatric patients with Hunter syndrome in August 2020. Denali expects to announce data from an interim analysis of safety and biomarker data on CSF GAG reduction by year end 2020. Based on preclinical data showing that GAG reduction in the CSF correlates with GAG reduction in the brain after systemic administration of ETV:IDS, Denali considers a reduction of CSF GAG levels by approximately 50 percent in patients to be proof-of-concept for its TV technology. Furthermore, an approximate 50 percent reduction in CSF GAG levels is anticipated to be associated with subsequent improvements in lysosomal function and neurodegeneration biomarkers; therefore, additional biomarkers of lysosomal function and neuroaxonal injury (Nf-L) will be measured in the ongoing Phase 1/2 trial.

The Company expects additional safety and biomarker data from the Phase 1/2 trial to be available in mid-2021. The Phase 1/2 trial is designed to inform dose selection to evaluate the effects of treatment with DNL310 on neurocognitive outcomes in a potential subsequent Phase 2/3 pivotal trial. Virtual R&D Day Webinar Agenda

The following topics and speakers will be featured at Denalis virtual R&D Day webinar (all times are Eastern Time):

1:00 1:30 p.m. Introduction and Blood-Brain Barrier Transport Vehicle (TV) Overview Ryan Watts, Ph.D., Chief Executive Officer

1:30 1:50 p.m. Hunter Syndrome: Overview Simon Jones, MRCPCH, MBChB, Consultant in Paediatric Inborn Errors of Metabolism, Willink Unit, Manchester Centre for Genomic Medicine, Saint Mary's Hospital; Medical Director, NIHR Manchester Childrens Clinical Research Facility; Honorary Senior Lecturer, University of Manchester

1:50 2:20 p.m. TV Flagship Program: ETV:IDS (DNL310) Carole Ho, M.D., Chief Medical Officer & Head of Development

2:20 2:40 p.m. Q&A Session 1

2:40 2:50 p.m. Break

2:50 3:20 p.m. TV Portfolio Programs Joe Lewcock, Ph.D., Chief Scientific Officer

3:20 3:30 p.m. Unlocking the TV Platform Potential Alex Schuth, M.D., Chief Operating Officer

3:30 4:00 p.m. Q&A Session 2

Virtual R&D Day Webinar Information

The live webinar will begin at 1:00 p.m. Eastern Time and conclude at approximately 4:00 p.m. Eastern Time. Registration is accessible on theinvestor pageof Denalis website. Following the webinar, a replay will be available for a limited time on Denalis website.

About Denalis TV Platform

The BBB is essential in maintaining the brains microenvironment and protecting it from harmful substances and pathogens circulating in the bloodstream. Historically, the BBB has posed significant challenges to drug development for CNS diseases by preventing most drugs from reaching the brain in therapeutically relevant concentrations.

Denalis TV platform is a proprietary technology designed to effectively deliver large therapeutic molecules such as antibodies, enzymes, proteins, and oligonucleotides across the BBB after intravenous administration. The TV technology is based on engineered Fc fragments that bind to specific natural transport receptors expressed at the BBB and are delivered to the brain through receptor mediated transcytosis. Denali research has shown that in animal models, antibodies and enzymes engineered with the TV technology have demonstrated more than 10- to 30-fold greater brain exposure than similar antibodies and enzymes without this technology. Improved exposure and broad distribution in the brain may increase therapeutic efficacy by enabling widespread achievement of therapeutically relevant concentrations of product candidates. The most advanced program using the Companys TV technology is ETV:IDS (DNL310) for Hunter syndrome (MPS II), currently in a Phase 1/2 study.

About Denali Therapeutics

Denali Therapeuticsis a biopharmaceutical company developing a broad portfolio of product candidates engineered to cross the blood-brain barrier (BBB) for neurodegenerative diseases. Denali pursues new treatments by rigorously assessing genetically validated targets, engineering delivery across the BBB and guiding development through biomarkers that demonstrate target and pathway engagement. Denali is based in South San Francisco. For additional information, please visitwww.denalitherapeutics.com.

SOURCE: Denali Therapeutics

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Denali Therapeutics to Highlight Progress Across Broad Biotherapeutics Portfolio for Neurodegeneration Enabled by Its Blood-Brain Barrier (BBB) TV...