Denali Therapeutics is focused on addressing neurodegenerative and lysosomal storage diseases through innovative therapeutic discovery and development. The company leverages recent scientific advancements in genetics and cell biology to identify pathways that contribute to neurodegeneration, particularly in diseases such as Alzheimer’s, Parkinson’s, and ALS. Denali's research and development strategy emphasizes selecting genetically linked targets, engineering drug candidates to effectively cross the blood-brain barrier (BBB), and utilizing biomarkers to guide clinical development. Their portfolio includes a range of drug candidates at various stages, aimed at directly addressing the underlying causes and risk factors associated with these diseases.

A key aspect of Denali's approach is their proprietary platform technology designed to enhance the delivery of large molecules across the BBB. This technology utilizes receptor-mediated transcytosis (RMT) to facilitate the transport of therapeutic antibodies and recombinant enzymes into the brain, significantly improving their efficacy. Additionally, Denali is engineering small molecule therapeutics to overcome the challenges posed by efflux pumps that typically prevent these drugs from entering the brain. By focusing on both large and small molecules, Denali aims to develop effective treatments that can meaningfully improve the lives of patients suffering from neurodegenerative diseases.

United States

Denali Therapeutics is 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.

Central Nervous System (CNS)

Genetic Diseases

Inflammatory disorders

Nervous System Diseases

Denali Therapeutics

Hunter syndrome MPS II

The Iduronate 2-sulfatase enzyme (IDS) is responsible for breaking down heparan and dermatan sulfates in the lysosome and thereby maintining celluar homeostasis.&nbsp; Genetic defects in IDS lead to a deficiency in IDS and cause Hunter Syndrome (or MPS II), which is characterized by abnormalities in the skeleton, heart, respiratory system, and the brain. DNL310 (or ETV:IDS) is a recombinant IDS enzyme engineered to cross the blood-brain barrier and to replace the IDS enzyme and treat neuropathic and systemic forms of the disease.

DNL310 (tividenofusp alfa)

Cutaneous lupus erythematosus

Lupus nephritis

Ulcerative colitis

RIPK1 is a critical signaling protein in the tumor necrosis factor receptor pathway and is a regulator of inflammation and cell death. Increased RIPK1 activity drives inflammation and cell necroptosis thoroughout the body and RIPK1 inhibition has been shown to have beneficial effects in preclinical models of many systemic inflammatory diseases. DNL758 is a potent and selective inhibitor of RIPK1 developed for the treatment of autoimmune diseases such as rheumatoid arthritis and peripheral inflammatory disease.

DNL758 (CNS-penetrant RIPK1 inhibitor)

Parkinson's disease

LRRK2 is the most common genetic risk factor for Parkinson's disease, and is involved in maintaining a healthy cellular environment by regulating lysosomal function.&nbsp; Increased levels of LRRK2 lead to lysosomal dysfunction, which contributes to neurodegeneration and the formation of Lewy bodies, a central pathology of Parkinson's disease. DNL151 is a potent, selective and brain-penetrant small molecule inhibitor of LRRK2 and is Denali's clinical candidate for Parkinson's disease.

BIIB122/DNL151 (LRRK2 Inhibitor)

Amyotrophic lateral sclerosis

Modulation of eIF2B activity with DNL343 is a novel and targeted investigational approach with first-in-class potential for the treatment of ALS. eIF2B is an intracellular protein complex that regulates protein synthesis and is required for neuronal health and function. When neurons experience stress, activation of the ISR pathway leads to suppression of eIF2B activity, resulting in impaired protein synthesis and formation of stress granules. Stress granules are thought to be a precursor of TDP-43 aggregation, which is a hallmark pathology in ALS. DNL343 is designed to activate eIF2B and thereby restore protein synthesis, disperse TDP-43 aggregates, and improve neuronal survival. DNL343 is an investigational therapeutic and has not been approved by any regulatory authority for any commercial use.

DNL343 (eIF2B Activator)

Multiple sclerosis

SAR443820 is a CNS-penetrant RIPK1 inhibitor &nbsp;discovered and developed by Denali scientists. Sanofi leads Phase 1 and &nbsp;Phase 2 development of SAR443820 for ALS and MS and leads co-development of SAR443820 with Denali in Phase 3 clinical trials for ALS, MS and Alzheimer’s disease. Sanofi completed a Phase 1 trial of SAR443820 in healthy volunteers in which robust target engagement was &nbsp;demonstrated at doses that were generally well tolerated. Based on these &nbsp;results, Sanofi decided to initiate the HIMALAYA Phase 2 study in ALS &nbsp;and plans to initiate a Phase 2 study in MS.

SAR443820/DNL788 (CNS-Penetrant RIPK1 Inhibitor)

BIIB122 (DNL151)

Frontotemporal dementia with GRN mutations

TAK-594/DNL593 (PTV:PGRN)

Sanfilippo Syndrome

DNL126 (ETV:SGSH) is an investigational, intravenously administered, ETV-enabled N-sulfoglucosamine sulfohydrolase (SGSH) replacement therapy designed to cross the BBB and address the behavioral, cognitive, and physical manifestations of MPS IIIA (Sanfilippo syndrome Type A).

Denali Therapeutics

Company Details