Company: DNLI
Filing Date: 2025-02-27
Form Type: 10-K
Source: 0001714899-25-000066
Chunk: 117

Company: Denali Therapeutics Inc.
Filing Date: 2025-02-27
Form: 10-K
Item: Item 1
Chunk 117
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 cisLALA, the ATV:Abeta construct remains "immune silent" when bound to TfR, thus minimizing the risk of anemia from reticulocyte loss. We are advancing DNL921 (ATV:Abeta) and DNL628 (OTV:MAPT) targeting Abeta and tau, respectively, for Alzheimer’s disease, as well as DNL422 (OTV:SNCA) targeting alpha synuclein for Parkinson’s disease. 

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Figure 4: Superior biodistribution across all brain regions in non-human primates with ATV (left) and OTV (right) compared to non-TV-enabled standard antibody and ASO. 

In addition to our current focus on neurodegenerative and lysosomal storage diseases, we are exploring programs in oncology, inflammation, neuromuscular disease, and metabolic disease (Figure 5). We may develop these additional programs ourselves in the future or seek partnerships.

Figure 5: Denali’s TV technology provides opportunities for platform expansion.

We believe that we can further expand our portfolio by targeting other BBB receptors that may confer different properties from targeting TfR. For example, we are targeting CD98hc, an amino acid transporter highly expressed on the BBB (Figure 6). Our preclinical studies have established TVCD98hc as a modular brain delivery platform with favorable kinetic, biodistribution, and safety properties distinct from previously reported BBB platforms. We believe that the distinct properties of our two TV platforms, TVTfR and TVCD98hc may enable selection of the optimal platform for a given drug target thereby expanding our portfolio opportunities.

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Figure 6: TVTfR targets the transferrin receptor and TVCD98hc targets the CD98hc an amino acid transporter. Both receptors are highly expressed on the BBB and can be utilized for brain delivery of biotherapeutics.

Biomarker-Driven Development and Approval

As part of our strategy, we identify and validate biomarkers which are relevant for both animal models and human trials and are critical for selecting patients, predicting and measuring target engagement, supporting dose selection and enabling decisions on progression of product candidates to the next phase of development. When practicable, we are developing patient selection biomarkers for our programs to enable identification of patients with the relevant disease biology and stage of disease likely to benefit from targeted therapy in order to increase the likelihood of success of clinical trials. Ultimately, we expect to positively impact market acceptance of these targeted therapies, driven by high and meaningful response rates within the targeted population as