Company: DNLI
Filing Date: 2025-02-27
Form Type: 10-K
Source: 0001714899-25-000066
Chunk: 132

Company: Denali Therapeutics Inc.
Filing Date: 2025-02-27
Form: 10-K
Item: Item 1
Chunk 132
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) program

The accumulation of Abeta plaque in the brain is a defining feature of Alzheimer's disease. Recently approved Abeta-directed antibody therapeutics were shown in clinical studies to reduce Abeta plaque and have modest efficacy in slowing disease progression; however, these therapies have safety concerns including the potential for amyloid-related imaging abnormalities ("ARIA") in the brain, which is a major barrier to their broad adoption in treating Alzheimer's disease. Thus, there is a significant opportunity for improving the efficacy and safety of Abeta-directed antibodies, and we are using our ATV platform to develop the next generation of these therapies.

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Our ATV:Abeta program utilizes the ATV platform to enable increased brain exposure and target engagement of Abeta plaques while avoiding ARIA. In preclinical studies in mice, ATV:Abeta was shown to be superior in reducing amyloid plaque load (Figure 15A) and oligomeric Abeta load (Figure 15B) compared to a conventional Abeta antibody, while essentially eliminating ARIA (Figure 15C). These preclinical studies provide the first mechanistic understanding of how ARIA can be prevented by virtue of ATV-enabled brain delivery of Abeta antibodies through microvessels and largely bypassing arteries, which contain the majority of the vascular amyloid that is responsible for inducing ARIA. Furthermore, our unique Fc engineering allows for conditional effector function through a cisLALA mutation, which preserves the ability for ATV:Abeta to engage microglia for plaque phagocytosis while mitigating TfR-related hematology liabilities such as depletion of reticulocytes (Figure 15D).

Figure 15: Preclinical data showing superior amyloid plaque reduction (A), superior oligomeric plaque reduction (B), fewer to no ARIA events (C), and preservation of reticulocytes (D).

Discovery Programs

In addition to our development portfolio for neurodegenerative and lysosomal storage diseases, we have a robust discovery effort to further expand and capture the full potential of our TV platform to enhance delivery of biotherapeutics to all tissues in the body. We are pursuing opportunities of unmet need in multiple disease areas including oncology, inflammation, neuromuscular disease, and metabolic disease. For example, using ATV, we have engineered mono- and bispecific formats of HER2 antibodies. Human epidermal growth factor receptor 2 ("HER2") is a growth factor receptor that is over-expressed in multiple cancers, including breast, colorectal, and gastric cancer