Poster: Mechanism of action of adrabetadex for treatment of Niemann-Pick disease type C

Citation: Burchard J, et al. Mechanism of action of adrabetadex for treatment of Niemann-Pick disease type C. Poster presented at: National Niemann-Pick Disease Foundation (NNPDF) Family and Medical Conference; July 2026.

Plain Language Summary: Results of animal studies examining how adrabetadex (formerly VTS-270, cyclodextrin) works inside the brain: where it goes, how long it stays active, and how effectively it clears the cholesterol buildup that drives neurological damage in infantile-onset Niemann-Pick disease type C (I-NPC).

What is this study about?

This research looked at the science behind how adrabetadex works by using animal models of I-NPC. NPC is a rare, progressive genetic disease caused by a faulty protein (NPC1 or NPC2) that normally helps move cholesterol out of lysosomes, the cell’s built-in digestive and recycling centers. When this process fails, cholesterol builds up inside the lysosomes, disrupting their function and that of related cellular compartments. At the same time, the rest of the cell is left without enough cholesterol to operate normally. Together, these problems cause cells in the brain, including neurons, to malfunction and eventually die. The infantile-onset form is the most severe and fast-progressing type of NPC, with neurological symptoms appearing before age 6 due to how severely the protein is affected and how quickly cholesterol accumulates. 

Adrabetadex is an investigational (not yet U.S. Food and Drug Administration (FDA) approved) treatment designed to directly address this problem of cholesterol accumulation in lysosomes. Understanding exactly how and where it works, and for how long, is critical to knowing whether it can be an effective foundational treatment for I-NPC.

How does adrabetadex work?

To understand adrabetadex's mechanism, it helps to know what normally happens to cholesterol in the brain. Inside healthy neurons, cholesterol is transported out of lysosomes for use around the cell, and when there is excess, converted into a molecule called 24(S)-hydroxycholesterol (24[S]-OHC). This is then exported from the brain into the bloodstream, accounting for roughly 85% of how the brain gets rid of excess cholesterol.

In NPC, this whole process breaks down. Cholesterol gets stuck in lysosomes because the NPC1/NPC2 transport system is faulty. Adrabetadex is thought to act as a "molecular shuttle"; it enters the lysosome, picks up the trapped cholesterol, and helps move it out, essentially bypassing the broken transport system. Once cholesterol is freed from the lysosome, it is then available for normal downstream processes, and any excess can be converted to 24[S]-OHC for export from the brain.

Adrabetadex is given directly into the spinal fluid by lumbar puncture (also known as an intrathecal injection), rather than being swallowed or infused into the bloodstream. This is the same fluid that bathes the brain, so adrabetadex can reach brain cells directly without having to cross the blood-brain barrier, which most treatments cannot do effectively.

What did the study do?

The researchers conducted a series of laboratory experiments in two well-established animal models of NPC, mice and cats, to answer three questions:

• Does adrabetadex reach all parts of the brain after being injected into the fluid surrounding the brain and spinal cord, including deep regions that are hardest to access?
• Does a single dose maintain active concentrations in the brain long enough to justify dosing every two weeks?
• Does adrabetadex reduce the trapped cholesterol inside brain cells (target engagement), and does it do so in a dose-dependent way, meaning more treatment leads to more cholesterol clearance?

Mice and cats with either a complete or partial loss of NPC proteins received a single injection of adrabetadex directly into the fluid that bathes the brain and were studied over two weeks. Brain samples were analyzed for adrabetadex concentrations, cholesterol levels and levels of 24(S)-OHC, the marker that indicates cholesterol is successfully being moved out of the brain.

What the study found:

The research produced four important findings about adrabetadex:

• Spreads throughout the entire brain. After a single central injection, adrabetadex was detected in both superficial (outer, cortical) brain regions and deep regions, including the cerebellum, which controls movement and coordination and is one of the areas most severely affected in NPC. Superficial regions showed about 2.3 times higher concentrations than deep regions, highlighting that adequate dosing is needed to ensure deep areas receive sufficient exposure.
• Sustains therapeutic levels for at least 2 weeks. In both mice and cats, adrabetadex levels in the brain and spinal fluid stayed within the range needed to keep the cholesterol-clearing process active for the full two-week period between doses. 
• Dose-dependently reduces trapped cholesterol. In NPC cats treated before they developed symptoms, brain sections showed that areas of cholesterol accumulation shrank as the adrabetadex dose increased in both the outer region and the cerebellum. 
• Increases the export of excess cholesterol from the brain. In NPC mice, levels of 24(S)-OHC were significantly lower than in healthy mice, indicating that cholesterol trafficking was impaired. Treatment with adrabetadex significantly raised these levels, showing that the treatment had restored the brain's ability to move cholesterol out of cells. Notably, because cholesterol continues to accumulate over time, this marker also signals that repeated dosing will be needed to sustain the effect.

Why does this matter?

These findings provide the mechanistic foundation, the "why it works", behind the clinical benefits of adrabetadex seen in patients. Understanding that the treatment reaches the whole brain, stays active for two weeks, and directly clears cholesterol in a dose-dependent way helps explain why it has been associated with slowed disease progression and improved survival in children with I-NPC.

The data also help explain the specific dosing approach: because cholesterol keeps accumulating in NPC even while adrabetadex is working, the treatment needs to be given regularly (every two weeks) to stay ahead of the ongoing buildup. This is similar to the logic behind other chronic diseases. Because NPC continues throughout life, treatment also needs to continue to keep cholesterol moving normally.

Finally, the finding that deep brain regions like the cerebellum require sufficient drug exposure to be adequately treated reinforces the importance of appropriate dosing, not underdosing, particularly for the most severely affected areas of the brain.

What this means for patients:

These animal studies provide important scientific support for how and why adrabetadex may work as a treatment for I-NPC. They show that when adrabetadex is injected into the fluid surrounding the brain, it spreads throughout the brain, remains active long enough to be effective, and clears trapped cholesterol that damages neurons.

For families, this research offers a clearer picture of what adrabetadex is doing inside the brain and why the dosing schedule is designed the way it is. It also supports the case for adrabetadex as a foundational therapy in I-NPC, one that addresses the root cause of neurological damage, rather than just managing downstream symptoms.

What this means for families:

For families, understanding how a treatment works can provide confidence that it is addressing the underlying cause of the disease, not simply treating its symptoms.

These studies show that adrabetadex reaches the parts of the brain most affected by NPC, remains active long enough to support dosing every two weeks, and helps restore the normal movement of cholesterol inside brain cells. Together, these findings help explain why adrabetadex has been associated with slower disease progression and improved survival in children with infantile-onset NPC in clinical studies.

Because NPC continues to cause cholesterol to build up throughout a child's life, ongoing treatment is needed to keep cholesterol moving normally. These findings support adrabetadex as a foundational therapy for I-NPC by addressing the underlying biological problem that drives neurological damage.