AAN 2023: Phase 1/2 trial to test AskBio’s gene therapy in patients

Clinical trial will examine how AB-1001 affects brain cholesterol

Marisa Wexler, MS avatar

by Marisa Wexler, MS |

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A brain illustration for the AAN conference.

Asklepios Biopharmaceutical (AskBio) has launched a first-in-human clinical trial testing AB-1001 — an experimental gene therapy designed to modulate cholesterol metabolism in the brain — in people with Huntington’s disease.

The trial is currently recruiting participants at a site in Paris. It is open to adults, ages 18 to 65, with early-stage Huntington’s and carrying at least 40 CAG repeats in the HTT gene — the disease’s underlying cause.

The study’s design was discussed in a poster at the American Academy of Neurology (AAN) 2023 Annual Meeting, held April 22–27 in Boston and virtually. The poster was titled “Investigating the Effects of Brain Cholesterol Metabolism Using CYP46A1 Gene Therapy in Subjects with Huntington’s Disease.”

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What is cholesterol’s role in the brain?

Cholesterol is a fatty molecule that plays a diverse array of important roles in the body. Within the brain, cholesterol is important for maintaining the health of nerve fibers and the connections between nerves.

Although cholesterol is critical for brain function, it is unable to pass from the bloodstream into the brain or vice versa. Instead, brain cholesterol is manufactured within the brain by a type of cell called glia.

If levels of cholesterol in the brain get too high, then the neuron-specific CYP46A1 enzyme converts cholesterol into a different molecule that can be shipped out of the brain.

Accumulated data have suggested that cholesterol processing in the brain is disturbed in people with Huntington’s, and that patients have reduced levels of CYP46A1, leading to an abnormal buildup of cholesterol inside the brain.

What is AB-1001?

AB-1001 (previously known as BV-101 or BV-CYP01) is an investigational gene therapy originally developed by BrainVectis, which was acquired by AskBio in 2020. It uses a modified and harmless adeno-associated virus to deliver to brain cells a copy of the gene encoding CYP46A1.

By increasing the levels of the enzyme, the therapy is expected to normalize cholesterol metabolism in the brain, which may help slow neurodegeneration.

In animal models of Huntington’s, treatment with AB-1001 was shown to restore cholesterol metabolism and improve motor function, as well as reduce levels of nerve damage markers and Huntington’s hallmark toxic protein aggregates.

“Preclinical results show the potential for CYP46A1 gene therapy with AB-1001 to demonstrate therapeutic benefits in subjects with [Huntington’s] and rationalize progression to the first in-human Phase 1/2 clinical trial,” the researchers wrote in the poster.

The main goal of the new Phase 1/2 trial (NCT05541627) is to assess the safety of AB-1001 in up to 18 people with early Huntington’s and specifically to identify the highest dose that can be given without unacceptable safety issues.

Participants enrolling in the trial will initially enter into a screening phase lasting eight to 12 weeks depending on patient availability. Then, they will receive a single treatment with AB-1001, administered directly into the caudate and putamen, two brain regions that are highly affected in Huntington’s.

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How long will trial participants be monitored?

After treatment, participants will be followed closely for 52 weeks (one year), with another four years of follow-up.

In the first, dose-finding part of the trial, the first three to six participants will receive AB-1001 at a dosage of 400 million vector genomes per microliter (vg/mcL). Vector genome is a unit used to measure the number of active gene therapy particles.

If safety data from this initial group are positive, the second group of three to six participants will get a higher dose of 1.1 billion vg/mcL.

These data will be used to select the best dosage to be tested in six additional patients within the trial’s dose-expansion portion.

In addition to safety, researchers will also examine the gene therapy’s preliminary efficacy through changes in disease-relevant brain structures based on MRI scans and scores of the composite Unified Huntington’s Disease Rating Scale. This validated scale accounts for cognition, motor skills, and the ability to function independently in daily life.

The study will also assess changes in Huntington’s biomarkers, nerve damage markers, cholesterol metabolism, and quality of life.