Voyager’s tau-reducing therapies show promise in preclinical studies

Company plans to submit applications on both to test therapy in humans

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by Steve Bryson, PhD |

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VY-TAU01, Voyager Therapeutics’s investigational therapy designed to prevent the formation of harmful tau tangles in the brains of people with Alzheimer’s disease, was well tolerated and showed promising pharmacological properties in preclinical studies.

Based on these findings, the company expects to submit an application to the U.S. Food and Drug Administration seeking to test the therapy in human patients by June, according to a press release.

Meanwhile, Voyager’s brain-penetrating gene silencing therapy candidate reduced human tau production in the brains of an Alzheimer’s mouse model. The company anticipates  submitting a similar application in 2026.

“The Voyager team is increasingly excited about the potential for treatments targeting pathological tau to play an important role in improving clinical outcomes for patients suffering with Alzheimer’s disease,” said Todd Carter, PhD, chief scientific officer of Voyager.

Data on both programs was presented as posters at the 2024 International Conference on Alzheimer’s and Parkinson’s Diseases and Related Neurological Disorders (AD/PD 2024), held this month in Lisbon, Portugal.

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Tau tangles contribute to brain cell death, cognitive decline

Tau is a protein that normally helps stabilize the internal molecular skeleton of nerve cells in the brain. In Alzheimer’s, tau twists into abnormal shapes, which link together into what is called tau tangles that contribute to brain cell death and cognitive decline. Preventing tau build-up in the brain could be a way to slow the progression of Alzheimer’s.

“Recent third-party data with tau-targeted investigational therapies have demonstrated reduced spread of pathological [disease-causing] tau, as measured by tau PET imaging, and favorable trends in cognition,” Carter noted.

VY-TAU01 is an antibody-based therapy designed to bind to abnormally shaped tau while sparing normal forms of tau. Compared with other tau-targeted therapies, VY-TAU01 binds to a different region of tau, thus effectively blocking the formation of tau tangles, according to the company website.

The therapy is intended to be administered via intravenous (into-the-vein) infusion into patients with mild dementia or mild cognitive impairment due to Alzheimer’s.

The first poster, titled “Pharmacokinetics and Tolerability of VY-TAU01, an Anti-tau Antibody for the Treatment of Alzheimer’s Disease, in P301s Mouse and Nonhuman Primate,” showed that in mice and nonhuman primates, VY-TAU01 was well tolerated, with no adverse events noted and no evidence of immune responses against the therapy that may limit its efficacy.

Concentrations of the therapy, in both the bloodstream and cerebrospinal fluid, the liquid that surrounds the brain and spinal cord, were given in increasing dose levels. The time it took for half of VY-TAU01 to be eliminated from the body, or half-life, was 13 days, which was consistent with expected human antibody therapeutics. Similar findings were seen in mice modified to produce disease-causing tau.

A poster, dubbed “Intravenous Administration of BBB-penetrant AAV Containing Primary Artificial MicroRNA Targeting Tau Reduces Tau Broadly and Robustly in hTau Mouse Brain,” also was presented at the conference.

Lowering tau using anti-sense oligonucleotides, short DNA/RNA-like molecules designed to reduce tau production, has shown promise in preclinical and clinical studies. However, this approach requires repeated dosing either into the spinal canal or directly into the brain.

Voyager has developed a tau-lowering gene therapy that can cross the blood-brain barrier (BBB), which normally prevents large molecules such as antibodies from entering the brain, after an intravenous (into-the-vein) infusion.

Using its TRACER screening platform, the company discovered harmless, modified adeno-associated viruses (AAVs) that can cross the BBB after an intravenous infusion. These AAVs carry lab-made microRNAs, or short stretches of RNA, that specifically bind to tau messenger RNA (mRNA) and enhance its degradation. mRNA is an intermediate molecule that serves as a template for protein production.

Preclinical data showed a single intravenous dose of a tau-silencing gene therapy candidate in mice producing human tau, resulting in a broad AAV distribution across multiple brain regions. Moreover, the therapy demonstrated a dose-dependent reduction in the levels of tau mRNA of up to 90% and was associated with reductions in human tau protein levels of up to 74% across the brain.

“We look forward to continuing to advance our two programs targeting tau, and observing anticipated data read-outs from others in this space that will play an important role in further validating this target,” Carter said.