FDA Puts Voyager’s Gene Therapy Candidate VY-HTT01 on Clinical Hold

Patricia Inácio, PhD avatar

by Patricia Inácio, PhD |

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Branaplam and Huntington's

The U.S. Food and Drug Administration (FDA) is putting on hold Voyager Therapeutics’ request to test VY-HTT01, its investigational gene therapy for Huntington’s disease, in a clinical trial.

The clinical hold will be kept in place until certain issues with VY-HTT01’s chemistry, manufacturing, and controls are resolved, Voyager said in a press release. The company said the FDA issued the hold as the agency’s reply to an investigational new drug (IND) application the company had submitted for the gene therapy candidate in September.

Voyager now is expecting to receive detailed feedback from the FDA in the coming 30 days. The gene therapy company said it plans to work closely with the FDA in the resolution of these issues, so that VY-HTT01’s clinical development may advance to testing.

VY-HTT01 was designed to deliver a small RNA molecule, called microRNA (miRNA), that can “silence” the faulty huntingtin (HTT) gene. The therapy would prevent that faulty gene from being used to create the abnormal huntingtin (HTT) protein that causes the neurodegenerative disorder.

To deliver the miRNA to target cells in the brain, this gene therapy uses a harmless adeno-associated virus (AAV) capsid, or protein shell (called AAV1). Once inside the cells, the miRNA binds to another RNA molecule, called messenger RNA (mRNA), that contains instructions to make the faulty HTT protein. By interacting with HTT mRNA, the therapy’s miRNA effectively prevents cells from using it to create the faulty HTT protein that causes the disease.

In prior preclinical studies in large non-human primates, researchers used an MRI-based visual guide to administer a single dose of VY-HTT01 into specific regions in the brain, including both the thalamus and the putamen, as well as the thalamus alone.

After doing so, they found VY-HTT01 reduced the levels of HTT mRNA in deep brain tissues, including the caudate. Specifically, it reduced the levels in the caudate by an average of 68%, while lowering the levels in the putamen by 67%, and those in the thalamus by 73%. It also reduced HTT mRNA levels at a more superficial brain area, the cortex, by 32%.

The putamen and the caudate regions help control movement. Meanwhile, the thalamus is a key structure that controls the routing of information in the brain, including playing a role in sensory and motor signals, as well as regulation of consciousness and alertness.

VY-HTT01 was well tolerated for up to five weeks upon administration, and no gene therapy-related changes or adverse side effects were reported in the study animals.

These preclinical results, along with additional studies, supported Voyager’s  submission of the IND application for VY-HTT01.