FDA Lifts Hold on VY-HTT01 IND for Huntington Disease

Andre Turenne

The FDA has lifted a clinical hold placed on an investigational new drug (IND) for VY-HTT01, which is an AAV1-based gene therapy for patients with Huntington disease. The hold was placed on the application in October 2020, due to chemistry, manufacturing, and controls concerns from the FDA.

Following the approval of the IND application, Voyager Therapeutics, the company developing VY-HTT01, plans to initiate a phase 1/2 study for the agent later this year. The IND application was initially submitted in September 2020 and the company hopes to begin the study, which will be named VYTAL, later this year.

“The decision by the FDA regarding our IND application for VY-HTT01 for Huntington disease represents an important milestone for Voyager and is the result of years of commitment to developing an impactful new therapy to address this devastating disease,” Andre Turenne, president and chief executive officer of Voyager, said in a statement.

Huntington disease is the result of hereditary toxic gain of function mutations in the huntingtin (HTT) gene, which result in abnormal protein build up and eventual neuronal cell death. VY-HTT01 is an AAV1 capsid therapy that knocks down the activity of mutant HTT by interfering with mRNA.

In nonhuman primates, AAV1 was found to be superior to AAV2 for transducing corticostriatal tissue, leading to the use of the capsids for VY-HTT01. In these studies, AAV1-mediated gene therapy demonstrated durable reduction in HTT mRNA. Moreover, mouse models found that AAV1-mediated expression of small interfering RNA led to reductions HTT mRNA and HTT protein. These reductions were also associated with phenotypic improvements.

“Our investigational gene therapy has been designed to achieve broad knockdown of HTT mRNA throughout the brain via a one-time MRI-guided neurosurgical delivery,” Omar Khwaja, MD, PhD, chief medical officer and head of research and development of Voyager, said in a statement. “We are thrilled to be collaborating with leading experts in Huntington disease and neurosurgical delivery of gene therapies, as we begin the planned clinical evaluation of our promising candidate.”

The phase 1/2 study exploring VY-HTT01 in patients with Huntington disease will examine the therapy at varying doses. The study will assess patients with early manifestations of the disease. The primary end point of the dose escalation portion of the study will be safety and tolerability, with a secondary goal of uncovering a maximum tolerated dose. Other secondary end points will focus on biomarkers and clinical outcomes.

VY-HTT01 is wholly owned by Voyager Therapeutics, which is also developing therapies in collaboration with Neurocrine Biosciences. The AAV2-based gene therapy that was furthest along as part of this partnership transduced the human AADC gene and was known as NBIb-1817 or VY-AADC. This product was under exploration in Parkinson disease; however, in February 2021, the companies announced the termination of this program.

The decision to terminate the development program in Parkinson disease was preceded by a clinical hold placed on the RESTORE-1 phase 2 clinical trial. The clinical hold followed assessments from a Data Safety & Monitoring Board related to imaging and clinical assessments. The IND holder for the RESTORE-1 trial was Neurocrine, which was questioned by the FDA about the imaging findings and the potential role of NBIb-1817.

In addition to VY-HTT01, Voyager is also developing other wholly owned products, including VY-SOD102 for monogenic amyotrophic lateral sclerosis, vectorized Tau for tauopathies, and an additional undisclosed product. Outside of VY-AADC, Voyager and Neurocrine are also partnered on VY-FXN01 for Friedreich ataxia and an undisclosed product as part of a discovery program.