Neurocrine provides some good news in Huntington’s

Ingrezza could have some advantages over approved therapies, but a more important Huntington’s readout nears.

After failing to expand Ingrezza into Tourette’s, Neurocrine Biosciences had some good news yesterday with a positive pivotal result in Huntington’s chorea. The VMAT2 inhibitor now looks likely to get the nod for this new use, where it could have a safety edge over similarly acting marketed drugs from Teva and Lundbeck.

Still, even if approved, Ingrezza would only represent a treatment for one of the symptoms of Huntington’s, rather than actually slowing the course of this disease. But initial results are approaching for a potentially disease-modifying project, Uniqure’s gene therapy AMT-130.

Chorea win

The Huntington’s pipeline has seen several setbacks this year, with first Roche and Ionis’s tominersen, and then Wave Life Sciences’ WVE-120101 and WVE-120102, flunking clinical trials. These were all antisense projects that aimed to reduce the production of abnormal huntingtin protein, the cause of Huntington’s.

VMAT2 inhibitors, meanwhile, deplete dopamine at presynaptic nerve terminals, thereby reducing the jerky movements that are seen in some neurological conditions. Ingrezza is already approved for tardive dyskinesia, while Teva’s Austedo and Lundbeck’s Xenazine are marketed for Huntington’s chorea.

Based on the limited data available so far, Ingrezza looks at least as good as Austedo and Xenazine in Huntington’s. Neurocrine said after hours yesterday that its phase 3 Kinect-HD trial had met its primary endpoint, reducing the Unified Huntington’s Disease Rating Scale-Total Maximum Chorea score by 3.2 points versus placebo.

This stacks up against a 2.5-point placebo-adjusted benefit seen with Austedo, and 3.5-point benefit logged by Xenazine, though care should be taken when making cross-trial comparisons.

Safety could be the main differentiator: both Austedo and Xenazine have black boxes warnings of suicidal thoughts and behaviour, but Neurocrine said there no such problems were observed in Kinect-HD.

Ingrezza also has a convenience edge, with a simple once-daily dosing schedule, versus more complex regimens for the other two VMAT2 inhibitors.

Sellside consensus compiled by Evaluate Pharma puts Ingrezza’s sales in Huntington’s at $89m in 2026; the small size of the opportunity explains the group's muted 2% stock rise this morning.

Disease modifying

The real prize in Huntington's would be a drug that stops disease progression, and here there might soon be some clues about whether Uniqure is on to something with AMT-130. The project consists of an AAV5 vector carrying a microRNA designed to silence the huntingtin gene and inhibit production of mutant huntingtin protein.

Initial 12-month data from a phase 1/2 trial are due by the end of this year; however, these will come from just four patients, two who received sham surgery and two treated with the low dose of AMT-130, 6x1012vg/kg.

While tominersen and the failed Wave antisense projects were delivered intrathecally, AMT-130 is injected directly into the striatum, the brain region affected in Huntington’s, raising hopes of a different outcome this time.

Leerink analysts hope to see a clean safety profile and no long-term increase in neurofilament light chain, a marker of neuronal damage. Another measure to watch will be striatal volume, measured using MRI; the analysts note that early Huntington’s patients lose around 5-6% of this brain region per year.

Uniqure is set to report full data from all 10 patients in the low-dose cohort in mid-2022; the group is also treating patients with a high dose, 6x1013vg/kg.

Still, this is not the most advanced novel Huntington’s project in development: that honour goes to Prilenia’s pridopidine, once known as Huntexil. That asset’s pivotal trial, Proof-HD, recently completed enrolment, and data are due in early 2023.

Selected novel approaches in Huntington's disease
Project Company Description Status/trial details
Phase 3
Pridopidine Prilenia Therapeutics Sigma-1 receptor agonist Proof-HD, topline results due Q1 2023
Phase 2
ANX005 Annexon Bioscience Complement factor C1q antibody NCT04514367, initial data due Q4 2021
SAGE-718 Sage Therapeutics NMDA receptor regulator NCT05107128 completes Dec 2024 (cognitive function in HD)
Branaplam Novartis Survival motor neuron 2 protein regulator Vibrant-HD completes Dec 2025
Pepinemab (VX15) Vaccinex Semaphorin 4D antibody Ph2 Signal study failed in Sep 2020; development continues
Phase 1/2
AMT-130 Uniqure Gene therapy silencing huntingtin gene Initial data from NCT04120493 due YE 2021
WVE-003* Wave Life Sciences Stereopure huntingtin SNP3 antisense oligonucleotide (next-generation chemistry) NCT05032196 completes Dec 2022
*Takeda has option to co-develop and co-commercialise. Source: Evaluate Pharma &

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