2016: Advances and Challenges in HD Therapeutic Development

By: Meredith A. Achey, BM

The year 2016 brought a number of notable developments in HD research and therapeutic development. While an approved, disease-modifying treatment remains elusive, planning and execution of first-in-human trials investigating some of the most promising advances in therapeutic development continued in earnest. Improvements to existing symptomatic therapies moved another step closer to patient use. Researchers moved the boundaries of our understanding of neurodegenerative disease forward to propose new therapeutic targets and new directions for future work. There were disappointments for the HD community as well, with the failure of several promising compounds to show improvement in human trials; however, overall, 2016 brought the HD community a few steps closer to treatments that might slow or reverse the course of HD.

Several clinical trials concluded in 2016, with mixed results. The announcement of the results of First-HD brought hope for the approval of an improved drug treatment for chorea for HD patients. The FDA requested additional information before approving deutetrabenazine, and Teva resubmitted their New Drug Application (NDA) in October 2016. The company hopes to see the drug approved in the first half of 2017.1 Teva’s PRIDE study investigating a higher dose of pridopidine also took an interesting turn in 2016, as a preliminary analysis showed that the drug failed to improve Total Motor Score in HD patients, but may have been associated with improved Total Functional Capacity at 52 weeks. Teva elected to extend the trial to 52-weeks after they discovered that the drug slowed disease progression in model systems.2,3 And finally, in the last weeks of 2016, Pfizer ended the open-label extension of the Amaryllis trial after the drug showed no clinical benefit (see Brief report).4

Ongoing and new clinical trials in 2016 included some of the first gene-targeted approaches to be investigated in HD, as well as novel approaches to slowing the disease’s progression. Ionis continues its Phase I study using intrathecal infusions of antisense oligonucleotide (ASO) IONIS-HTTRx (see HD Insights, Vol. 13), and thus far the compound has been well-tolerated.5 Azevan Pharmaceuticals announced the initiation of the Phase II STAIR trial, funded through the NeuroNEXT initiative, which will evaluate the safety and tolerability of SRX246 in HD patients with irritability.5

Trials of immune-related compounds approved for, or showing promise in other CNS disorders in HD patients continued throughout 2016. Teva continues to evaluate laquinimod, an immune modulator, through the Legato-HD trial.5 The HSG and Vaccinex also plan to conclude the SIGNAL trial of monoclonal antibody VX15/2503 in 2017, as an August 2016 analysis showed no safety issues that would necessitate stopping or modifying the trial.6

Gene-targeted therapies in preclinical development came to the forefront in 2016. While IONIS-HTTRx is an ASO currently in clinical trials, WAVE Life Sciences also has a preclinical development program with which they hope to begin human trials in 2017, using targeted ASOs to selectively silence the mutated gene (see HD Insights, Vol. 15). Voyager Therapeutics, uniQure, Spark Therapeutics, and academic researchers including Dr. Beverly Davidson at the Children’s Hospital of Philadelphia, are focusing their gene-silencing efforts on viral vector-based delivery systems, using adeno-associated viruses to infect cells with a gene-silencing piece of genetic material.7-10

Looking ahead, 2017 promises to be an exciting year for the HD community. While nothing is certain and many potential therapies are still only in the early stages of human trials, the continuing exploration of novel approaches to treat the symptoms and the progression of HD will bring many new insights, and may continue to provide hope for patients and families that one day, there will be more treatments that can make a difference.

1Teva Announces FDA Acceptance of Resubmitted New Drug Application for SD-809 for Treatment of Chorea Associated with Huntington Disease [press release]. Jerusalem: Business Wire, Oct. 20, 2016. Available at http://www.businesswire.com/news/home/20161020005246/en/

2Teva Announces Results from Exploratory 52-Week Phase 2 PRIDE-HD Study of Pridopidine in Huntington Disease [press release]. Jerusalem: Business Wire, Sept. 19, 2016. Available at http://www.businesswire.com/news/home/20160919005508/en/.

3Carroll J. Sorry folks, the PRIDE-HD trial did NOT show that Pridopidine slows the progression of Huntington’s disease. HDBuzz Sept. 30, 2016; http://en.hdbuzz.net/227. Accessed Jan. 10, 2017.

4Wild E. Pfizer Amaryllis trial ends in disappointment: no improvement in Huntington’s disease symptoms. HDBuzz Dec. 16, 2016; http://en.hdbuzz.net/229. Accessed Jan. 10, 2017.

52016 Research Report. Huntington’s Disease Society of America. 2016. Available at http://hdsa.org/wp-content/uploads/2016/12/HDSA_RsrchInvstRpt2016.pdf Accessed Jan. 9, 2017.

6Vaccinex, Inc. Announces Continuation of the SIGNAL Clinical Trial [press release]. Global Newswire, Sept. 9, 2016. Available at https://globenewswire.com/news-release/2016/09/09/870828/0/en/Vaccinex-Inc-Announces-Continuation-of-the-SIGNAL-Clinical-Trial.html.

7uniQure’s technology: Excellence in gene therapy through innovative modular technology, proprietary manufacturing and the experience to achieve success. 2016; http://www.uniqure.com/gene-therapy/uniqure-technology.php. Accessed Jan. 9, 2017.

8Voyager Therapeutics. Product Pipeline. 2016; http://www.voyagertherapeutics.com/programs.php. Accessed Jan. 10, 2017.

9Spark Therapeutics. Our Scientific Platform & Programs. 2016; http://sparktx.com/scientific-platform-programs/. Accessed Jan. 10, 2017.

10Davidson Laboratory – Dominant Neurodegenerative Disease.  http://davidsonlab.research.chop.edu/research_dominent.php. Accessed Jan. 22, 2016.