The Huntington’s Disease Research Pipeline

A research “pipeline” is the process of creating, testing, and ultimately approving a new drug for use in humans. HDSA funds researchers and doctors doing HD research at different stages along the pipeline, and collaborates with industry partners to bring information about clinical trials to the public. We also fund human-centric research through the HD Human Biology Project and support young scientists through the Donald King Fellowships and Berman-Topper Career Development Fellowships.  

Preclinical research  

Basic research into what goes wrong in the brain in Huntington’s disease continues to provide insights into how the disease might be treated. As targets are identified, existing drugs and supplements known to address that target are reviewed and drug development efforts are instituted. 

Promising drugs are tested in animal models such as drosophila (fruit flies) and mice engineered to get Huntington’s Disease.  If the results are positive, a drug will be rigorously tested in one or more of the mouse models of HD. If a drug is effective and side effects are tolerable, toxicology studies are done and the drug can proceed to clinical trials. 

Clinical Trials of Drugs 

Once a drug is ready for testing in human patients, it must proceed through three phases of clinical trials. Phase 1 is a small trial (20-50 people with HD) testing safety. Phase 2 is a medium sized trial (50-200 people with HD) testing safety and effects of the drug on the body. Phase 3 is a large trial (200-1000 people) testing whether the drug helps with symptoms. A drug must be shown to be safe, well-tolerated, and effective before the FDA will approve it for human use.  

Observational trials 

Observational trials do not involve testing a drug – they simply look at human behavior and biology to learn more about HD, through neurological exams, cognitive tests, and blood or biosample donations. By observing and testing people with the HD gene over time and at different disease stages, researchers can discover what is changing inside the brain and body before and after the onset of HD symptoms. This is particularly important for the design of future trials that will need to measure the effectiveness of drugs before symptoms even appear.  

HD family members – gene positive, at risk, gene negative, and caregivers — can volunteer to participate in an observational trial like Enroll-HD 

A Dynamic Process 

Although the research pipeline appears to proceed smoothly from pre-clinical research to clinical trials, in practice it is much more dynamic.  Translational researchers may need to go back to basic researchers to have questions answered.  A drug may show clear signs of efficacy in preclinical testing but have serious side effects or require overly large doses to work.  Depending on its potential, there may be further efforts at developing the drug.  A drug that is successfully treating similar symptoms in another neurological disorder may move directly into clinical trials for HD patients. It is important for the HD community to know that Huntington’s research is going on in parallel. Basic research, translational research, and clinical trials are all in progress. There are more than two dozen drugs and supplements actively moving through the pipeline with dozens of others nominated for consideration. When one critical question is answered, efforts turn to other questions.  When one drug fails, resources are quickly redirected to researching more promising ones. 

To find out about the drugs and supplements currently moving through the research pipeline refer to the chart below. 

 

Therapies In the Pipeline 2020

 

Basic
Research
Preclinical R & D Clinical Development
Target Validation Lead Optimization Safety and Manufacturing Phase I Phase II Phase III

Tetrabenazine (Xenazine)

Lundbeck: Tetrabenazine is used to treat the involuntary movements (chorea) of Huntington’s disease. Tetrabenazine is a Vesicular Monoamine Transporter 2 (VMAT2) inhibitor, and  acts by decreasing the levels of the neurotransmitter dopamine in the synapse (space between neurons). In 2008 it was the first HD drug to be approved by the U.S. Food and Drug Administration (FDA).

Austedo (Deutetrabenazine)

TEVA Pharmaceuticals: Deutetrabenazine uses the same mechanism of action as tetrabenazine to treat the involuntary movements (chorea) of Huntington’s disease. Deutetrabenazine is broken down by the body more slowly than TBZ, which may mean that the drug could be taken fewer times per day, at a lower dose, or with fewer side effects than tetrabenazine.

Ingrezza (Valbenazine)

Neurocrine Biosciences: The KINECT-HD trial is testing valbenazine as a treatment for HD chorea. This drug is already approved to treat people with a disorder called tardive dyskinesia (TD). TD causes facial and limb movements due to drugs prescribed for certain psychiatric conditions. This Phase 3 trial is recruiting all over the United States.  

RG6042 ASO (GENERATION-HD1 Trial)

Roche/Genentech: Anti-sense oligonucleotides (ASOs) are a type of huntingtin-lowering drug that bind to the huntingtin mRNA (message) and result in a decrease in the level of huntingtin protein. The GENERATION HD-1 trial is testing an ASO called RG6042 lowers both expanded and normal huntingtin, an allele-non-specific approach. After a successful safety trial, there is a large Phase 3 trial underway, with 801 participants at 90 sites around the world.  

WVE-120101/120102 ASOs

Wave Life Sciences: Wave's ASO drugs take an allele-specific approach, lowering only harmful huntingtin by finding tiny genetic signals called SNPs on the expanded gene. The PRECISION HD-1 and PRECISION HD-2 trials are testing two ASO drugs in ~60 people each. In December 2019 Wave announced that WVE-120102 was safe and lowered mutant huntingtin, and that both trials would be expanded to include a higher dose. These trials have finished recruiting in the United States.  

VX15 (SIGNAL Trial)

Vaccinex: VX15 is a drug that binds to and blocks a molecule that may cause inflammation in the brain of individuals with HD.  The SIGNAL trial is a Phase II study to assess the safety, tolerability and effectiveness of VX15 in people at risk for developing HD. It has finished recruiting.  

SRX246 (STAIR Trial)

Azevan Pharmaceuticals:  SRX246 is an investigational drug to treat symptoms of anxiety and aggression in early stage HD patients. It acts by blocking vasopressin receptor 1a which plays a role in regulation of emotions. The STAIR trial has finished recruiting.  

Pridopidine (Pride-HD)

Teva Pharmaceuticals: The PRIDE-HD study tested the efficacy of pridopidine for improving movement symptoms in HD. This primary goal was not successful, but trial participants showed mild improvements in measures of independence in daily life.

SOM3355

SOM Biotech (Spain): SOM3355 is a vesicular monoamine transport (VMAT) inhibitor that acts similarly to tetrabenazine by interfering with how dopamine messages are passed between neurons. This company is focused on treating rare diseases by repurposing drugs that have already been developed and researched.  

Deep Brain Stimulation (DBS)

Medtronic: Deep Brain Stimulation involves implanting electrodes into a part of the brain called the globus pallidus to stimulate the nerves that fail to function in HD. There is a trial taking place in Europe to test whether a device called the ACTIVA® PC neurostimulator may help with HD chorea. 

Triheptanoin

Ultragenyx Pharmaceuticals: Triheptanoin is a type of oil called a triglyceride that is being tested as a dietary supplement in a small study in France and the Netherlands. The primary goal is to test whether it can prevent atrophy of brain areas affected by HD.

Cellavita (ADORE-DH Trial)

Azidus (Brazil): This study in Brazil is testing long-term IV injections of stem cells for the treatment of HD. After a successful safety study in a small number of individuals, the same participants will be recruited to receive the drug for a longer period of time, with no placebo, and all involved knowing about the treatment (known as an open-label extension study).  

Resveratrol

France: Resveratrol is a chemical that is found in red wine and some fruits, that may act like an antioxidant. It can be purchased as a supplement, but there is not yet evidence that it could be helpful in HD. The French government is supporting a controlled study of resveratrol to see if it can slow brain atrophy in early HD. 

AMT-130

uniQure: AMT-130 is a huntingtin-lowering drug that uses a type of harmless virus called an AAV5 vector, which carries a micro-RNA designed to silence the huntingtin gene. The therapeutic goal is to inhibit the production of the mutant protein by delivering this virus to the brain. This is the first gene therapy trial for HD, and it began in 2019. 

SAGE-718

Sage Therapeutics: Sage-718 is an NMDA receptor antagonist that has completed an early safety trial in Huntington’s disease patients. The goal is to treat cognitive changes associated with HD. 

Tasigna (Nilotinib)

Georgetown University: Nilotinib, also known as Tasigna, is a chemotherapy drug used for the treatment of leukemia. There is some evidence to suggest that it could alter levels of dopamine, a brain signaling molecule that is disrupted in HD. This is a small trial to determine if nilotinib is safe and alters dopamine in HD patients. 

INT41

Vybion: INT41 is an intrabody, a drug designed to disrupt the toxic huntingtin protein from doing damage in cells. It is delivered using an AAV virus and has shown some promise by reducing huntingtin and improving behavior in HD mice.  

P110

Mitoconix: Mitoconix is developing drugs that maintain the health of mitochondria, the cell’s energy powerhouses, in order to protect brain cells in HD. P110 improved pathology and behavior in HD mice.    

Small molecule htt-lowering

PTC Therapeutics and Novartis: Several companies are working on oral huntingtin-lowering therapies – a pill taken by mouth that could reach the brain and change how the HD gene produces the huntingtin RNA message and lower harmful protein levels.  

Huntingtin-lowering AAV-shRNA

Sanofi and Voyager Therapeutics: A small hairpin RNA or short hairpin RNA (shRNA) can be used to interfere with the huntingtin message and stop the toxic protein from being made. They are delivered to cells using a harmless virus called an adeno-associated virus (AAV). 

Htt-lowering ZFN

Takeda and Sangamo: Zinc finger nucleases can target regions of DNA to modify them or stop RNA from being made. Takeda and Sangamo are collaborating on a selective mutant huntingtin-lowering ZFN that has been successful in human cells in a dish. 

Htt-lowering AON

Biomarin: Biomarin is developing an anti-sense oligonucleotide (ASO, or AON), a type of huntingtin-lowering drug that binds to the huntingtin mRNA (message) and results in a decrease in the level of huntingtin protein. It is aimed at CAG repeats in all genes, not only huntingtin.  

EHP-102

Emerald Health: EHP-102 is an oral drug derived from cannabigerol, which is found in the cannabis plant. In preclinical studies it has shown neuroprotective effects. Emerald Health is developing this investigational therapy for Huntington’s disease.  

Dextromethorphan/Quinidine

University of Texas Houston: Dextromethorphan/Quinidine is used to treat emotional outbursts that can happen in certain neurodegenerative disorders. This small study is testing the safety and efficacy of using this drug combination for irritability in Huntington’s disease patients.  
FDA Approval
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