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.
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 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. HDSA is currently working on updated descriptions of these trials; please reach out to Dr. Leora Fox, Manager of Research and Mission Programs, firstname.lastname@example.org, with questions.
Therapies In the Pipeline 2021
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) for HD.
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. These differences may mean that the drug could be taken fewer times per day, at a lower dose, or with fewer side effects than tetrabenazine.
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.
Prilenia Therapeutics: In a previous study, PRIDE-HD, pridopidine did not meet key goals for treating HD movement symptoms, but trial participants showed mild improvements in functional capacity. New studies suggest that pridopidine activates a protein called the sigma-1 receptor, which could have positive effects on brain health. PROOF-HD is a larger and longer study that will test pridopidine's ability to help HD patients maintain their day-to-day function. It is recruiting now all over the United States.
RG6042 ASO (GENERATION-HD1 Trial)
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 800-participant GENERATION HD-1 trial was testing an ASO called RG6042 that lowers both expanded and normal huntingtin. Sadly, dosing in this trial was halted in March 2021 due to lack of benefit.
Wave Life Sciences:
Wave's ASO drugs aim to lower only harmful huntingtin by finding tiny genetic signals called SNPs on the expanded gene. The PRECISION HD-1 and PRECISION HD-2 trials tested two ASO drugs in ~60 people each. In March 2021 Wave presented data from these trials, and unfortunately neither drug effectively lowered huntingtin. For this reason, Wave has discontinued research on these two ASOs.
VX15 (SIGNAL Trial)
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 was a Phase II study to assess the safety, tolerability and effectiveness of VX15 in people at risk for developing HD. In October 2020 it was announced that the trial did not meet its key goals.
SRX246 (STAIR Trial)
SRX246 is an investigational drug to treat symptoms of anxiety and aggression in early stages of HD. It acts by blocking vasopressin receptor 1a which plays a role in regulation of emotions. The STAIR trial has completed, but results and next steps are pending.
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: DBS for HD 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.
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).
France: Resveratrol is a chemical that is found in red wine and some fruits and 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.
uniQure: AMT-130 is a micro-RNA drug designed to silence the huntingtin gene and inhibit the production of the mutant huntingtin protein. It is packaged inside a type of harmless virus called an AAV and delivered in a one-time dose via an MRI-guided brain surgery. There is a small safety trial ongoing in the USA.
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. Sage is planning a larger Phase 2 trial to begin in late 2021.
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.
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.
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.
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. Voyager’s drug will be delivered to cells via brain surgery using a harmless virus called an adeno-associated virus (AAV). The company recently received approval to move forward with planning a clinical trial in adults with HD.
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.
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.
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.
Wave Life Sciences:
Wave has developed a third ASO that aims to lower harmful huntingtin. This drug improves upon the chemistry of WVE120101 and WVE120102, and will enter clinical trials in Canada and Europe in late 2021.
Novartis: Branaplam is an oral drug that was originally developed by Novartis to treat a childhood disorder called spinal muscular atrophy. It was also found to lower huntingtin protein by interfering with the genetic "recipe” in a process known as RNA splicing. A Phase 2 trial in adults is anticipated to begin by the end of 2021.
PTC Therapeutics: PTC Therapeutics has also developed a splice modulator called PTC518 which reduces the levels of huntingtin in different animal and lab models of Huntington’s disease. A Phase I clinical trial in healthy people is currently underway to investigate the safety of PTC518.
University of Texas Houston: Dextromethorphan and Quinidine are 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 individuals with Huntington’s disease.
ANX-005 is an antibody given by IV that aims to help preserve connections between neurons (synapses) in the HD brain. It acts on a part of the immune system known as the classical complements pathway, which becomes overactive in HD. A Phase 2 trial has fully recruited.