The Research Pipeline - taking drugs from the lab to the clinic

Here's an overview of some of the more promising potential treatments moving through the research pipeline.

Marsha Miller, Ph.D. and Steve Ireland

Basic research into what goes wrong in the brain in Huntington’s continues to provide insights into how the disease might be treated. As targets are identified, existing drugs known to address that target are reviewed and drug development efforts are instituted. Promising drugs are tested in animal models such as drosophilia (fruitflies) and mice engineered to get Huntington’s Disease. If the drug is effective and side effects are minimal, toxicology studies are done and the drug can proceed to clinical trials. If the drug shows efficacy but the side effects are serious, the drug may be redesigned. Once a drug is ready for clinical trials, it must proceed though three stages before being approved as a treatment.

The chart below provides an overview of significant drug targets, drugs, and compounds in the research pipeline. As potential treatments move through the pipeline, some will perform well and receive high priority for future research funding. Others will be found to be ineffective and drop out. A drug that has positive effects in a cell model of the disease may not help a mouse model, for example. However, because research is proceeding in parallel, progress continues unabated. Resources can quickly be redirected away from unsuccessful efforts toward research that continues to hold promise. Each day brings us closer to treatments.

Some of the drugs or supplements below will be tested to see if they safely and effectively treat symptoms while others will be tested to see if they delay expected onset or slow progression of the disease. However, some symptomatic treatments may later be shown to treat the disease itself.

There are other compounds which have shown promise as potential treatments. This chart covers the ones where there appear to be efforts to take them to the next stage of the pipeline. There may be additional compounds of which we are unaware since the chart is based on published information. There may be developments in pharmaceutical or biotech companiess and in academic laboratories that haven't been publicized as yet.

HD Drug Pipeline


The students at Stanford University HOPES developed several pages that provide additional insight into the drugs and supplements in these trials. Click on the links titled something like "xxx for HD by HOPES" for more information.

Energy boosters

Energy metabolism is known to be impaired in Huntington's Disease. Both creatine and CoQ10 boost energy in the cell. In addition both act as antioxidants. Phase III clinical trials have been funded for both. The creatine trial will begin recruiting later in 2008; the CoQ10 trial has already started.
Creatine for HD by HOPES | CoQ10 for HD by HOPES.

Ethyl EPA is a purified version of eicosapentaenoic acid, an Omega 3 fatty acid found in fish oil. A Phase III clinical trial managed by the Huntington Study Group and sponsored by Amarin Pharmaceuticals was suggestive of benefit after six months of use but not conclusive. There may be an additional trial to resolve the issue.
Miraxion LAX-101 for HD by HOPES.

Dopamine blockers or stabilizers

Blocking or stabilizing the neurotransmitter dopamine has been shown to reduce chorea. In addition, there is evidence to suggest that normal amounts of dopamine may be toxic in the brain in Huntington's Disease.

Tetrabenazine is a dopamine depleter available in Europe and Canada; it has been approved by the FDA to treat chorea.
Tetrabenazine for HD by HOPES

ACR-16 is a dopamine stabilizer in Phase III clinical trials in Europe; Phase IIb trials will likely start in the U.S. before the end of 2008.


Tauroursodeoxycholic acid or TUDCA is an endogenous bile acid which inhibits mitochondrial apoptosis. It is currently in Phase I trials sponsored by the HSG; results are expected soon.

Methazolamide is an inhibitor of cytochrome c, an enzyme involved in apoptosis.

Neurologix is investigating the potential of gene therapy using the a mutated form of the XIAP gene. XIAP stands for x-linked inhibitor of apoptosis protein.

Glutamate blockers or stabilizers

The excitotoxicity theory holds that neurons are abnormally sensitive to glutamate; overstimulation by this important neurotransmitter can lead to cell death.
Glutamate Blockers for HD by HOPES

Memantine is a glutamate stabilizer that is FDA approved to treat Alzheimer's dementia. Because memantine might also address excitoxicity in HD and because clinical reports from physicians try memantine for HD patients have suggested that it may improve cognitive symptoms, memantine is now in Phase II clinical trials.
Memantine for HD by HOPES

Unfortunately Dimebon trials didn't show any significant positive results and Medivation is no longer going to pursue it.  It's been removed from the Huntington's Disease Pipeline.
Dimebon for HD by HOPES

BDNF inducers

Brain derived neurotrophic factor (BDNF) protects brain cells and promotes neurogenesis, the growth of new ones. Levels of BDNF are known to be reduced in the brains of HD patients. SSRI (selective serotonic reuptake inhibitor) antidepressants are known to elevate BDNF and one such antidepressant, Celexa, is in Phase II clinical trials. In addition, Cortex pharmaceuticals has an ampakine in preclinical testing and Raptor pharmaceuticals is planning Phase II trials of cysteamine; both induce BDNF.
BDNF Inducers for HD by HOPES | Cysteamine for HD by HOPES

CEP-1347, an anti-apoptosis drug was found to improve the R6/2 mice by increasing BDNF levels.

Other neurotrophic factors and mimetics

In addition to BDNF, researchers are also looking at other neurotrophic factors and synthetic compounds that mimic their effects with the hope that they will be neuroprotective in HD patients. One candidate is fibroblast growth factor 2 which promoted neurogenesis and extended survival time in the R6/2 mice. It is still in preclinical testing.

Ceregene has developed a viral vector for delivering a gene for the neurotrophic factor neurturin into the brain. This potential treatment is in Phase II clinical trials for Parkinson's Disease and preclinical testing for Huntington's Disease. Trophos has a lead candidate which is neuroprotective in a striatal cell model of HD.

HDAC inhibitors

The dysregulation of gene transcription has been shown to be a significant problem in Huntington's Disease. The HD protein interferes with the normal expression of genes. Histone deacetylase inhibitors may be able to reverse or partially reverse this dysfunction. Envivo has a candidate drug which performed well in preformed well in preclinical testing and a Phase I clinical trial is planned for later in 2008. Repligen has licensed an HDAC inhibitor from Scripps Research Institute which reduced pathology and at least partially restored gene transcription.
HDAC Inhibitors for HD by HOPES


Huntington's disease is a disease of aging in that cells in the areas of the brain that are affected by HD are for some time able to cope with the challenges presented by the mutant protein. As we age, our cellular defense mechanisms become less efficient. There is a group of genes called sirtuins which appear to regulate aging. In the spring of 2008 Sirtris Pharmaceuticals announced that there is new data showing that in a preclinical model of Huntington's disease, mice live longer and have less disease pathology in the brain with increased SIRT1 expression. Sirtris has several compounds with induce SIRT1 expression.

One problem that increases with aging which is thought to be particularly damaging in HD is oxidative stress. During energy metabolism, free radicals of oxygen are produced which can damage proteins, lipids, and DNA if there aren't enough antioxidants available with which to bond. As mentioned above, creatine and CoQ10 are antioxidants. Intellect Neurosciences is doing preclinical studies with their synthetic version of Indole-3-propionic acid.
Antioxidants for HD by HOPES


The normal huntingtin's protein is cleared away from the cell through the ubuiqitin proteosome system. This housekeeping process is not effective with the HD version of the protein. There is an alternate way to clear away the HD protein called autophagy. Link Medicine has a candidate drug still in preclinical testing.

Metal chelators

Both excess copper and excess iron have been shown to contribute to HD pathology. Pipex Pharmaceuticals, in collaboration with researchers at the VA Medical Center at Ann Arbor, is doing preclinical testing of their copper chelator. Varinel, an Israel Pharmaceutical company is testing their copper chelator in HD mouse models with funding from CHDI.
Metal Chelators for HD by HOPES

A2A receptor antagonists

Research shows that there is an aberrant amplification of the adenosine 2A receptor signaling in striatal cells in people with Huntington's Disease. Kyowa Pharmaceuticals has an A2A receptor antagonist called KW-6002 (istradefyllin) that is in clinical testing for Parkinson's disease.

Caspase 6 inhibitor

When an HD mouse model was engineered to be resistant to caspase 6, the HD protein was not cleaved, the protein did not accumulate in the nucleus of the cell, and the mice did not develop Huntington's Disease. CHDI is funding the development of a safe and effective caspase 6 inhibitor.
Caspase 6 for HD by HOPES

Genetic Approaches

If the HD gene could be stopped from expressing itself, the result could be a virtual cure.  Anylam and Lundbeck are working on ways to interference with messenger RNA so that instructions to make the HD protein are not sent out. An issue is that it may be necessary to develop allele specific ways to do this so that only the HD protein is shut down and the normal huntingtin's protein continues to be expressed.
RNAi for HD by HOPES

The antisense approach being taken by Isis is somewhat different in that it is possible for a drug to do this on a periodic basis; the goal is to find an optimal time in which the cell can recover from the HD protein without being harmed by the absence of the normal protein.  Recently, a way to allele specific antisense silencing of the gene has been discovered.

Restorative Technologies

Research with the HD mice suggests that stopping the HD gene from expressing itself would result in improvement even well into the progression of the disease. However, restorative treatments will likely be necessary for full recovery of later stage patients. ReNeuron has a line of stem cells which has shown efficacy in a cell model of HD. Preclinical work is being done.


  • Dimebon was removed after a Phase III clinical trial failed.
  • Cogane (a potential BDNF inducer) was removed from the pipeline after disappointing preclinical results.
  • Minocycline was removed from the pipeline following disappointing results in the phase II trials.
  • ACR-16 moved a little further through the pipeline into phase III trials
  • Links to the Stanford University HOPE site, for more information, were added.

Nutritional supplements Creatine (HSG) - funded CoQ10 (HSG) - recruiting Ethyl EPA (Amarin's Miraxion) - one study completed, more data needed Dopamine blockers or stabilizers Tetrabenazine (Prestwick) - awaiting an FDA decision ACR-16 (Neurosearch) - planned for 2008 Anti-apoptosis TUDCA (HSG) - in progress Methazolamide (HSG) - in progress Gene Therapy (Neurologix) - in progress Glutamate blockers or stabilizers Memantine - in progress Dimebon (Medivation) - in progress BDNF inducers Citalopram (Celexa) - in progress Ampakines (Cortex) - in progress Cysteamine (Raptor) - Raptor pharmaceuticals is planning a Phase II trial of delayed release cysteamine later in 2008 CEP-1347 (Cephalon) Other neurotrophic factors and mimetics FGF-2 (Neurobiological Technologies) - studies with the Buck Institute Neurturin (Ceregene) - AAV delivery TRO47498 (Trophos) HDAC inhibitors EVP-0334 (Envivo) - 3rd qtr 2008 HDACi 4b (Scripps Institute) - licensed to Repligen Antioxidants/anti-aging CoQ10 analogs (Edison) Oxigon (Intellect Neurosciences) Sirtuin inducers (Sirtris) Autophagy Verapamil Clonidine Metal chelators Coprexa (copper) (Pipex) - in collaboration with the VA Medical Center at Ann Arbor M30 (iron) (Varinel) A2A receptor antagonists KW-6002 (Kyowa) Caspase 6 inhibitor CHDI funded Genetic Approaches RNAi (Sirna) RNAi (Alnylam) Antisense (Isis) Restorative Technologies ReN005 (ReNeuron) - stem cell line