The bad news is that a proven treatment to delay the progression of HD is still probably several years out. The main holdup is likely to be the time it takes to prove the safety and efficacy of new HD treatments in clinical trials and then obtain Food and Drug Administration (FDA) approval for them.
The good news is that finally there is significant research taking place in all the disciplines that lead from basic research to an approved treatment. This work is being done by talented individuals and motivated companies who feel time pressure to obtain results. And we do have a possible wildcard…a drug currently undergoing the last stages of clinical trials for Parkinson’s Disease. It is also showing positive results in early stage drug screening tests for HD. More on that later in this report.
The 2007 HD Therapeutics Conference was a forum for drug discovery and development, jointly sponsored by the Cure HD Initiative (CHDI) and the High Q Foundation (High Q). These are two HD organizations that between themselves specialize in translational research and drug development. More information on their activities can be found elsewhere on the HD Lighthouse web site (www.hdlighthouse.org) and on each of their sites, www.chdi-inc.org and www.highqfoundation.org.
The conference was attended by approximately 140 HD researchers worldwide, especially those in translational research, compound screening, and drug development. It also included a number of our outstanding HD basic researchers and clinical trial experts.
This was the second annual therapeutics conference and the plan is to hold these yearly. Compared with last year’s meeting, there were far more biotech and pharmaceutical company representatives in attendance this year. Many of these individuals gave presentations of their work in HD. That was very encouraging, since some of these companies have good compounds developed for other diseases that may work on disease pathways known to be involved in HD.
The HD Family Perspective
A number of HD family advocates and communicators also were present. LaVonne Goodman, MD; Malcolm Casale, Ph.D.; Ann Covalt and I were there, all current or past editorial contributors to the HD Lighthouse. I had the honor of making the keynote address on the first night, giving the family perspective on living with HD. Some of the researchers had never met someone with Huntington’s Disease, so I told it like it is and the importance to families of their work. It is always very encouraging when HD research organizations go out of their way to involve HD families in their activities like this. Thank you CHDI and High Q.
Research Gaps Are Being Filled
I’m impressed with how many of the gaps that existed just three years ago between basic research and effective treatments for HD have been filled. CHDI is acting like a virtual pharmaceutical company. That means that rather than do drug development work in-house, they identify the work that needs to be done and then partner with the best specialist companies and other scientists worldwide to get the job done quickly and accurately. These companies are retained only if they are outstanding experts in their fields and are committed to doing their work at a fast pace.
An announcement was made at the meeting of the creation of another HD treatment group, the HP Therapeutics Foundation. No, that is not a misprint. “HP” stands for Huntington Project. My understanding is that once compounds developed by CHDI are ready for testing in humans, the HP Therapeutics group will shepherd them through any required clinical trials, FDA approval and regulatory approvals in other countries.
Therapeutic Targets and Methods of Treatment
One thing that has been learned over the years is that HD is a disease where a lot of different things go wrong. Researchers have found key molecular targets for many of these problems, with the goal that a drug or other technology can be focused on one or more of them to treat the disease. Presentations at the meeting discussed a number of the newly identified targets that could lead to possible treatments. Researchers also have identified the special problems of delivering these potential treatments to the brain, such as the special protective sheath known as the “blood-brain barrier” that keeps many molecules out of the brain. The sophisticated human blood-brain barrier was probably an evolutionary adaptation to keep toxic substances from injuring the brain, but for therapeutic purposes it complicates delivering effective treatments for neurological diseases.
Several of the potential compounds discussed in other reports on the HD Lighthouse web site had their status updated at the meeting. Histone deacetylase (HDAC) inhibitors remain high on the list of interesting compounds. So does the neuroprotective protein called brain derived neurotrophic factor (BDNF). CHDI stated that it is open to all treatments and delivery methods, including small molecule oral drugs, delivery by muscular or venous injection, using an implanted pump, tissue transplants and other modalities. But a scientist working for them stated that in all likelihood the first treatments for HD will be small molecule drugs taken orally.
Screening to Identify Potential Therapeutics
Did you know that there are approximately 2,000 drugs in active use worldwide? Many of these have already been approved by our own FDA. If one of these could be shown to help people with HD, the delays caused by the need for long clinical trials to demonstrate safety and efficacy could be reduced.
A speaker discussed a project underway to screen all 2,000 drugs to find those that may help slow or stop the disease. Since HD affects many different systems in the brain, these same researchers are testing all 2,000 compounds combined with a second compound from the list to see if combining them together further improves the effectiveness of the treatment. It may even be possible that two compounds that are ineffective by themselves might combine to be a good therapy. That’s about two million combinations to test…no wonder they call it high throughput screening! During the meeting speakers described the techniques they use to turn this into a manageable activity.
Following this initial screening, the compounds showing positive effects are then run through additional cell-based tests (called “assays”) that measures other aspects of potential efficacy. Surviving compounds are then being tested in animal models for HD leading up to a decision as to whether they should go into a clinical trial in humans.
And even that is not the end of this work. As additional compounds are identified that might be effective in HD, they are being run through these same assays as well. It’s clear that our HD researchers are not leaving any stone unturned.
Improving Potential HD Treatments
For some time now we have had nutritional supplements and approved drugs that have shown some efficacy in HD animal models. Some of these, like coenzyme Q10 (CoQ10) and creatine, have even been tested in HD patients. The trouble is that either these trials have not been the controlled studies that are considered the gold standard for drug approval, or they have not shown efficacy at a statistically significant level in accordance with the original trial design.
Speakers at the meeting described some of the technologies they are using to make these compounds more effective. For example, one company is actually taking apart the CoQ10 molecule and putting it back together again in a different configuration. They are modifying the “head”, the part that they believe is doing good things, to make it even more effective. They are changing the “tail” so that the drug is more soluble and so that more of it gets through the blood-brain barrier and into the neurons that need protection. The goal is that the modified compound will be a better CoQ10 that has improved efficacy as an HD treatment.
Creatine is another nutritional supplement that is being given the designer drug treatment. Like CoQ10, this compound is believed to help keep the energy-producing parts of cells, called the mitochondria, alive and doing their job. Many HD patients, including my wife, are taking creatine today, since it is relatively inexpensive and readily available at nutritional stores. The problem with creatine is that it needs to get in the brain and then be converted to phosphocreatine in order to be effective. To do this conversion takes energy that the cell is lacking as the disease progresses. Taking creatine phosphate directly isn’t a solution, since this has an even harder time getting into the affected neurons.
So what to do? One company at the meeting is developing what is called a “pro-drug” of phosphocreatine. A pro-drug is a compound that more easily goes to the right place in the body and then is converted into the desired compound within the targeted cell. The creatine pro-drug more easily crosses the blood-brain barrier and neuronal cell walls. Then it enters the mitochondria and is converted in phosphocreatine…just what the cells need. Since the Huntington Study Group is proposing new trials on CoQ10 and creatine, I hope that they will consider using these designer forms rather than the standard nutritional supplements.
The main point here is that many very creative methods are being tried to increase the efficacy, safety and delivery of therapeutic compounds to the neurons and other cells affected in HD. And this work is not limited just to drugs. New methods of delivering RNA interference, neuronal stem cells, and protective proteins like BDNF are being worked on quite seriously. You can read about many of these potential treatments elsewhere on the HD Lighthouse web site.
Clinical Trials: The Big Time Delay
So with all this activity, what is the biggest time delay in getting a treatment to HD patients? Two words: clinical trials. If a drug or other treatment, like RNA interference or stem cell therapy, is new and not already approved by the FDA, then a series of controlled clinical trials needs to be run to determine the safety and efficacy of the treatment before the FDA approves it to be marketed in the U.S.
Normally this is a three phase process extending over a period of several years and involving hundreds or thousands of patients. Clinical trials are extremely expensive as well. Following these trials, a new drug application (NDA) needs to filed with the FDA. Then the FDA reviews it in a process averaging 18 months or so before a final decision is made concerning approval.
For those readers not familiar with this process, you can read about it elsewhere on the HD Lighthouse site, or on sites such as the Huntington Project (www.huntingtonproject.org), where current and planned clinical trials for HD are listed.
The exceptions to this clinical trial and FDA approval delay might be presumably safe compounds that are either readily-available nutritional supplements or treatments already approved by the FDA for other uses that do well in the HD screening tests. Your doctor, if willing, is able to write a prescription for an approved drug for any use.
Although not discussed at the conference, there is one drug out there, Tetrabenazine, (called Nitoman in the U.S. and Canada) that may see FDA approval in the near future. This drug has been approved and used for many years in the United Kingdom and other countries to treat the motion disorder symptoms of HD. If approval of Nitoman is granted by the FDA, this will be a positive step forward. While Nitoman has not been shown to alter the course of HD, it can improve symptoms in a manner which improves the patient’s quality of life.
Please Sir, Some Help for an Orphan?
Did you know that Huntington’s Disease is an orphan? It is to the FDA. The short definition of an orphan disease is one where 200,000 or fewer people have the disease in the U.S. Estimates are that there are approximately 30,000 individuals with HD in the U.S. So we are definitely an orphan disease. Alzheimer’s, with an estimated 4.5 million affected individuals, and Parkinson’s, with 600,000 or more, are not.
Orphan disease status has some benefits. Big pharmaceutical companies in the past ignored orphan diseases because of their small market potential. In 1983 Congress passed the Orphan Drug Act to make it easier and sometimes faster for companies developing orphan drugs to do clinical trials and obtain FDA approval for them. The Act also provides certain other marketing benefits to such companies. The provisions of this Act are administered by the FDA’s Office of Orphan Products Development. A representative from that office attended the conference and described some of the programs that help expedite clinical trials and FDA approval. It looks like there may be a way to take advantage of HD’s orphan status to reduce the time required for clinical trials and FDA approval. I’m sure that the new HP Therapeutics Foundation will be looking into that quite closely.
The Possible Positive Wildcard
The one big wildcard at the meeting was a compound made by Kyowa Pharmaceuticals, called KW-6002. It is in a class of compounds known as adenosine A2A receptor antagonists. These receptors are concentrated on the medium spiny neurons that are affected by HD. Recently the A2A receptor has been identified as being a potential target for an HD treatment, and KW-6002 has shown positive results in the high throughput HD screening tests mentioned earlier. CHDI is planning further tests of KW-6002 in the next year.
So why is this compound a possible positive wildcard? It’s because the compound is already in Phase III clinical trials to treat Parkinson’s Disease. I contacted the company and they told me that they plan to file an NDA with the FDA later in 2007 for use in treating Parkinson’s. If all goes well, they could see FDA approval of their drug by sometime in 2009. At that point, if animal model testing of KW-6002 in HD is also positive, then this may give individual neurologists the confidence to prescribe it for treating HD, even if it hasn’t been formally approved for that use.
There is a word of caution however. A study in Italy indicates that in some situations activation of the A2A receptor can be neuroprotective, so interfering with it, as KW-6002 does, may not be a good idea in all circumstances. More study is needed. However, for the near future, KW-6002 may be the wildcard to watch.
The Conference Take-Home Message
I believe that the overall take-home message of this conference for HD families is that an effective treatment for HD in reality is still likely to be several years off. But it is also clear that CHDI and High Q have put together a strong network of researchers in many different disciplines that are working together to find such a treatment and bring it to the stage of clinical trials. The new HP Therapeutics Foundation will take this a step further into clinical trials and through FDA approval and approvals in other countries.
Please note that CHDI and High Q are “sister” private foundations. CHDI also receives support from the Huntington’s Disease Society of America. As Dr. Pacifici emphasized, CHDI is a “collaborative enabler”, working with many others to “rapidly discover and develop drugs that prevent or slow the progression of Huntington disease”.