Huntington Study Group 2006 Annual Meeting Report

HD Lighthouse Contributing Editor's Comment:

-- Tim O'Neil, M.D.
Posted to the HDL: 13 Dec 2006

Introduction

As a HD family member, I have been closely following the developments involving HD over the past few years. When my new found friend and Lighthouse Editor Dr. Marsha Miller suggested that I attend the 2006 Huntington Study Group (HSG) Annual Meeting in her place, I eagerly accepted. Marsha could not attend since she was scheduled to speak at her local HSDA chapter meeting.

HSG Chairman Dr. Ira Shoulson invited me to the meeting after Marsha requested that I attend in her place. I headed nervously to St. Louis with my wife for the November 8-11 meeting. We were excited to be alone without the kids for a few days, but I had hoped to attend the meeting with Marsha to gain some navigational experience regarding the HSG meeting and HD advocacy in general. Well, as the old cliché states: “no time like the present”, and into the deep end of the HD research I dove.

The Fourteenth Annual Meeting of the HSG had 222 attendees from North America, Europe and Australia. The dedication and enthusiasm of the attendees was remarkable. The daily schedule began at 7:00am and finished after 8:00pm.

For more information on the HSG, please see http://www.huntington-study-group.org. and www.huntingtonproject.org. Additionally, for Marsha Miller’s and Jim Tretheway’s exhaustive report on the 2005 HSG annual meeting, please see HDL: HSG 2005 Annual Meeting Report. Their report explains the different organizations involved in HD research and funding and the interrelationships between the organizations. This report will attempt to minimize duplicating the 2005 report and the HSG website information.

The Huntington Study Group

Dr. Karl Kieburtz of the University of Rochester utilized his self proclaimed “bully pulpit” during his brief presentation about the Clinical Trial Coordination Center in Rochester, NY to reminisce about the inaugural meeting of the HSG in 1993 at the Bethesda, MD Hyatt. The meeting consisted of twelve people. The twelve pioneers spent most of the day deciding whether or not it was worthwhile to meet again the following year.

Generally, when an executive of a government proclaims that the state of their government is sound, I often am skeptical. The state of the HSG appears to be excellent. It has over 350 members and is growing. The HSG’s funding has more than doubled over the past four years. In 2002, 88% of the HSG’s research support came from government sources (NIH-NINDS and FDA Orphan Products Division) and 12% from a variety of foundation grants. In 2006, the HSG’s research support is derived from government (53%), industry (20%) and foundations (27%) sources, including HDSA and the High Q Foundation. The High Q Foundation funding has increased dramatically over the past four years.

More importantly, the HSG currently has positioned itself well to expand its clinical research programs in the future. In 2005, the HSG had seventy-two research sites listed. Fifty-eight of the sites were active in one or more of the clinical or observational trials, including forty-six or more preparing to participate in 2CARE and forty-five or more participating in COHORT.

The HSG unveiled a new program entitled “HSG Training Initiative 2006-2008” during the state of the HSG presentation. The purpose of the program is to help the HSG begin and conduct high quality scientific research studies more efficiently. Continuing researcher education, training of principal investigators, development of “Tiger-Team” study sites, and nurturing of HSG working groups are some of the objectives of the training initiative. The “Tiger-Team” sites will strive to improve their operational readiness to conduct early phase trials as well as improve their efficiency in fulfilling each site’s individual institutional obligations including navigating the Investigational Review Board (IRB) process. The HSG working groups will be nurtured by encouraging single site pilot and exploratory studies as well as enhancing communication with working group participants outside of North America.

New HSG Clinical Trial Plans

Two new HSG clinical trials have submitted grant applications to NIH. The study the furthest along in the NIH approval process is the Creatine Phase III (CREST-E) trial. This trial is a phase 3 clinical trial. The principal investigator of the CREST-E is Steven Hersch, MD, PhD of Massachusetts General Hospital. The pharmaceutical company Avienca is providing the creatine a portion of the trial’s funding. The CREST-E study received a favorable “score” from the FDA Orphan Products Division after its initial submission. The proposal is scheduled to be resubmitted to the NIH in March. Hopefully, the HSG will begin enrolling study participants later in 2007.

The CREST-E study plans to enroll 650 participants at up to 65 HSG study sites. Participants must have been diagnosed with HD. They must have a total functional capacity (TFC) of greater than or equal to 7. The study will be a randomized, double blinded and placebo controlled. The study may have an open label phase. CREST-E will study participants over a three year period with three interim analyses. Participants will take 30 grams of creatine per day under current study plans after gradually increasing their creatine intake.

The primary outcome measured by the CREST-E study will be the change in TFC over the 36 month period. Secondary outcome measurements will include the UHDRS, a quality of life measure, changes in serum 8-Hydroxydeoxyguanosine (8OHdG) and 8-Hydroxyguanosine (8OHrG) levels and morphometric MRI.

The second proposed clinical trial to submit a grant application is the PREQUEL trial. The PREQUEL trial made its initial submission to NINDS on November 1. The acronym PREQUEL is derived from the study’s title: Study in PRE-manifest Huntington’s disease of coenzyme Q10 (UbiquinonE) Leading to preventive trials. The study’s principal investigator is Christopher Ross, MD, PhD, of Johns Hopkins University. Kevin Biglan, MD, PhD, of the University of Rochester is Co-Investigator.

PREQUEL will be Phase 2 clinical trial. The study will be randomized, double blinded and placebo controlled. Current plans call for the study to enroll 90 individuals who are known to carry the HD gene but not yet developed signs of HD. The study will enroll participants over an eighteen month period, hopefully beginning in fall of 2007. Each participant will be randomized to one of three groups to be studied over a 20 week period. The three groups will be a placebo group, a 1200mg of CoQ dose group, and 2400mg of CoQ dose group.

Like all Phase 2 clinical trials, the primary goal of the study is to establish safety and tolerability of CoQ at the study’s dosages in the study’s population. The secondary goals of the study include establishing the biological activity of CoQ by assessing changes in serum 8OHdG and 8-OHrG. Of note, this is the first drug trial in a pre-manifest HD population. Participants must be HD gene positive (CAG >36), but not be diagnosed with clinical HD to participate in the study.

Biomarkers

The scientific session of the conference was entitled “Biomarkers for Huntington’s disease”. Several speakers discussed the advantages and disadvantages of biomarkers. Discovery of reliable and sensitive biomarkers to measure neurodegenerative changes in HD should accelerate research.

Marc Walton, MD, PhD of the FDA began the session with a presentation entitled “Perspectives on Biomarker Development”. Dr. Walton noted that appropriate biomarkers for any disease can lead to shorter clinical trials with smaller sample sizes of patients and lower economic cost. Such a biomarker may provide easier measurements and a more objective outcome or result than subjective tests (i.e. UHDRS or TFC). Dr. Walton mentioned that biomarkers are not without hazards including misleading the researchers by not correlating well with actual disease onset or progression.

Jamshid Arjomand, PhD, of the High Q foundation noted during his presentation, “Biomarker Discovery in HD” that researchers do not expect any single biomarker to track progression of HD throughout the life of the disease. He commented that the HSG COHORT study could greatly aid in the discovery of biomarkers.

Dr. Hersch discussed the peripheral biomarkers 8OHdG and 8OHrG. Both markers appear to be markers for oxidative damage in neurons that can measured via a blood test. Researchers have known for several years that 8OHdG is elevated in other neuronal injury diseases such as stroke, Parkinson’s disease and Alzheimer’s disease. 8OHdG has been shown to be elevated in early manifest HD as well as pre-manifest HD. Both the CREST-E and PREQUEL study described previously are planning to use 8OHdG and 8OHrG as measures of secondary outcomes.

Elizabeth Aylward, PhD of the University of Washington and Diana Rosas, MD, MS of the Massachusetts General Hospital gave fascinating presentations regarding the use of neuroimaging as biomarkers for HD. A significant portion of their data was derived from the PREDICT-HD study participants.

Dr. Aylward’s talk, “Striatal Volume Imaging Changes in Manifest and Pre-Manifest HD” discussed the use of MRI as a biomarker. MRI appears to be an excellent candidate for use as a biomarker in pre-manifest HD. Dr. Aylward noted striatal volume decreases 4 to 6 percent over a two year period in HD as well as pre-manifest HD. Striatal volume loss on MRI could help to indicate when treatment for HD should begin in the future.

Dr. Rosas’s presentation was titled “The Incredible Shrinking Cortex in HD”. Dr. Rosas’s data showed that while the striatum of the brain is most vulnerable to the mutant huntingtin protein, thinning of the cortex of the brain occurs early in pre-manifest HD as well. Differences in cortical thinning of specific regions of the cortex may explain why affected individuals can exhibit such different symptoms. Dr. Rosas also noted that the rate of cortical thinning was decreased approximately 50% for subjects taking high dose creatine in an earlier CREST clinical trial.

Each presenter thanked the HD family members who participated in the observational and research trials.

Conclusions

Occasionally when talking with parents of my patients I remark that it is my goal to be their child’s second best advocate. It is understood that parents are their children’s best advocate. The HSG appears to be doing a wonderful job at being the HD families’ number two advocate. In the short time span of fourteen years they have organized a vast network of worldwide research and treatment centers, scientists, and support staff. The HSG “machine” appears to be humming along at a good pace while priming itself to lead the study of meaningful treatments for HD.

The HSG is overcoming the new and necessary privacy laws such as HIPAA (Health Insurance Portability and Accountability Act of 1996) to streamline the sharing of data as well as recover data from previous studies. Different regulations between states and countries regarding privacy must also be dealt with by the HSG. A few members commented to me that the research grant application process sometimes involves duplication of regulatory function between governmental agencies (FDA and NIH) and individual university IRBs.

The HD families can continue to improve our support of the discovery of treatments for HD. We can increase our participation in research studies; many have less exclusion criteria than in the past. We can increase our raising of money to support research. We can lobby our legislators to raise more government money for HD research and for government programs to support HD families. We can lobby our legislators to insure that government agency regulation of scientific research methodology is appropriate for rare diseases such as HD. We can continue to support each other.

The HSG meeting proved to be an exciting and educational trip for me. I met many dedicated, gifted, and friendly researchers. Indeed, we are steadily advancing towards successful treatments for HD.

Source:

printer friendly version

	Read the HDAC/HDLighthouse Forum. Post your comments