HD Clinical trials

1. HD Clinical trials Russell L. Margolis, M.D. May 15, 2008

2. Types of HD clinical trials • Observational trials • What is the course of HD • What factors might be monitored to predict progression? • Clinical trials for symptomatic HD • Testing safety at different doses • Symptomatic outcomes • Slowing disease progress • Presymptomatic trials: delaying onset

3. Huntington Study Group A non-profit group of physicians and other health care providers from medical centers in the United States, Canada, Europe and Australia. Found in 1993 with the goal of conducting multisite HD clinical research About 70 centers and 400 investigators Leadership: Executive Committee, chair Ira Shoulson, M.D. • Administration: • Located at the University of Rochester, in Rochester, NY • Clinical Trials Coordinating Center (60 staff members) • Biostatistics Center (25 faculty and staff)

4. HSG working groups • Clinical correlates: factors that predict onset and decline • Surgical approaches: • Neuropsychology • Behavioral (psychiatric) • Animal models (determining most promising) • Genetic correlates (genetic factors that modify age of onset) • Clinical trials initiative (advising on possible trials)

5. Main clinical tool: UHDRS • Unified Huntington’s Disease Rating Scale • Parts • Motor • Cognitive • Functional • Other tools • Quantified neurological examination (Hopkins) • Irritability and apathy scales • standard depression rating tools

6. UDHRS motor

7. UDHRS motor

8. UHDRS: diagnostic confidence

9. UHDRS: Behavioral assessment Each item rated 0-4 on frequency and 0-4 on severity Depressed mood Apathy Low self-esteem Suicidal thoughts Anxiety Irritable behavior Disruptive or aggressive behavior Perseveration/obsessional thinking Compulsive behavior Delusions Hallucinations

10. UHDRS: Total functional capacity Total functional capacity score has served as an exclusion criteria in studies seeking a mildly affected population (e.g., score must be more than 7 or 9)

11. Co-enzyme Q10 And Remacemide Evaluation in Huntington's Disease (CARE HD) • Rationale • Remacemide— • NMDA receptor antagonist, • chosen based on glutamatergic toxicity hypothesis • Coenzyme-Q10 • anti-oxidant • factor in mitochondrial energy production • Design: • Double blind placebo controlled • Remacemide (600 mg/day), Coenzyme-Q10 (600 mg/day) , both, or neither • 347 enrolled patients from 23 sites • Primary outcome: Total Functional Capacity after 30 months • Powered to detect a 35-40% slowing of decline in function

12. CARE HD: Study group characteristics Groups well-matched. Individuals about 5 years since symptom onset.

13. CARE HD treatment arms

14. CARE HD outcomes Primary outcome measure—Total functional capacity: CoQ slowed functional loss by 13% (p =.15)—not significant. No effect of remacemide Trend toward CoQ slowing functional declince on other measures Trend of CoQ benefit on two cognitive measures, and on behavioral measure Trend toward improvement of chorea by remacemide No benefits of combining the two drugs

15. CARE HD conclusions • Remacemide • may have symptomatic effect on chorea • does not slow disease progression • Common side effects—dizziness and nausea • Coenzyme-Q10: of interest, but not yet recommended • effect small, if any • In U.S. freely available, but expensive (>$100/month) • Considered a nutritional supplement so not regulated as carefully as pharmaceuticals • (Advice to patients varies by practioners)

16. Follow-up to CARE HD: “Coenyzme Q10 in Huntington's Disease (2CARE)” • 608 individuals from 46 sites • 2400 mg/day CoQ (4x CARE HD dose) vs. placebo • Primary outcome: change in total functional capacity over 5 years • Powered to detect 20% slowing of decline in function • Enrollment has now started

17. Important observational trials • PREDICT-HD: Neurobiological Predictors of Huntington's Disease • To determine the earliest signs of HD and when they begin • To determine the most accurate tests for detecting onset • To determine factors that influence age of onset • Enrollment: presymptomatic gene positive individuals, and gene negative controls • Assessments: • UHDRS clinical assessment • comprehensive neuropsychological testing • MRI • Currently 1000 individuals enrolled

18. Important observational trials (2) • PREDICT-HD: Neurobiological Predictors of Huntington's Disease • PHAROS: Prospective Huntington At Risk Observational Study To be discussed in afternoon talk about presymptomatic disease COHORT:Cooperative Huntington’s Observational Research Trial • Goal: establish longitudinal course of HD • Subjects: affected, presymptomatic, and controls • Plan: yearly visits • detailed history at each visit • Medical, neurological, cognitive exams each visit • Blood and urine samples • Based in part on successful 30 year longitudinal study at Johns Hopkins

19. RESPOND-HD:

20. TREND-HD: A Multi-Center, Double-Blind, Randomized, Placebo-Controlled Trial of Ethyl-EPA (Miraxion™) in Subjects with Mild to Moderate Huntington’s Disease Miraxion (AMR101) (ethyl-eicosapentaenoic) (ethyl-EPA) is a semi-synthetic derivative of a long chain highly unsaturated fatty acid derived from fish. • Potential mechanisms of action: • replenishment of the lipid bi-layer in damaged neurons • (2) reducing the over production of enzymes (PLA2) associated with cell death • (3) stabilizing mitochondrial integrity Preliminary small scale study in Hd patients in 2003 showed possible effect Therefore, two large scale studies launched simultaneously in U.S. and Europe. Goal: Establish short term effect of ethyl-EPA to gain approval from United States Food and Drug Administration

21. TREND HD: Study design • 6 month double blind, placebo controlled, followed by 6 months of open label treatment with the drug for all interested • 1 gram twice a day of ethyl-EPA vs. placebo • 316 HD patients with early disease enrolled from 41 sites • Primary outcome measure • “TMS-4”, a portion of the UHDRS motor score that includes • Chorea, dystonia, finger tap speed, dysdiadokinesis, ocular pursuit, rigidity, tongue protrusion, tandem walk, retropulsion

22. TREND-HD: organization of HSG studies Amarin, Inc. (Pharmaceutical company with patent) Analysis and manuscript Huntington Study Group (Rochester) Study design informed consent financial contracts Money and protocols Data and problems External monitor Study site 1 Physician PI Coordinator laboratory Study site 2 Physician PI Coordinator laboratory Study site 3 Physician PI Coordinator laboratory Study site 4 Physician PI Coordinator laboratory

23. TREND-HD initial results From Amarin press release, April 24, 2007 “Amarin Corporation … today announces top-line results from its two Phase III clinical trials of Miraxion to treat Huntington’s disease (HD). … Study data showed no statistically significant difference in either study between Miraxion and placebo with regard to the primary and secondary endpoints.” “Commenting on today’s announcement, Rick Stewart, Chief Executive Officer of Amarin, said, “We are extremely surprised and disappointed by these top-line results, and we are analyzing the data in order to better understand the full and complete data set and outcomes.” Stock of Amarin falls by about 90% Rick Stewart resigns by the end of the year. But later analyses more optimisitc

24. 6 months on placebo, then 6 months on drug 12 months on drug Final conclusion: Of potential benefit, but will need further study!

25. Other recently completed HD clinical trials • Tetra-HD: Tetrabenazine • A randomized, double-blind, placebo-controlled, 12-week study of 84 HD patients with significant chorea, at 16 study sites. • Reduction of chorea by 25% • Likely to be approved for clinical use in U.S. shortly

26. On-going trials: slowing disease progression • Minocycline: (DOMINO: A Multi-Center, Double-Blind, Pilot Study) • Antibiotic with anti-cell death and antioxidant properties • 100 HD patients followed for 18 months • Creatine: (CREST-E) • Antioxidant, protects mitochondria • Delayed death in HD mouse models • possible delay of progression in pilot human studies • 400 patients, 8 grams/day, 40 sites, 3 years • Outcome to include brain imaging as well as clinical measures

27. On-going trials: cognition as main outcome • Atomoxetine: (single center, double-blinded placebo controlled) • norepinephrine reuptake inhibitor • Goal: assess attention and cognition; secondarily motor and functional changes • 20 patients with HD studied over 2 months • Citalopram: (CIT-HD) (single center, double-blinded placebo controlled) • SSRI antidepressant • 20 people with HD studied for 5 months • Outcome measures: executive function, other cognitive and functional measures, and brain imaging. • Dimebon: (DIAMOND, multiple site placebo controlled) • Anti-histamine with glutamatergic, anticholinesterase and maybe mitochondrial properties • Helped cognition in animal memory models, of some help in Alzheimer’s • 90 patients over 90 days in a Phase II trial • Outcomes: motor, cognition and function • Memantine multisite phase III trial • Glutamateric (NMDA) receptor antagonist, approved for Alzheimer’s • 72 HD patients, 3 months double-blind placebo, 3 months all on drug • outcome is cognition

28. An invitation • Dr. Shoulson invites the Chilean group to join the HSG! • Key requirements • Demonstrate proficiency with rating instruments • Sufficient infrastructure, such as a research coordinator • Advantages • Contributing to advancement in treatment • Input into the future of the field • Keeping up with the latest developments • Patients often very enthusiastic about participating • Payment for participation can help support a clinic