How Many People Have Huntington Disease?

InsightsTM HD periodical A Huntington disease research

Issue No 1 -- Fall 2011

Research Round-up World Congress on HD: Meet the Investigator Meet the Company Lise Munsie overviews Melbourne, Australia Lead TRACK-HD Prana Biotechnology CEO recent developments in Dr. Mahmoud Pouladi investigator Sarah Tabrizi Geoffrey Kempler discusses HD basic research, recaps highlights from this shares her thoughts on the the potential for PBT2 to imaging, and clinical year’s international most promising basic improve cognition in research. meeting of world Huntington disease. Page 3 research in HD. researchers in HD. Page 5 Page 9 Page 4 Status Report: Clinical Trials At a glance -- information on current clinical trials in HD. Page 8

By: Emily Fisher and Alicia Semaka Figure 1: Minimum Prevalence of HD Globally There are two ways to answer the question “how many people have Huntington disease (HD)?” The ﬁrst is by determining the prevalence (i.e., the proportion of a population that has a given condition at a particular point in time), and the second is by determining the incidence (i.e., the number of people who will develop a condition over a deﬁned period of time) of HD. Prevalence answers the question of “how many people currently have HD?” and incidence answers the question of “how frequently are people being diagnosed with HD?” Research suggests that the answers to both of these questions are changing and perhaps increasing. These changes will have important Warby et al. 2009. Additional references may be viewed at biological, economic, and social http://www.hdinsights.org/Publications.html implications for the future. (continued on Page 2...)

HD InsightsTM, Vol. 1 Copyright © Huntington Study Group 2011. All rights reserved. 1 HD INSIGHTSTM How Many People Have HD?, cont... The prevalence of HD has been reported underlying the disease; with a genetic patients and families are reaching out to to vary with ethnicity and geographical test now available, diagnosing HD has medical service providers and becoming location, confirming that demographic become more precise. Patients with involved in HD research, and their differences influence the number and atypical symptoms, late disease onset, increased involvement in the HD composition of individuals with HD. and negative family histories are more community provides an ideal Since HD is believed to have major likely to be diagnosed, reflecting a likely opportunity to reassess the global origins in Northern Europe,2 it is not increase in the number of persons living prevalence of HD. surprising that populations of Northern with the disease. However, fear of European descent are recorded as having experiencing genetic discrimination from While the need to establish new baseline the highest prevalence of HD in the health insurers, among family members, prevalence estimates for HD is apparent, world.3 In the 1970‘s and 1980’s, a or in social settings14 may prevent some these figures must be frequently revised number of studies around the globe individuals from disclosing that they are to determine how the prevalence of HD examined the prevalence of HD. In either at-risk or premanifest for HD, thus changes over time. Factors such as the Europe it was estimated that an average making it difficult to accurately identify projected demographic shifts in median of 4 – 7 persons per 100,000 were every patient in a given population. age and our increasing longevity will affected with the disease.4,5,6,7 Canadian likely impact the prevalence of HD in the studies suggested 2.4 – 8.4 persons per A brief review of the number of patients coming years. With an aging population 100,000 had HD.8,9 In the United States, cared for by the Huntington disease that is expected to live longer, more it was estimated that 4.1 – 5.2 persons Association in the United Kingdom (UK) individuals who have late onset HD will per 100,000 were living with the indicated that approximately 6700 be diagnosed, thus increasing the disorder.10,11 Figure 1 reviews additional individuals in the UK are currently number of affected individuals. global prevalence estimates for HD. living with HD. This means that 12.4 per Accurate prevalence estimates are vital While a number of studies have 100,000 persons or 1 out of every 8,065 to ensuring that there is appropriate examined the prevalence of HD, very individuals may be affected with HD15. access to clinical services and support for few studies have investigated the Although these numbers at best provide patients and families. Additionally, since disease’s incidence. Findings from a minimum prevalence estimate in the medical and research funding is often Minnesota, USA suggested that 3 UK, since the Association does not care allocated on the basis of the disease individuals per million were diagnosed for all HD patients in England and burden on society, it is imperative to with HD each year between 1950-1989.12 Wales, the numbers do demonstrate that know the true prevalence of the disease In British Columbia, Canada, 6.9 previous prevalence figures are likely in order to secure proportional financial individuals per million were diagnosed underestimated. Fortunately, recent support for HD research and care. With each year between 1987-1999.13 increases in HD awareness and access to a combined global effort from HD information and support, developments patients, families, researchers, and In recent years, the accuracy of of legislations dedicated to preventing caregivers, we will finally be able to published prevalence estimates for HD genetic discrimination, and accurately answer the question: “How has been called into question. The continuations of promising basic and many people have Huntington disease?” majority of prevalence estimates for HD clinical HD research have had impact on were conducted prior to the the willingness of individuals to involve identification of the genetic mutation themselves in the HD community. More

1 Hayden, MR. Huntington’s Chorea. New York: Springer, 1981. 2 Warby, SC et al. Expansion in the Huntington Disease Gene Is Associated with a Speciﬁc and Targetable Predisposing Haplogroup, American Journal of Human Genetics 2009;84:351–366 3 Caro AJ. Huntington’s Chorea; a clinical problem in East Anglia. PhD thesis, University of East Anglia. 4 Quarrell OWJ, Tyler A, Jones MP, et al. Population Studies of Huntington’s disease in Wales. Clin Genet 1988;33(3):189-95. 5 Simpson A, Johnston AW. The prevalence and patterns of care of Huntington’s disease in Grampian. Br J Psychiatry 1989;155:799-804 . 6 Harper, PS. The epidemiology of Huntington's disease. Human Gen 1992;89:365-376. 7 Barbeau A, Coiteux C, Trudeau JC, Fullum G. La Choree de Huntingdon chez le Canadiens Francais, Union Medicale de Canada 1964;93:1178. 8 Shokeir MHK. Investigations on Huntington’s disease in the Canadian Prairies I. Prevalence. Clin Genet 1975;7(4):345-8. 9 Reed TE and Chandler JH. Huntington’s chorea in Michigan. I. Demography and genetics. Am J Hum Genet. 1958;10(2):201-25. 10 Folstein SE, Chase GA, Wahl WE, et al. Huntington Disease in Marlyland: Clinical Aspects of Racial Variation. Am J Hum Genet 1987;41(2):168-79. 11 Kokmen E, Ozekmekpi S, Beard M, et al. Incidence and prevalence of Huntington's disease in Olmsted County, Minnesota (1950 through 1989). Arch Neurol 1994;51(7): 696-8. 12 Almqvist E, Elterman D, MacLeod P, Hayden MR. High incidence rate and absent family histories in one quarter of patients newly diagnosed with Huntington disease in British Columbia. Clin Genet 2001;60(3):198-205. 13 Bombard Y, Veenstra G, Friedman JM, et al. Perceptions of genetic discrimination among people at risk for Huntington's disease: a cross sectional survey. BMJ 2009;338:b2175.

2 Copyright © Huntington Study Group 2011. All rights reserved. HD InsightsTM, Vol. 1 HD INSIGHTSTM Research Round-Up By: Lise Munsie In the lab... In the scanner... In the clinic... Basic research into the biochemical pathways Basic research and Recent efforts in drug discovery for HD have underlying the pathogenesis of HD clinical research are shifted to exploring different methods for continues, with the aim of targeting these bringing us closer silencing the allele that codes for mutant pathways for drug delivery. PGC1α, which to disease- huntingtin. Allele-specific silencing using controls many aspects of oxidative modifying antisense oligonucleotides (ASOs) has been metabolism, has been a focus of recent treatments for successful in non – brain-related disorders, efforts. Huntington disease, and with recent advances in chemistry, Martin and colleagues showed that an but sensitive biomarkers are needed to pharmacology and drug delivery, the upstream activator of PGC1α may be assess disease progression and the efficacy of possibility of using ASOs to treat brain involved in the characteristic down- new treatments. Neuroimaging has now disorders is becoming more realistic. Recent regulation of PGC1α in HD patient brain and come into the spotlight to assist with this clinical efforts have explored novel muscle samples.2 They also used a task, and large-scale, multi-site longitudinal approaches to improve ASOs and have transcriptional readout of an HD rat model studies such as TRACK-HD and PREDICT- sought to develop ways to silence the allele to show that MSK1, a nuclear protein kinase HD have recently released neuroimaging that codes for mutant huntingtin, while with low striatal levels in HD patients, is study results. sparing the normal allele. responsible for PGC1α activation. When The TRACK-HD team led by Dr. Sarah Gagnon and overexpressed, MSK1 can activate PGC1α, Tabrizi in London used magnetic resonance colleagues showed possibly through histone H3 imaging (MRI) data to investigate clinical, that ASOs with phosphorylation, and lead to positive cognitive, oculomotor and neuropsychiatric certain chemical outcomes in the HD rat model. indicators of HD.2 They saw progression in modifications can Taherzadeh-Fard and colleagues looked at prodromal HD over a 12-month period, and specifically silence genetic modifiers via single nucleotide found that brain imaging measurements the allele that polymorphisms (SNPs) in HD patients, and were the strongest and most consistent codes for mutant huntingtin, although the showed that downstream PGC1α measures when tracking disease progression. mechanism of this silencing remains 2 transcription factors NRF-1 and TFAM are TRACK-HD’s data has established an unknown. Interestingly, these effects were genetic modifiers of the age of clinical onset association between MRI neuroimages and protein and not transcript-dependent. of HD.3 These data strongly support clinically meaningful measures of disease Fiszer and colleagues used repeat-targeting modulation of PGC1α activity as a potential progression. Furthermore, the study RNA duplexes to discriminate between therapeutic approach in HD. provides baseline data to estimate the expanded and non-expanded alleles, and to sample sizes required to detect meaningful Labbadia and colleagues mediate RNA-induced silencing complex treatment-mediated improvements in a (RISC) – dependent target silencing.3 They investigated the therapeutic clinical trial. potential of activating used a duplex of pure CUG/CAG repeat chaperones for HD.4 They The PREDICT-HD team led by Dr. Jane sequences to silence the allele that codes for used HSP990, a brain- Paulsen reported that their MRI data mutant huntingtin, and they increased allele penetrating HSP90 inhibitor indicate that increased CAG length is selectivity by introducing single or double that can be administered associated with more rapid progression of C>U substitutions in an effort to modulate 3 orally, and showed that striatal atrophy. RISC activity. while activating chaperones Diana Rosas and colleagues used MRI to Chung and colleagues found that an via the heat shock response investigate the possible correlation between overexpressed antisense strand at the HD is initially therapeutic, the heat shock age of onset and rate of brain atrophy.4 The locus (huntingtin antisense – HTTAS) has the response is gradually attenuated as disease study showed that individuals whose motor ability to modulate huntingtin expression, its progresses. The shut-down of the heat shock symptoms appeared before the age of 40 sense transcript counterpart.4 These results response seems to be linked to epigenetic years had an increased rate of brain atrophy. suggest that continued investigation of modifications, and indicates that this The study also found that topological overexpressed antisense strands and their approach, although potentially beneficial, distribution of cortical thinning was highly ability to decrease huntingtin expression may be more complicated than originally dependent on the age of onset and not should be pursued. hoped. necessarily on the length of CAG repeats.

1 Martin E, Betuing S, Pagès C, et al. Mitogen and stress – activated 4 Tabrizi SJ, Scahill RI, Durr A, et al. Biological and clinical changes in 7 Gagnon KT, Pendergraff HM, Deleavey GF, et. al. Allele-selective protein kinase 1 – induced neuroprotection in Huntington's disease: premanifest and early stage Huntington's disease in the TRACK-HD inhibition of mutant huntingtin expression with antisense role on chromatin remodeling at the PGC-1-alpha promoter. Hum study: the 12-month longitudinal analysis. Lancet Neurol 2011;10(1): oligonucleotides targeting the expanded CAG repeat. Biochemistry Mol Genet 2011;20(12):2422-34. 31-42. 2010;49(47):10166-78. 2 5 Taherzadeh-Fard E, Saft C, Akkad DA, et al. PGC1alpha Aylward E, Mills J, Liu D, et al. Association between Age and 8 Fiszer A, Mykowska A, Krzyzosiak WJ. Inhibition of mutant downstream transcription factors NRF-1 and TFAM are genetic Striatal Volume Stratiﬁed by CAG Repeat Length in Prodromal huntingtin expression by RNA duplex targeting expanded CAG modiﬁers of Huntington disease. Mol Neurodegener 2011;6(1):32. Huntington Disease. PLoS Curr 2011;3:RRN1235. 3 Labbadia J, Cunliffe H, Weiss A, et al. Altered chromatin 6 Rosas HD, Reuter M, Doros G, et al. A tale of two factors: what repeats. Nucleic Acids Res 2011;39(13):5578-85. architecture underlies progressive impairment of the heat shock determines the rate of progression in Huntington's disease? A 9 Chung DW, Rudnicki DD, Yu L, Margolis RL. A natural antisense response in mouse models of Huntington disease. J Clin Invest 2011; longitudinal MRI study. Mov Disord 2011;26(9):1691-7. transcript at the Huntington's disease repeat locus regulates HTT 121(8):3306-19. expression. Hum Mol Genet 2011;20(17):3467–77.

The four-day World Congress was held in Melbourne, Australia

By: Mahmoud Pouladi, PhD The 2011 World Congress on Colin Masters revealed Prana Paul Muchowski spoke about the peripheral Huntington’s Disease in Biotechnology’s plans to conduct clinical effects of mutant huntingtin on central HD trials of their metal chelator PBT2 as a Melbourne, Australia, brought pathology. He presented data suggesting that treatment for HD. Abnormal interactions pharmacological modulation of molecular together HD clinicians, basic between copper and/or iron and mutant targets (i.e. antagonism of kynurenine 3- huntingtin in the brain of HD patients have scientists, patients, families, monooxygenase or agonism of cannabinoid long been suspected, and treatment with and support groups. Peter receptor type 2) in the periphery could be PBT2 may benefit these patients. Clinical Harper and Sarah Tabrizi gave trials of PBT2 are scheduled to commence in beneficial in HD. the opening addresses. late 2011 in Australia and the USA. Robert Pacifici presented CHDI’s vision for a Peter Harper presented historical highlights Three scientists presented their efforts to target-based, hypothesis-driven approach to of HD, emphasizing the uniqueness of the reduce levels of mutant huntingtin in HD drug discovery in HD. He pointed out that HD community among other gene carriers and clinical patients. Frank different animal models of HD may be useful neurodegenerative disease communities. He Bennett from Isis Pharmaceuticals presented for modeling different aspects of HD, and said the HD community should take pride in an update on the company’s efforts to silence that there is no such thing as a ‘good’ or ‘bad’ the closeness that exists between HD the mutant huntingtin allele, using antisense animal model. He also talked about the value scientists, clinicians, patients and patient oligonucleotides (ASOs). Don Cleveland of exploratory studies and observations made families. He ended his presentation with the presented data that indicate that short-term in HD patients, echoing the call for idea that HD should no longer be regarded as silencing of expression of mutant huntingtin participation of HD gene carriers and patients untreatable, given the current state of using ASOs is sufficient to improve in clinical research. research and understanding in the HD phenotypes in a mouse model of HD. Beverly community. Davidson presented her findings on shRNA Michael Hayden discussed the changing and miRNA – mediated approaches to prevalence of HD. He said that the increase in Sarah Tabrizi spoke about HD disease silencing the expression of mutant huntingtin the proportion of elderly people in the global pathways and mechanisms that are currently in mice and rhesus monkeys. In the monkeys, population is likely to increase the prevalence the subject of therapeutic efforts. She said that the reduction of endogenous huntingtin of HD and its associated burden. many pharmacological candidates targeting levels in the posterior putamen had no these pathways will be entering clinical trials adverse effect on measures of motor function The Congress also featured perspectives on over the next two years. She presented and learning. international models of HD care from findings from the TRACK-HD study, in Daniela Rae (Europe), Andrew Churchyard which various measures, particularly those of Anthony Hannan discussed the influence of (Australia), Amanda Krause (South Africa), brain atrophy, showed significant environmental factors on HD disease Francisco Cardoso (South America), deterioration over a 1–2 year period. The progression. Dr. Hannan and his colleagues Darshana Sirisena (Sri Lanka). results indicate that therapeutic interventions have used mouse models of HD to in early HD may be possible. Professor demonstrate that environmental enrichment Robi Blumenstein gave the Congress closing Tabrizi also announced the launch of a new stimulates hippocampal neurogenesis, and presentation, and outlined the three elements study, TrackOn-HD, which aims to enhances synaptic function in HD. He he believes will be essential for a successful investigate neural compensatory mechanisms suggested that environmental or HD trial: an effective treatment; methods to that may delay cognitive decline in HD gene pharmacological interventions that measure the positive effects of treatment; and carriers. strengthen synaptic function should be the active participation of HD gene carriers in pursued as potential HD treatments. clinical research.

NAME: Sarah Tabrizi

CURRENT POSITION: Professor of Clinical Neurology at University College London EDUCATION: PhD Biochemistry University College London MBChB University of Edinburgh CURRENT HD ACTIVITIES: Dr. Tabrizi is leading efforts in translational medicine. She is lead investigator of the TRACK-HD study that investigates the neurobiology of premanifest and early onset HD and has already been successful in identifying biomarkers that can be used to track the progression of neurodegeneration from its onset in HD patients. She is also researching immunobiology in HD, and cellular mechanisms of protein misfolding diseases. HOBBIES: Spending time with family, reading, and running. Sarah Tabrizi, MBChB, PhD LAST BOOK READ: Herzog by Saul Bellow. It was great but heavy going!

Dr. Tabrizi established her own consulting clinic and specialist HD clinic in 2003. Since then, she has published more than 120 peer-reviewed articles, which have appeared in Molecular Cell, Lancet Neurology, Nature Communications, Journal of Experimental Medicine, EMBO Journal and PNAS. In addition to her ongoing projects in HD immunobiology, protein misfolding, and the TRACK-HD study, she serves on executive panels for the UK HD association, the European HD Network and NINDS. Dr. Tabrizi sat down with HD InsightsTM at the World Congress on Huntington’s Disease to discuss her HD research and hopes for the future of HD. Excerpts from the discussion are below.

INSIGHTS: What drew you to Huntington disease?

TABRIZI: My PhD supervisor Tony Schapira took me to a nursing home just outside London called Stagenhoe, where there were many patients with advanced Huntington disease. I was struck by the patients and how warm they were, how interested they were in the research. Then I met Gill Bates who had just published about her HD mouse. I followed up with the work Gill had done and also worked with her during my PhD.

My PhD work cemented my interest in the disease. Once you start working in Huntington disease you get hooked.

INSIGHTS: You presented that a number of different biological markers that you're helping develop track with HD. Can you tell us which of these biomarkers you view as the most promising?

TABRIZI: The markers that I've been most impressed with are the structural imaging markers – caudate volume, striatal volume, and whole brain atrophy. These are the markers that I think are the most promising and the most robust at this stage.

However, a number of cognitive and quantitative motor markers are also important. We are developing these markers with our TRACK-HD team. The interesting part about the imaging is that we need to understand more about what these structural changes mean biologically. We need to understand what the pathological substrate is and the functional relevance of these imaging changes. That's something through our ongoing work we're seeking to do – to look at neural compensatory networks and functional plasticity.

INSIGHTS: You talked a little bit about your initial skepticism of structural imaging and how that's been converted.

HD InsightsTM, Vol. 1 Copyright © Huntington Study Group 2011. All rights reserved. 5 HD INSIGHTSTM Meet the Investigator, cont... TABRIZI: My initial skepticism was that whether imaging would demonstrate convincing change, whether it would be robust enough, and whether you would be able to remove inter-scan variability to get good scan quality. Now I understand a great deal more about how the technologies. We have advanced ways of studying the brain, particularly with 3T MRI; we can very accurately and carefully map regions of the brain with very high sensitivity and low measurement error. Imaging gives us insight into regional changes. I've become converted in that imaging does appear to correlate very closely to functional and cognitive decline. INSIGHTS: At the conference you also identified classes of experimental compounds that hold promise for Huntington disease. Can you discuss which of these you think holds the most promise? TABRIZI: I wanted to give an overview of the compounds that were potentially neuroprotective or disease-modifying that would be going into clinical trials in the next 24 to 36 months. Phosphodiesterase inhibitors – phosphodiesterase 10 inhibitors, for example – are promising in pre-clinical data and have the potential to enhance synaptic function. Other compounds currently at or near clinic that have great potential are the KMO inhibitors that target peripheral immune cells. Also promising are those that use approaches such as ASOs and RNAi and aim to lower mutant huntingtin or enhance mutant Huntington clearance and/or correct gene transcriptional dysregulation, such as the SIRT1 inhibitor (Siena BioTech). In pre-clinical targets, the HDAC4 inhibitors are potentially exciting. INSIGHTS: You mentioned phosphodiesterase 10 inhibitors had promising pre-clinical data. Can you tell us about that? TABRIZI: There are two published recent papers in HD mouse models. In one, they use phosphodiesterase 10 inhibition treatment in primary striatal cultures, while in the other they have partly corrected synaptic dysfunction and transcriptional dysregulation. This is promising in that cAMP/cGMP downstream signaling has multiple beneficial effects on synaptic function and gene regulation INSIGHTS: How will those beneficial effects on synaptic function lessen the burden of Huntington disease? TABRIZI: Huntington disease causes early synaptic functional defects and loss of the cortico-striatal neural circuitry, as shown in numerous mouse model studies. Synaptic function is essential for memory, learning, and overall brain function, and very early neuronal loss and synaptic dysfunction occurs in Huntington disease. We know from TRACK-HD data that neuronal loss is also very likely to occur early in HD gene carriers. This is potentially reversible. If we can somehow promote synaptic function and promote synaptic plasticity, we can allow the brain to compensate for ongoing pathogenic effects of mutant huntingtin. INSIGHTS: In the next few years what are the most promising avenues of research that we can expect to see coming out of the Tabrizi lab? TABRIZI: I have a number of projects that are ongoing. I'm working on basic science and protein misfolding cell biology, particularly using prion cell biology as a model for protein misfolding biology. We're looking at trying to understand how the misfolded prion proteins move around and use that as a model to take it forward to look at for example, mutant huntingtin trafficking. We're also developing a number of human ex-vivo cell culture models to try and look at HD in a cell culture dish, as well as starting projects in which we probe the function of wild-type in peripheral human HD cells. On the more translational side, I have a big program looking at the role of the immune system and immune biology in modifying Huntington disease, while also investigating how wild-type and mutant huntingtin levels may vary between patients, how they may correlate with each other, and how they may link to disease progression. Finally, Track-On-HD is a new study aiming to explore neural compensatory networks and functional plasticity in the premanifest stage of Huntington disease. It's essential to understand functional plasticity moving forward, especially in terms of future trials for pre-manifest individuals. Despite striking brain changes over time, our subjects are able to function at a high level. There must be remodeling and functional plasticity of synapses for this to occur. We're using a number of novel methods to look and see if we can identify these neural compensatory networks. Clearly this will also give functional relevance to structural imaging. These are the main projects over the next two years and hopefully we'll get some exciting and important data. INSIGHTS: Thank you very much and your final thoughts? TABRIZI: The meeting here in Melbourne has been really exciting. There's a great feeling of positivity. The families that are here feel the progress has been made, and that we're working together avidly to try and find potential treatment for Huntington disease. It is a great community.

DATE EVENT LOCATION ABSTRACT DEADLINE

November 12-16, 2011 Society for Neuroscience Conference Washington, D.C. Closed

February 22-23, 2012 Clinical Neurology and Tel Aviv, Israel November 20 2011 Neurophysiology Update Symposium

February 27-March 1, 2012 CHDI HD Therapeutics Conference Palm Springs, CA January 13, 2011

June 8-10, 2012 Huntington Disease Society of Las Vegas, NV Not yet posted America National Convention

June 17-21, 2012 Movement Disorder Society Dublin, Ireland Open October 3, 2011 International Congress

September 8-11, 2012 European Federation of Neurological Stockholm, Sweden Not yet posted Societies Congress

October 7-10, 2012 American Neurological Association Boston, MA April, 2012 Meeting

To have your conference added to the list for future publications please e-mail HD InsightsTM at [email protected]

T O LEARN MORE ABOUT HD I NSIGHTSTM, INCLUDING HOW TO CONTRIBUTE OR HOW TO HAVE YOUR EVENT OR TRIAL HIGHLIGHTED, PLEASE VISIT US AT WWW. HDINSIGHTS. ORG

SPONSOR STUDY PHASE PRINCIPAL DESIGN TRIAL SITES CONTACT/ AGENT INVESTIGATOR LENGTH STATUS Randomized double blind study to see if 47 total - Huntington Study National Institute Coenzyme III Merit Cudkowicz, 5 years coenzyme Q10 is effective in slowing the U.S., Group: of Neurological Q10 MD, MSc worsening of symptoms of Huntington Canada, Disorders and 800-487-7671 disease Australia Stroke

Randomized double blind study to test 60 total - Huntington Study National Center Creatine III Steven M Hersch, 3 years whether high-dose creatine can slow the U.S., Canada, Group: for MD, PhD progressive functional decline that occurs in Australia, Complementary adult persons with early clinical features of New Zealand 800-487-7671 and Alternative Huntington disease Medicine

Randomized controlled study to compare the 1 total - Bachoud-Levi Assistance Olanzapine, III Anne-Catherine 1 year beneﬁcial and adverse effects of 3 different Europe Anne-Catherine, Publique - Tetrabenazine Bachoud Levi, PhD neuroleptics in Huntington disease PhD: +33 (0)1 49 81 Hôpitaux de Paris and Tiapride 23 01 Randomized, double blind, placebo-controlled 18 total - Goran Westerberg, Siena Biotech Selisistat, II Ralf Reilmann, MD 3 months parallel-group design at two dose levels of Europe PhD: gwesterberg@ SEN0014196 SEN0014196 in early-stage Huntington disease sienabiotech.it patients

Randomized double blind study of the 10 total - Novartis: +41 61 Novartis AFQ056 II Ralf Reilmann, MD 46 days efﬁcency, safety, and tolerability of AFQ056 in Europe 324 1111 Pharmaceuticals reducing Chorea

Randomized double blind study testing the 13 total - Elaine M Julian- National Institute Coenzyme II Christopher A. Ross, 20 weeks tolerability of treatment with 600, 1200 or 2400 United Baros, BS: of Neurological Q10 MD, PhD mg per day of coenzyme Q10 in pre-manifest States 585-273-2879 Disorders and participants carrying the CAGn expansion for Stroke Huntington disease Enrollment Complete Randomized double blind study testing the 3 total - N/A Charite Epigallo- II Josef Priller, MD 1 year efﬁcacy and tolerability of (2)- Europe University catechin epigallocatechin-3-gallate (EGCG) in changing Gallate cognitive function in patients with Huntington disease

Open label, single group assignment study to 22 total - N/A Neurosearch A/S Pridopidine II Karl Kieburtz, MD 2 years assess the long-term safety of 45 mg of U.S. and MPH pridopidine in Huntington disease Canada Ongoing participants

Randomized double blind study of the effect 3 total - Blair Harrison, National Institute Citalopram II Leigh J Beglinger, 16 weeks of Citalopram on tolerability, functional United MPH: 319-353-4411 of Neurological PhD measures, motor performance, and psychiatric States Disorders and status Open until Dec ’11 Stroke

Open label, single group assignment study to 1 total - N/A Ongoing, National Creatine II Diana Rosas, MD, 12 months further assess the long-term safety and United recruitment Institutes of MS tolerability of up to 30 grams of creatine daily States complete Health in Huntington disease participants

Open-label, randomized, parallel group 6 total - Goran Siena Biotech Selisistat, I Francis Walker, MD 14 days design at one dose level of SEN0014196 in United Westerberg,PhD: SEN0014196 early stage Huntington disease patients States gwesterberg@ sienabiotech.it

Randomized, double blind, placebo controlled 6 total - Goran Siena Biotech Selisistat, I Bernhard 14 days parallel group design at two dose levels of Europe Westerberg,PhD: SEN0014196 Landwehrmeyer, SEN0014196 in early-stage Huntington disease gwesterberg@ MD patients sienabiotech.it **All studies are currently enrolling, unless otherwise noted Sources: www.clinicaltrials.gov and World Health Organization

NAME: Prana Biotechnology

HEADQUARTERS: Parkville, Victoria, Australia

STOCK PRICE AS OF 10/05/11: $1.59 52 WEEK RANGE: $1.13-4.50

MARKET CAPITALIZATION AS OF 10/05/11: $42.4 million Geoffrey Kempler, CEO Prana Biotechnology EMPLOYEES: Approximately 10!

Prana Biotechnology’s research is driven by the hypothesis that metal protein attenuating compounds bind transition metals and prevent oligomerization of amyloid proteins in Alzheimer disease and of the huntingtin protein in Huntington disease. Prana Biotechnology CEO Geoffrey Kempler sat down with HD InsightsTM at the World Congress on Huntington’s Disease to discuss Prana’s research in neurological disease modiﬁcation. Excerpts from the discussion are below.

INSIGHTS: Could you tell us a little bit about Prana?

KEMPLER: Prana began in 1997 as a private company through some seed capital ﬁnancing that came in from myself and a friend of mine, Barry Lieberman. We became interested in some work that was happening at Harvard Mass General. The work was on the amyloid protein and the role of metals in facilitating the aggregation of this protein into oligomers and plaques.

What we were doing was considered heretical because we were really the ﬁrst group to start to understand the metal binding sites on these proteins, and that these metals were driving the aggregation of the proteins.

We supported our research very privately. We had a peripheral concept growing that was already available in the market and matched our scientiﬁc theory. There, we could do that concept work.

By us understanding the mechanism that’s behind protein aggregation, we’ve been able to drive an enormous amount of academic publications through our support laboratories at Harvard, here in Melbourne at the Mental Health Research Institute and the University of Melbourne, and at some other collaborations we’ve had in various parts of the world.

INSIGHTS: It makes a lot of sense that a company like yours might be interested in Alzheimer disease, which has a very large market. Tell us why you are interested in Huntington disease.

KEMPLER: You imagine that companies always look at market size and market opportunity, and that’s true. I don’t want in any way diminish that as a focus. We know that cognition is one of the key areas of deﬁcit in Huntington disease patients. We know that it’s a major aspect of Alzheimer disease, but we also know that there’s some normal cognitive decline that comes just with the aging process even if you don’t have either of these diseases.

KEMPLER, cont.: In the animal experiments that we’ve done, we’ve demonstrated that our drug PBT2 actually had profound effects on a memory test that we gave to old mice that were not transgenically modified to have either Alzheimer disease nor Huntington disease. These mice were able to effectively complete the task post-treatment with the drug as effectively as young healthy mice. It told us that the drug would be useful wherever there is a cognitive deficit, particularly where that cognitive deficit emphasizes executive function deficit, such as early in the disease process.

INSIGHTS: So among the disorders that affect cognition, what attracted you speciﬁcally to Huntington disease?

KEMPLER: I think it was the advocacy of the Huntington disease researches. We have been approached by different researchers and different diseases, and we’re a little company so we can’t take on everything. But the people in Huntington disease were able to instill their conﬁdence of our own drug in this indication. From a pragmatic perspective we saw that it was a disease where we could come along, present our case, get some attention, and actually see if we can bring beneﬁt to patients.

INSIGHTS: Where there any researchers in particular who were especially strong advocates?

KEMPLER: I think I would have to certainly begin with Professor Ira Shoulson from Georgetown University, who had a lot of inﬂuence in our thinking, as well as Steve Hersch from Massachusetts General Hospital in Boston.

INSIGHTS: What did they do to persuade you?

KEMPLER: They were able to look at our data, explain the relevance of it to Huntington disease patients, and work with our scientists to generate new data. They were able to prepare feedback on what we’d produced and what others had produced, and really helped us understand that we might have a unique position with our drug.

INSIGHTS: There’s only one FDA approved treatment for HD right now. You are also aware that the Dimebon study failed to show beneﬁt on cognition relative to placebo. How did that affect your thinking about coming into with a new compound to look at cognition in Huntington disease?

KEMPLER: We’ve spent so long on the outside of the accepted paradigms that we’re quite comfortable living in that little space. We feel that we’re likely to be in a pretty small group if not a bit unique amongst the drugs that actually have some promise.

INSIGHTS: Looking forward, what are your hopes for Prana and for Huntington disease?

KEMPLER: My big hope for Prana is that the many, many years of dedicated effort by outsiders, our staff, the investors, and by the community patient groups that have cooperated in our clinical trials and in our advocacy will be rewarded by PBT2 in the ﬁrst instance. Getting approval for a drug that could bring cognitive beneﬁt to patients with Huntington disease will parallel our ongoing important work in Alzheimer disease.

We actually have an entire strategy that’s probably gone for the very high bar, and that’s to deal with the actual underlying disease process that’s behind each of these diseases.

My hope for Prana in the very short-term is that we’ll be seen by the Huntington disease community as the drug in Phase II that appeared out of nowhere because it was from an Alzheimer universe.

HD I NSIGHTSTM THANKS L UNDBECK FOR ITS GENEROUS SUPPORT

Our mission is to promote, disseminate, and facilitate research in Huntington disease by producing content that will be valuable and informative to the global community of HD researchers in academia and industry. To fulfill this mission, we have assembled a distinguished editorial board, outstanding writers, and a first rate production team. The editorial board represents four continents and has representatives of academia, industry, and the HD community. Our writers are some of the rising stars in HD research, and our production team has creative and dedicated individuals with diverse talents. In each issue, we will bring you insights from the leading scientists, innovators, and companies developing therapeutics for HD. In addition, we will keep you current on the emerging science, the proceedings from major HD meetings, and clinical trials in the field.

The genesis of HD InsightsTM came from the Huntington Study Group, which saw a need to disseminate research in the ﬁeld, and from Lundbeck, which provided a generous unrestricted educational grant to help launch this periodical.

In our ﬁrst year we plan on producing three issues timed to national and international meetings of HD researchers. To receive a free subscription to HD InsightsTM, simply email [email protected] with your name and organization. All of our content as well as bios and disclosures are available online at www.hdinsights.org.

As a new periodical aimed at meeting the needs of our readers, we are especially interested in your thoughts and suggestions for people to interview, events to cover, and ideas to explore. Also as a new periodical, we are eager to secure support to make HD InsightsTM an enduring periodical that informs and motivates over 1000 scientists, physicians, and drug developers speciﬁcally interested in HD. If you have ideas, want to contribute, or are eager to support, please contact me at [email protected].

Together we can advance research and eventually therapeutics for Huntington disease.

-- R AY D ORSEY, MD E DITOR, HD I NSIGHTSTM

Editorial Board Members Contributors Ray Dorsey, MD — Editor, Johns Hopkins University Emily Fisher Donald Kennedy, PhD — Stanford University Alicia Semaka, M.Sc. Nobuyuki Nukina, MD, PhD — Riken Brain Science Institute Mahmoud Pouladi, PhD Rodrigo Osorio — Agrupacion Chilena de Huntington Lise Munsie Bernard Ravina, MD — Biogen Idec Kristin Darwin, BS Ralf Reilmann, MD — University of Munster Paige Nichols, BA Sarah Tabrizi, MBChB, PhD — University College London Leslie Thompson, PhD — University of California Irvine Publication Staff Robin Taylor — Production Editor Huntington Study Group Martin Holmes — Technical Editor Shari Kinel, JD — HSG Executive Director Todd Bernhard — Copy Editor Liz McCarthy, BA — HSG Administrative Manager Vinayak Venkataraman, BS — Website Designer Jillian Lowell, BS — HSG Event Planner Dave Kolko — Distribution Specialist

For more information on HD InsightsTM, please visit us at www.HDInsights.org