Volume 7

HD Insights Volume 7 (PDF)

Meet the Investigator

Dr. Kathleen Clarence-Smith

Dr. Kathleen Clarence-Smith


NAME: Kathleen (Kitty) Clarence-Smith, MD, PhD

CURRENT POSITION: Chairman of the Board of Chase Pharmaceuticals; Partner, KM Pharmaceuticals Consulting (clients include Lundbeck).

EDUCATION: MD and PhD in Neurosciences, Université de Tours, France; Residency in Neurology, Salpêtrière, Paris, France; post-doctoral fellowship at Johns Hopkins University School of Medicine, Department of Pharmacology and Experimental Therapeutics.

HOBBIES: Reading, currently Walter Isaacson’s Steve Jobs.

Dr. Kathleen Clarence-Smith has dedicated her career to developing novel pharmaceuticals and bringing them to market. As the founder and CEO of Prestwick Pharmaceuticals, she helped bring tetrabenazine, the first FDA approved treatment for HD, to the US. She has held senior positions in major pharmaceutical companies (Roche, Sanofi, and Otsuka) and authored over 100 peer-reviewed publications. Dr. Clarence-Smith discussed the history and future of HD therapies with HD Insights. The following is an edited transcript of the conversation.

HD INSIGHTS: How did you first become interested in HD?

CLARENCE-SMITH: I read a Victorian novel when I was nine years old, the diary of somebody who knew that one of his parents had a disease that he would also have. The book ends with, “This is where I stop; I now have the shakes.” I thought it was a horrible disease, since you knew exactly what was going to happen to you, and then it happened. And of course, as I read the diary as a child, I kept hoping that it would turn out that he didn’t have the un-named disease. Much later, when I studied medicine, I realized that the disease I had read about in my childhood must have been HD. When I was 20, I knew a family who had HD, and was again confronted with the sadness and concerns about the children faced by families affected by this disease. I had absolute faith that biochemistry could find a drug that would stop or slow the disease.

HD INSIGHTS: As founder and CEO of Prestwick Pharmaceuticals, you were instrumental in bringing tetrabenazine to market in the United States. Did you ever think that your interest in finding a biochemical treatment for HD would lead to an approved drug?

CLARENCE-SMITH: No, I never thought of that in those days. I just knew that I wanted to find a cure, and I kept hoping that I would either read something in the literature which would point to the cure, or that I would be able to do real research into finding the cure.

HD INSIGHTS: How did you become interested in tetrabenazine?

CLARENCE-SMITH: I met Dr. Joseph Jankovic at a meeting, and he knew that I was working on trying to get drugs approved by the FDA. He wanted more than anything to see tetrabenazine approved in this country. I called the company who manufactured tetrabenazine in Europe and managed to convince them that it was possible to get this drug approved in the United States, and I was able to raise money to do it.

HD INSIGHTS: What are the current limitations of tetrabenazine?

CLARENCE-SMITH: It seems to only treat chorea, and clearly we also need treatments for the cognitive impairment and behavioral symptoms seen in HD. It remains to be seen whether we need three different treatments, or one yet-to-be-discovered therapy for all the disease symptoms. A lot more work needs to be done to understand the physiopathology of the cognitive impairment. For behavioral symptoms, I think that tetrabenazine has not been completely studied. I would have expected that a drug such as tetrabenazine that acts on the dopamine axis would also improve behavioral symptoms. Today, I’m leaning towards a need for three treatments, but sometimes you get surprised in drug discovery and development.

HD INSIGHTS: Tetrabenazine is usually prescribed three times daily and has some side effects. Are there ways that the drug can be improved?

CLARENCE-SMITH: Yes. I am a consultant to Lundbeck, who markets the drug in the USA, and I have been examining this problem for the past two months. I think that some of the side effects are related to the very interesting pharmacokinetic profile of tetrabenazine. It has a very sharp peak, and a short half-life. Some of the side effects – sedation in particular – are likely linked to this sharp peak, so if it were possible to blunt the peak with a novel formulation, you might ameliorate some of the side effects. It would also be nice to extend the duration of action. If you look at the pharmacokinetics, patients are rapidly getting on, and then rapidly getting off.1 That fluctuation seems very uncomfortable for patients. A formulation that could both blunt the peak and prolong the duration of action would improve patient experiences with tetrabenazine.

HD INSIGHTS: Do you have any advice for innovators who are looking to develop new pharmaceutical treatments for HD?

CLARENCE-SMITH: I think one of the most difficult obstacles to getting innovative drugs from bench to market is the transition between the lab bench and the clinic. Preclinical people work on new drugs in the lab, in rats and mice and primates, and then the drug passes to the clinic to be tested in patients. That transition is often not well negotiated. Usually, not enough work is done on the animal model, leading to an incomplete understanding of what may be expected in humans. You must completely and critically understand the animal model information to know what to do in patients. For example, humans sometimes have different enzymes and different ways of metabolizing drugs than animal models. I remember a drug developed about 40 years ago that was a miracle drug for treatment of myocardial infarct in dogs, but when it was used in humans, it was absolutely inactive. It turned out that the drug’s effectiveness depended on an enzyme present in dogs, but not in humans. The other thing is that while patients participate in clinical trials at all stages of the disease, animal models are usually treated at the same stage of the disease. You really should study your drug in many stages of the disease in animals first, to measure the stage beyond which it is not going to help. For example, if the animal models were to show that the drug always slows the disease whenever you start treatment, why would you not also enroll individuals with more advanced disease in your

studies? But if the animal model were to show that it only works if you give it early, then you do not want to enroll patients at an advanced stage in your trials because you will get a negative result. And it will be unfair to the patients – this drug could have worked if it had been studied properly.

HD INSIGHTS: Dr. Clarence-Smith, thank you for bringing the first FDA-approved treatment for HD to market, and for your continued efforts in developing new therapeutics for HD and other conditions.


1 Kenney C, Hunter C, Davidson A, Jankovic J. Short-term effects of tetrabenazine on chorea associated with Huntington’s disease. Mov. Disord. 2007;22(1):10–13. doi: 10.1002/mds.21161.

PREDICTions: Using High-Performance Computing to Visualize the HD Brain

By: Hans Johnson, PhD

For more than a decade, the PREDICT-HD study has followed approximately 1,400 individuals around the world, including both premanifest carriers of the mutant Huntingtin allele and normal control individuals, in an attempt to identify the earliest signs of HD. PREDICT investigators at 28 sites obtain yearly MRI scans and cognitive, behavioral, and physical assessments. This enormous dataset has spurred researchers at the University of Iowa to develop novel algorithms and apply advanced computing techniques to the analysis of this imaging data. Dr. Hans Johnson, Director of the Image Processing Lab at Iowa Mental Health Clinical Research Center, is the chief technical officer for the study. Here, he describes some of the advanced computing techniques currently utilized to analyze thousands of MRIs to identify and characterize HD-related changes in the brain.

The Scalable Informatics, Neuroimaging, Analysis, Processing and Software Engineering (SINAPSE) group focuses primarily on creating specialized software tools to efficiently process and analyze enormous quantities of neuroimaging data to accelerate brain research. SINAPSE has identified novel imaging markers of early HD using high-performance computing to analyze multi-modal brain scans.1 High performance computing refers to the use of supercomputers or computer clusters to solve advanced computation problems too complex for single workstations.

figure 1Between November 2012 and March 2013, the group analyzed approximately 5,000 brain images from both control individuals and individuals with premanifest HD. More than 350 compute years (one compute year equals one computer running full-time for one year) were applied, producing more than 40 terabytes of intermediate data. One analysis lead to the development of individualized brain atlases that depict brain structure and enable detailed analysis of changes over time (Figure 1). In another project, the group used high-performance computing resources with FreeSurfer, a software program that integrates hundreds of MRI images to create three-dimensional digital reconstructions of the brain, to separate white matter areas from the rest of the brain in over 200 MRI scans from individuals with premanifest HD.2 As large-scale, international observational studies continue to generate large amounts of imaging data, the ability to quickly and accurately process these data will become essential to timely analysis and reporting.

Data from PREDICT continue to be cataloged and shared with HD clinicians and researchers worldwide, and can be combined with data from other HD studies to explore relationships between brain imaging markers and clinical, psychiatric, movement, mood, and genetic aspects of HD. (For a list of publications, visit PREDICT-HD Publications and Presentations.) Multiple avenues of exploration of HD progression have emerged from the imaging data, including white matter changes, grey matter loss, white matter tractography, default mode compensatory networks, and functional connectivity.2-5 In the future, these analyses may contribute to a more precise, objective measure of the progression of HD that could inform the design of clinical trials of novel therapeutic agents.

HD Insights would like to thank Amanda Miller, LMSW, Jeffrey Long, PhD, and Dawei Liu, PhD, for their assistance in preparing this article.

Editor’s Desk: Randomized Controlled Trials in Populations At Risk for HD

At the HSG 2013 HD Clinical Research Symposium, Kevin Biglan, MD, MPH, Associate Professor of Neurology at the University of Rochester Medical Center, presented the results of the PREQUEL study, which evaluated the safety and tolerability of three different doses of Coenzyme Q10 (CoQ10) in individuals with premanifest HD (see HD Insights, Vol. 6). Retention of study participants was approximately 93% and CoQ10 was well tolerated in the study. Serum CoQ10 levels increased, but a biomarker of oxidative stress remained unchanged.6The study’s Principal Investigator, Chris Ross, MD, PhD, Professor of Psychiatry, Neurology and Neuroscience at Johns Hopkins Medicine, commented that the study will “greatly increase the feasibility of [future] trials” in this population and is “complementary to [the approach] of the PRECREST study.”

The PRECREST study, published online in Neurology earlier this month, investigated the safety and tolerability of high-dose creatine in 64 individuals with pre-manifest HD and 50% at-risk for HD. Ten of the 32 individuals randomized to creatine discontinued participation in the placebo-controlled phase. Neuroimaging results showed treatment-related slowing of cortical and striatal atrophy. Together, both studies lay the foundation for broad participation and evaluation of individuals who are at risk for HD in future, possibly preventive, clinical trials.7


1 Harrington D, Liu D, Smith M, et al. Neuroanatomical correlates of cognitive functioning in prodromal Huntington disease. Brain and Behavior. 2014 Jan; 4(1):29-40.

2 Nopoulos PC, Aylward EH, Ross CA, et al. PREDICT-HD Investigators Coordinators of Huntington Study Group (HSG) (2010). Cerebral cortex structure in prodromal Huntington disease. Neurobiol Dis. 2010 Dec;40(3):544-54. doi: 10.1016/j.nbd. 2010.07.014. Epub 2010 Aug 2.

3 Nopoulos P, Magnotta VA, Mikos A, et al. Morphology of the cerebral cortex in preclinical Huntington’s disease. Am J Psychiatry 2007;164(9):1428-34. doi:10.1176/appi.ajp. 2007.06081266 !

4 Paulsen, Jane S. Functional imaging in Huntington’s disease. Exp Neurol. 2009 Apr;216(2):272-7. doi: 10.1016/j.expneurol. 2008.12.015. Epub 2009 Jan 3.

5 Aylward E, Liu D, Nopoulos P, et al. Striatal volume contributes to the prediction of onset of Huntington disease in incidence cases. Biol Psychiatry. 2012 May 1;71(9):822-8. doi: 10.1016/j.biopsych.2011.07.030. Epub 2011 Sep 9.

6 Killoran A, Biglan KM, Beal F, et al. The PREQUEL Multi-Center Phase II Study of Coenzyme Q10 in Pre-Manifest Huntington Disease. [abstract] 2013 Annual Meeting of the American Neurological Association. 2013 Oct. 13-15.

7 Rosas HD, Doros G, Gevorkian S, et al. PRECREST: A phase II prevention and biomarker trial of creatine in at-risk Huntington disease. Neurology. 2014 Feb 7. [Epub ahead of print]

Meet the CEO

Dr. Pratik Shah

Dr. Pratik Shah


NAME: Pratik Shah, PhD, MBA

CURRENT POSITION: President, Chief Executive Officer, and Director of Auspex Pharmaceuticals

EDUCATION: PhD in Biochemistry and Molecular Biology and MBA, University of Chicago.

HOBBIES: Spending time with family, traveling the west coast, and reading; recently finished Michael Lewis’ Boomerang.

Dr. Shah strives to integrate his training in the biological sciences with his training in finance in order to bring new therapies to patients with unmet medical needs. In addition to his work with Auspex, Dr. Shah serves on several boards of companies in the life sciences. He served as founding investor in a company called CNS Therapeutics, which focused on developing intrathecal pharmaceuticals. He also co-founded a company building high-end robots to automate pharmaceutical research and spent time at McKinsey & Company serving a variety of clients in the pharmaceutical and medical products area.

Editor’s Letter

Welcome to the latest edition of HD Insights, released at the 9th Annual CHDI Huntington’s Disease Therapeutics Conference. HD Insights brings you the latest in HD research, and we are grateful to the HSG, our sponsors, and our more than 1500 subscribers for their continuing support of this mission.

Throughout this issue, we explore the past, present, and future of tetrabenazine, the first FDA-approved treatment for HD. We profile Dr. Kathleen Clarence-Smith, who championed the approval of tetrabenazine by the FDA. We explore Auspex Pharmaceuticals’ lead compound SD-809, a deuterated analogue of tetrabenazine currently in phase III clinical trials. Dr. Pratik Shah, CEO of Auspex, comments on the company’s current projects and describes his hopes for the future. And Dr. Lise Munsie brings you a round-up of current research in HD, including new insights into the mechanisms of tetrabenazine. Also in this issue, we are pleased to feature the highlights of 2013’s HSG Annual Meeting and Clinical Research Symposium, brought to you by Dr. Christina Vaughan. Dr. Hans Johnson describes the use of high-performance computing in the analysis of PREDICT-HD imaging data, and we examine the results of two recently completed randomized controlled drug trials in premanifest HD. We continue to update you on the status of clinical trials, and to give you a glimpse into HD research in Canada.

The HD community is fortunate to benefit from the increasing number of sponsors developing novel therapies for HD. HD Insights relies on the support of these firms to bring their leaders, their compounds, and their research to more than 1500 readers around the globe. If you are interested in becoming a supporter, please contact me at editor@hdinsights.org

We welcome new contributors, suggestions for topics, and suggestions for how we can better serve you. If you or someone you know is interested in contributing to HD Insights, or if you have ideas that you would like to share with 1500 HD researchers and clinicians around the world, please contact me at editor@hdinsights.org . Finally, subscription to HD Insights is always free: simply send us an email at subscribe@hdinsights.org










Ray Dorsey, MD



Editorial Board Members

Ray Dorsey, MD — Editor, University of Rochester

Donald Kennedy, PhD — Stanford University

Nobuyuki Nukina, MD, PhD — Riken Brain Science Institute

Rodrigo Osorio — Agrupacion Chilena de Huntington

Bernard Ravina, MD — Biogen Idec

Ralf Reilmann, MD, PhD — George Huntington Institute

Sarah Tabrizi, MBChB, PhD — University College London

Leslie Thompson, PhD — University of California Irvine

Huntington Study Group

Shari Kinel, JD — HSG Executive Director

Liz McCarthy, BA — HSG Administrative Manager


Meredith Achey, BM

Hans Johnson, PhD

Lise Munsie, PhD

Christina Vaughan, MD, MHS

Publication Staff

Meredith Achey, BM — Deputy Editor

Robin Taylor — Production Editor

Martin Holmes — Technical Editor

Dave Kolko — Distribution Specialist

For more information on HD Insights, or to receive a free subscription, please visit us at www.hdinsights.org  or email us at editor@hdinsights.org .

Research Round-Up

By: Lise Munsie, PhD

In cell biology…

The exact molecular mechanism of the huntingtin (Htt) protein is largely unknown. A paper from Dr. Solomon Snyder’s lab at Johns Hopkins that probes the link between Htt and the striatal-specific protein Rhes was recently published in the Journal of Biological Chemistry.1 This paper implicates Rhes in mTOR-independent autophagy, and demonstrates that binding of mutant Htt (mHtt) with Rhes inhibits the autophagic function of Rhes in a PC12 cell model. Autophagy becomes more important in aging cells; therefore, alterations to Rhes in HD could explain striatal-specific degeneration, as well as the late-onset characteristics of HD.

Transcriptional dysregulation is another known factor in the progression of HD. A recent report in Human Molecular Genetics from McFarland and colleagues describes the binding of Htt to the transcription factor MeCP2, using fluorescence lifetime imaging to measure Förster resonance energy transfer (FLIM-FRET).2 This report indicates that Htt binds to MeCP2, primarily in the nucleus. Binding of MeCP2 with Htt is enhanced in the presence of mHtt and may be involved in the change in BDNF levels that are characteristic of HD.

Another major theme in HD pathology is energetic defects due to mitochondrial dysfunction. Gouarné and colleagues report on mitochondrial respiratory function in different neuronal populations in a rat model of HD in their recent paper published in PLOS ONE.3 The oxygen consumption rate and extracellular acidification rate were reduced in striatal neurons, but not in cortical neurons in the presence of physiological factors, indicating a specific defect in glycolysis in the striatal neurons.

1 Mealer RG, Murray AJ, Shahani N, et al. Rhes, a striatal-selective protein implicated in Huntington disease, binds Beclin-1 and activates autophagy. J Biol Chem. 2013 Dec 9;doi:10.1074/jbc.M113.536912jbc.M113.536912.

2 McFarland KN, Huizenga MN, Darnell SB, et al. MeCP2: a novel Huntingtin interactor. Hum Mol Genet. 2013 Oct 18;doi: 10.1093/hmg/ddt499.

3 Gouarné C, Tardif G, Tracz J, et al. Early deficits in glycolysis are specific to striatal neurons from a rat model of Huntington disease. PLOS ONE. 2013 Nov 26; 8(11): e81528. doi:10.1371/journal.pone. 0081528.

In pharmaceuticals…

pharmTetrabenazine (TBZ), a catecholaminedepleting agent first used for the treatment of schizophrenia, has great efficacy in hyperkinetic movement disorders. However, its mechanism of action remains incompletely understood. TBZ noncompetitively inhibits VMAT2, and Ugolev and colleagues recently uncovered additional mechanisms involved in the compound’s interaction with VMAT2.1 Using directed evolution and mutant isolation in yeast, the group found conserved glycine and proline residues that are required for TBZ binding, and found that the binding site for TBZ is distinct from the substrate binding site on VMAT2.

TBZ can cause parkinsonian symptoms due to a decrease in dopamine D2 Receptor transmission. A report by Podurgiel and colleagues in Neuroscience looks at tremulous jaw movements in rats, which are mimetic of parkinsonian tremor. The report aims to determine whether A2a antagonists could attenuate tremulous jaw movements induced by TBZ.2 The researchers found that MS3-X or A2a knockout attenuates tremulous jaw movements; therefore, an A2a inhibitor could be used in concert with TBZ as an anti-parkinsonian drug.

Shen and colleagues examined the long-term safety and efficacy of TBZ in an observational open-label study of 145 patients who were followed for one to 11 years. Patient response to TBZ did not vary based on the severity of chorea nor concomitant drug use. The most common adverse events reported were somnolence, insomnia, depression, accidental injury, and dysphagia. The study concluded that TBZ is nevertheless safe and effective for the treatment of chorea in HD patients.3

1 Ugolev Y, Segal T, Yaffe D, et al. Identification of conformationally sensitive residues essential for inhibition of vesicular monoamine transport by the noncompetitive inhibitor tetrabenazine. J Biol Chem. 2013 Sep 23; 288:32160-32171.

2 Podurgiel SJ, Nunes EJ, Yohn SE, et al. The vesicular monoamine transporter (VMAT-2) inhibitor tetrabenazine induces tremulous jaw movements in rodents: implications for pharmacological models of parkinsonian tremor. Neurosci. 2013 Oct 10;(250): 507-519.

3 Shen V, Clarence-Smith K, Hunter C, Jankovic, J. Safety and efficacy of tetrabenazine and use of concomitant medications during long-term, open-label treatment of chorea associated with Huntington’s and other diseases. Tremor Other Hyperkinet Mov. 2013 Oct 22; 3. pii: tre-03-191-4337-1.

In neuroscience…

brainHuntingtin (Htt) has important effects on the specific properties of nerve cells. Xu and colleagues designed an elegant mouse model that selectively expresses exon1 mutant Htt (mHtt) in synaptic terminals, achieved by tagging mHtt to SNAP25.1 Their results show that this model has age-dependent neurological symptoms of HD, and alterations in synaptic transmission. They also show that Htt can bind the polyproline-rich regions of synapsin-1. Alterations to this binding by mHtt may be responsible for pre-synaptic defects.

A recent paper published by Parsons and colleagues finds a presynaptic role of wildtype Htt.2 In the YAC18 mouse model there is an increase in the amount of synaptic PSD95, and the size of the PSD95 clusters in medium spiny neurons cocultured with cortical neurons. This effect was observed in medium spiny neurons even when only the cortical neurons were over-expressing Htt, indicating a presynaptic effect leading to alterations in PSD95. This increase in PSD95 clustering occurs concomitant with an increase in palmitoylation of PSD95, and requires the actions of brain-derived neurotrophic factor. Consequently, the effects of Htt on synaptic architecture need to be further studied, because Htt knockdown is currently a promising pharmacological approach for treatment of HD.

Finally, Wojtowicz and colleagues examine astrocytes, a currently understudied part of neuronal circuitry with respect to HD. They found that the release of nonsynaptic GABA from depolarized astrocytes, by the action of GAT-3, is strongly reduced in HD mice.3 This suggests that regulating GAT-3 may be a therapeutic target for HD symptoms.

1 Xu Q, Huang S, Song M, et al. Synaptic mutant huntingtin inhibits synapsin-1 phosphorylation and causes neurological symptoms. J Cell Biol. 2013 Sep 30;202(7):1123-1138.

2 Parsons MP, Kang R, Buren C, et al. Bidirectional control of postsynaptic density-95 (PSD-95) clustering by huntingtin. J Biol Chem. 2013 Dec 17; doi: 10.1074/jbc.M113.513945jbc.M113.513945.

3 Wojtowicz AM, Dvorzhak A, Semtner M, Grantyn R. Reduced tonic inhibition in striatal output neurons from Huntington mice due to loss of astrocytic GABA release through GAT-3. Front Neural Circuits. 2013 Nov 26; 7:188. doi: 10.3389/fncir.2013.00188.

Prana Releases Promising Results

Prana Biotechnology released promising results from its phase 2 study of PBT2 in individuals with mild to moderate Huntington disease. In a randomized, double-blind, placebo-controlled study, 104 (95%) of 109 study participants completed the 26-week study on one of the three study arms – PBT2 250mg daily, PBT2 100mg daily, or placebo. Serious adverse events were more common in those on active drug (nine) than on placebo (one), but only one was deemed by site investigators to be related to study drug.

In addition, on the principal secondary efficacy endpoints, Prana reported a statistically significant improvement on the Trail Making Test Part B, a test of executive function, in those randomized to PBT2 250mg. These results were similar to Prana’s earlier phase 2 study in Alzheimer disease in which those randomized to PBT2 250mg had statistically significant improvements on both the Trail Making Test Part B and the Category Fluency Test. In the Huntington disease study, the improvement in executive function, which is impaired early in the disease, was also accompanied by a small, favorable signal in a key measure of functional capacity. No significant improvements were seen on other secondary efficacy measures in the study. A small (n=6) pilot imaging sub-study suggested reduced brain atrophy in those exposed to PBT2.

PBT2 is a metal-protein attenuating compound that may affect metal mediated oligomerization of huntingtin. In the R2/6 mouse model of Huntington disease, daily oral administration of PBT2 improved motor performance of the mice, increased body and brain weight, and increased the lifespan of the mice by 26%. The phase 2 study was the first assessment of the drug in individuals with Huntington disease.

Dr. Diana Rosas, an Associate Professor of Neurology at Harvard Medical School and the study’s co-principal investigator, said, “I am very excited about (the study)… the drug is targeting a key pathological process that has been identified as significant in (HD) in both transgenic mouse models and in human disease, (and) in as little as six months, we were able to measure a potential clinical benefit and most importantly a potential slowing of progression… Finally, the addition of novel potential biomarkers, one of the first multi-center studies to do this, is also very exciting and provocative.

In its press release on the study results, Prana indicated that it plans to advance PBT2 to a pivotal phase 3 clinical trial.


1 Prana Biotechnology. Prana announces successful phase 2 results in Huntington disease trial. (press release)

2 Lannfelt L, Blennow K, Zetterberg H et al. Safety, efficacy, and biomarker findings of PBT2 in targeting Abeta as a modifying therapy for Alzheimer’s disease: a phase IIa, double-blind,

randomised, placebo-controlled trial. Lancet Neurol 2008;7:779-86.

3 Cherny RA, Ayton S, Finkelstion DI et al. PBT2 reduces toxicity in a C. elegans model of polyQ aggregation and extends lifespan, reduces striatal atrophy and improves motor performance in the R6/2 mouse model of Huntington’s disease. J Hunt Dis 2012; 1:211-219.

Meet the Company

auspexhomeVITAL SIGNS

NAME: Auspex Pharmaceuticals


STOCK PRICE AS OF 2/13/2014: $22.20


EMPLOYEES: about 20

Pratik Shah, PhD, MBA, is the President, Chief Executive Officer, and Director of Auspex Pharmaceuticals. He came to Auspex in 2007 as an investor, and has since led the company as Chairman or Executive Chairman to shape its focus on Huntington disease and other orphan indications. “I first got involved in Auspex because I was intrigued by the possibility of improving drugs using a new technology (deuteration),” he said. “I was compelled by the opportunity to bring SD-809 to the market. It’s rare to get a chance to be involved all the way from the discovery of the drug to its ultimate commercialization. I consider this a blessing.” Dr. Shah recently shared with HD Insights Auspex’s current work, its recently completed Initial Public Offering (IPO) and his hope for the company’s future. Below is an edited transcript of his thoughts.

HD INSIGHTS: What is the value of deuteration of pharmacological agents?

SHAH: The side-effects, problematic drug-drug interactions, and patient to patient variability of certain drugs are driven by their short half-life, and removal from the body by liver enzymes. These issues can create challenges for patients and physicians.

It’s really remarkable how a small change of hydrogen to its heavy isotope deuterium, when engineered into exactly the right molecule at exactly the right positions, doesn’t just change the drug – it has the potential to transform the drug. It does so by slowing down the elimination of the drug from the body, reducing fluctuations in blood levels. These transformations can be achieved without changing the drug’s binding to the target, and therefore its efficacy. If a drug is better tolerated or is needed fewer times per day, it can be used by more patients, and create a better experience for patients and families.

HD INSIGHTS: Why deuteration of tetrabenazine?

SHAH: While tetrabenazine is a very efficacious drug, it is a textbook case of a short half-life drug with resulting limitations. Our Chief Medical Officer was the head of development at Prestwick Pharmaceuticals, and led the effort to receive FDA approval of tetrabenazine. He recognizes that there is more work to be done for treating patients with chorea. Auspex has been working to use deuteration to solve these challenges, and while deuteration has been applied to other treatments by a number of companies in various stages of clinical development, we believe that Auspex’s SD-809 program is the most advanced so far.

Possible benefits of deuteration of tetrabenazine include lower dose, less frequent administration, the potential for better tolerability & safety, reduced drug-drug interactions, reduced need for genotyping, reduced inter-patient variability, and reduced potential for QT prolongation. As a result, we hope to be able to take SD-809 into areas where tetrabenazine was never formally developed such as Tourette syndrome and tardive dyskinesia. In addition to a Phase 3 clinical trial with individuals with HD, we are embarking on a Phase 2/3 trial in tardive dyskinesia, and a Phase 1b preliminary safety & efficacy study in adolescents with tics associated with Tourette syndrome. We have seen promising data with our human studies comparing SD-809 to tetrabenazine so far. These results have been encouraging, and we are hoping to further understand the impact of deuteration by conducting the First-HD and ARC-HD clinical trials.

HD INSIGHTS: On February 5, 2014, Auspex completed an IPO listing on the NASDAQ Exchange. On the first day of trading, the company’s stock price opened at $15.00 and closed at $15.66 and raised $84 million for the company. What does the IPO mean for Auspex?

SHAH: This important milestone in the progress of our company further enables us to deliver on our mission to develop and commercialize new therapies for patients with HD, a variety of movement disorders and other orphan diseases. The IPO also makes more visible our long-term commitment to develop treatments for HD, and gives the company additional resources to support education and awareness initiatives.

HD Research around the World: Canada

By: Lise Munsie, PhD

Canada-FlagInvestigators across Canada are heavily involved in HD research; these teams tackle a broad array of HD related research topics ranging from basic cell biology and biochemistry of the huntingtin (Htt) protein, to therapeutic leads and large clinical trials.

On the east coast, Dr. Eileen Denovan-Wright’s lab at the University of Dalhousie focuses on the cell biology of Htt in mouse models. Her group explores altered gene expression and its consequences in the brain. Their current research focuses on cannabanoid receptors. Dr. Denovan-Wright’s group recently published a manuscript that looks at the dysregulation of genes in the cytokine and endocannabinoid systems in HD. They posit that activation of p65/ RelA, which co-regulates expression of cytokine and endocannabinoid receptor genes, may prove beneficial in HD.1

In Ontario, Dr. Ray Truant’s lab at McMaster University is looking at the normal function of Htt and related dysfunction of mHtt, using cell models and biophotonic techniques.Dr. Truant’s lab uses advanced and elegant techniques, described in their recent paper published in Human Molecular Genetics, that looks at fluorescently tagged Htt, in aggregates, in live cells.2 Also in Ontario, Dr. Mark Guttman, a movement disorder neurologist affiliated with the University of Toronto, is heavily involved in PREDICT-HD, as well as caring for HD patients across the province.

In the prairies, Dr. Simonetta Sipione’s lab at the University of Alberta uses a multi-disciplinary approach to study mechanisms behind HD for the drug discovery pipeline. In the past year this group uncovered GM1 as a therapeutic lead for HD treatment.3

Finally, the west coast province of British Columbia is a hotbed for HD research.

The Centre for Molecular Medicine and Therapeutics, affiliated with the University of British Columbia (UBC), houses the labs of Dr. Michael Hayden (see HD Insights, vol. 4) and Dr. Blair Leavitt (see HD Insights, vol. 3). These multi-faceted labs perform advanced HD research, including elucidating molecular mechanisms involved in the progression of HD, using many different mouse models.4 Dr. Hayden’s group has been heavily involved in developing therapeutics for HD, specifically antisense oligonucleotide (ASO) development for in vivo Htt knockdown (see HD Insights, vol. 3).5 In addition to their laboratory work, both Dr. Leavitt and Dr. Hayden are heavily involved in clinical trials, including the TRACKHD study,6 patient-based research, and HD genetic research.7 Also at UBC, Dr. Lynn Raymond’s lab specializes in neuroscience-related techniques including electrophysiology.8 With respect to HD, her group investigates the role of neurotransmitter receptors and the neuron-specific role of Htt and related dysfunction in HD.9

1 Laprairie RB, Warford JR, Hutchings S, et al. The cytokine and endocannabinoid systems are co-regulated by NF-kappaB p65 RelA in cell culture and transgenic mouse models of Huntington’s disease and in striatal tissue from Huntington’s disease patients. J Neuroimmunol. 2013 Dec 12; pii: S0165-5728(13)00339-1. doi: 10.1016/j.jneuroim.2013.12.008.

2 Caron NS, Hung CL, Atwal RS, Truant R. Live cell FRET and protein dynamics reveal two types of mutant huntingtin inclusions. Hum Mol Genet. 2013 Dec 11; doi: 10.1093/hmg/ddt625.

3 Di Pardo A, Maglione V, Alpaugh M, et al. Ganglioside GM1 induces phosphorylation of mutant huntingtin and restores normal motor behavior in Huntington disease mice. Proc Natl Acad Sci USA. 2012 Feb 28; 109(9):3528-33. doi: 10.1073/pnas. 1114502109.

4 Mazarei G, Budac DP, Lu G, et al. Age-dependent alterations of the kynurenine pathway in the YAC128 mouse model of Huntington disease. J Neurochem. 2013 Dec; 127(6):852-67. doi:10.1111/jnc.12350.

5 Ostergaard ME, Southwell AL, Kordasiewicz H, et al. Rational design of antisense oligonucleotides targeting single nucleotide polymorphisms for potent and allele selective suppression of mutant Huntingtin in the CNS. Nucleic Acids Res. 2013 Nov; 41(21):9634-50.

6 Franciosi S, Shim Y, Lau M, Hayden MR, Leavitt BR. A systematic review and meta-analysis of clinical variables used in Huntington disease research. Mov Disord. 2013 Dec;28(14): 987-94. doi: 10.1002/mds.25663.

7 Semaka A, Hayden M. Evidence-based genetic counselling implications for Huntington disease intermediate allele predictive test results. Clin Genet. 2013 Nov 20; doi: 10.1111/ cge.12324.

8 Milnerwood AJ, Parsons MP, Young FB, et al. Memory and synaptic deficits in Hip14/DHHC17 knockout mice. Proc Natl Acad Sci USA. 2013 Nov 25; 110:20296-20301.

9 Parsons MP, Kang R, Buren C, et al. Bidirectional control of postsynaptic density-95 (PSD-95) clustering by huntingtin. J Biol Chem. 2013 Dec 17; doi: 10.1074/jbc.M113.513945jbc.M113.513945.

If you are interested in contributing a piece that highlights research in your part of the world, please contact us at editor@hdinsights.org.

Meet the Compound: SD-809 (dutetrabenazine)

Image source: Auspex Pharmaceuticals, Inc. United States Securities and Exchange Commission Form S-1: Registration Statement. Filed December 20, 2013. www.nasdaq.com/markets/ipos/filing.ashx?filingid=9241956 . Accessed January 21, 2014.

Image source: Auspex Pharmaceuticals, Inc. United States Securities and Exchange Commission Form S-1:
Registration Statement. Filed December 20, 2013. www.nasdaq.com/markets/ipos/filing.ashx?filingid=9241956 . Accessed January 21, 2014.

Molecular Formula: C19H21D6NO

Molecular Weight: 324 g/mol

Mechanism of Action: Tetrabenazine reversibly inhibits monoamine re-uptake, which depletes monoamines and reduces involuntary movements.1 Auspex Pharmaceuticals, developer of SD-809, has shown that deuteration of tetrabenazine may slow its metabolism and decrease the need for large repeated doses.2,3

A Brief History of Deuterated Pharmaceuticals

By: Meredith Achey, BM

Deuteration, the selective substitution of deuterium for hydrogen in compounds that have known biological effects, can slow metabolism of these compounds by decreasing the rate of chemical reactions required to break down the compound, an effect known as the deuterium isotope effect.4 Deuteration has been explored since the 1960s as a way to potentially decrease toxicity of drug metabolites and extend biological half-life.2,4-8 As evidenced by the failure of several deuterated compounds prepared to date, deuteration can result in unexpected metabolic changes that render some deuterated compounds more toxic or less effective than their non-deuterated analogs (Table 1). However, several pharmaceutical firms have recently begun trials with promising new deuterated formulations, including Auspex Pharmaceuticals’ deuterated analog of tetrabenazine (SD-809) for use in individuals with HD and other hyperkinetic movement disorders. Preliminarily, SD-809 shows similar efficacy to tetrabenazine at lower doses and with a longer duration of action.3 Clinical trials of SD-809 in HD are currently underway.9, 10


1 Paleacu D. Tetrabenazine in the treatment of Huntington’s disease. Neuropsychiatr Dis Treat. 2007 October; 3(5):545–551.

2 Tung R. The development of deuterium-containing drugs. Concert Pharmaceuticals. www.concertpharma.com/news/documents/IPT32ConcertPharma.pdf Accessed Dec 30, 2013.

3 Stamler DA, Brown F, Bradbury M. The pharmacokinetics of extended release SD-809, a deuterium-substituted analogue of tetrabenazine [abstract]. Mov Disord. 2013;28 Suppl 1 :765

4 Harbeson SL, Tung RD. Deuterated drugs as clinical agents. Annu Rep Med Chem. 2011 Oct. 12;46:412-414.

5 Yarnell AT. Heavy-hydrogen drugs turn heads, again. C&EN 2009; 87(25):36-39.

6 Blake MI, Crespi HL, Katz JJ. Studies with deuterated drugs. J Pharm Sci. 1975;64:367–391. doi: 10.1002/jps.2600640306

7 Kushner DJ, Baker A, Dunstall TG. Pharmacological uses and perspectives of heavy water and deuterated compounds. Can J Physiol Pharmacol. 1999 Feb; 77(2):79-88.

8 Sanderson K. Big interest in heavy drugs. Nature. 2009 Mar 19; 458(7236):269.

9 First time use of SD-809 in Huntington disease (First-HD).ClinicalTrials.gov. http://clinicaltrials.gov/ct2/show/NCT01795859. Accessed Dec. 2, 2013.

10 Long term safety study of SD-809 in patients chorea associated with Huntington disease (ARC-HD). ClinicalTrials.gov. http://clinicaltrials.gov/ct2/show/NCT01897896. Accessed Dec. 2,2013.

11 Elison C, Rapoport H, Laursen R, Elliott HW. Effect of deuteration of N-CH3 group on potency and enzymatic Ndemethylation of morphine. Science. 1961 Oct 13; 134(3485):1078-9.

12 Shao L, Abolin C, Hewitt MC, Koch P, Varney M. Derivatives of tramadol for increased duration of effect. Bioorg Med Chem Lett. 2006 Feb; 1 6(3):691-4. Epub 2005 Oct 27.













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