Meet the Compound


By: Meredith A. Achey, BM


COMPOUND: Artificial micro RNA targeting human huntingtin, carried by an adeno-associated virus 5 (AAV5) vector (AAV5-miHTT)

MECHANISM OF ACTION: Micro RNAs (miRNAs) target messenger RNA (mRNA) transcripts and lead to silencing of the gene by suppressing translation. uniQure’s design also incorporates DNA promoters to enhance transcription of the miRNAs in target tissues, and the AAV5 vector is especially effective in targeting liver and neuronal tissues.1 AMT-130 was selected in preclinical studies both for efficacy in lowering mutant huntingtin production and for minimizing off-target effects.2

Figure: HTT silencing gene therapy

(1) Adeno-associated viral vector silencing human HTT gene (AAV5-miHTT) binds to neuron cell-surface receptors and is internalized. (2) The viral vector is transported into the nucleus and then degrades, uncoating the miHTT transgene. (3) The miHTT transgene is expressed and processed by the endogenous RNA interference machinery. (4) The hairpin structured precursor of miHTT is transported to the cytoplasm and further processed to the final mature miHTT. (5) The mature miHTT binds HTT messenger RNA, and the RNA duplex is recognized by RNA-induced silencing complexes. (6) HTT messenger RNA is cleaved, resulting in lowering of huntingtin protein expression. Image and caption courtesy of uniQure.

1 Maczuga P, Lubelski J, van Logtenstein R, et al. Embedding siRNA sequences targeting Apolipoprotein B100 in shRNA and miRNA scaffolds results in differential processing and in vivo efficacy. Mol Ther. 2013;21(1):217-227.

2 Miniarikova J, Zanella I, Huseinovic A, et al. Design, Characterization, and Lead Selection of Therapeutic miRNAs Targeting Huntingtin for Development of Gene Therapy for Huntington’s Disease. Mol Ther Nucleic acids. 2016;5(3):e297.

Meet the Compounds: WVE-120101 and WVE-120102

Image source: Robinson R. RNAi Therapeutics: How Likely, How Soon? PLoS Biol. 2004 Jan;2(1):E28. Epub 2004 Jan 20. DOI: 10.1371/journal.pbio.0020028. Published under a Creative Commons 2.5 License.

Image source: Robinson R. RNAi Therapeutics: How Likely, How Soon? PLoS Biol. 2004 Jan;2(1):E28. Epub 2004 Jan 20. DOI: 10.1371/journal.pbio.0020028. Published under a Creative Commons 2.5 License.

By: Meredith A. Achey, BM
Manufacturer: WAVE Life Sciences
Molecular formula: Stereopure antisense oligonucleotide (ASO) targeting single nucleotide polymorphisms (SNPs).
Mechanism of action: WVE-120101 and WVE-120102 act by selectively binding mHTT mRNA, thereby selectively inhibiting production of mHTT. WAVE Life Sciences has developed a strategy to synthesize stereopure nucleotide-based therapies that may improve their efficacy and safety.1

Nucleotide-based gene silencing therapies such as RNA interference (RNAi) and antisense oligonucleotides (ASOs) represent some of the most promising potential therapies for genetic diseases such as HD. However, methods for their synthesis developed to date produce mixtures of stereoisomers, some of which are therapeutic, and others that may be less effective or potentially detrimental.1,2 WAVE Life Sciences has developed a propriety technology for the synthesis of stereopure nucleic acid therapeutics3-5 with the potential to improve therapeutic efficacy and reduce harmful effects.6
The company hopes to develop stereopure nucleic acid therapies for a variety of genetic diseases, including central nervous system disease such as HD, and a number of genetic disorders that affect other organ systems.7

WAVE’s most advanced HD programs currently encompass two compounds that target different single nucleotide polymorphisms (SNPs) common to the mutant allele. The company plans to file investigational new drug applications for both of these compounds this year, and has received orphan drug designation in the US for its lead candidate, WVE-120101.8 These compounds target the two most common SNPs associated with mHTT.9 Current efforts by Ionis in the first human trial of a gene-silencing nucleotide-based therapy do not target mHTT selectively (see HD Insights, Vol. 13), although preclinical data have not suggested a significant decrease in efficacy nor increase in potential harm from a non-selective approach.10 However, interest in more selective approaches has continued because the possibility for off-target effects with non-selective silencing remains problematic.11-15

Pfister and colleagues9 reported that they have been able to develop small interfering RNAs (siRNAs) that target specific SNPs to treat approximately 75% of individuals with HD. In 2015, targeting approaches were further refined with the discovery that targeting three common haplotypes could enable selective silencing of the HD gene in approximately 80% of patients.13 The use of stereopure synthesis to enhance the delivery and efficacy of these highly targeted compounds may further refine ongoing efforts to develop an effective and safe gene-silencing therapy for HD.

Table. Selected studies of allele-specific gene-silencing therapies

Study Year Type of therapy Most promising target SNP(s) Summary
Skotte NH et al.16 2014 ASO rs7685686_A Allele-specific, high affinity ASOs targeting different SNPs associated with HD could together offer allele-selective silencing to approximately 50% of patients, and non-selective silencing to the remainder.
Drouet et al.12 2014 shRNA rs363125, rs362331, rs2276881, rs362307 shRNA delivered with a lentiviral vector to cellular and animal models showed in vitro and in vivo silencing of mHTT.
Yu D et al.17 2012 ss-siRNA Targets CAG repeat ss-siRNA targeting expanded CAG repeats led to selective silencing of mHTT expression in an HD mouse model.
Abbreviations: ASO: Antisense oligonucleotide; shRNA: small hairpin RNA; ss-siRNA: single-stranded small interfering RNA; SNP: single nucleotide polymorphism

1. Wild EJ, Tabrizi SJ. Targets for future clinical trials in Huntington’s disease: What’s in the pipeline? Mov Disord. 2014 Sep 15;29(11):1434-45. doi: 10.1002/mds.26007. Epub 2014 Aug 25.
2. De Mesmaeker A, Altmann K-H, Waldner A, Wendeborn S. Backbone modifications in oligonucleotides and peptide nucleic acid systems. Curr. Opin. Struct. Biol. 1995;5(3):343-355.
3. Butler D, Iwamoto N, Meena M, et al. Chiral control. Google Patents; 2015.
4. Verdine GL, Meena M, Iwamoto N. Novel nucleic acid prodrugs and methods of use thereof. Google Patents; 2012.
5. Verdine GL, Meena M, Iwamoto N, Butler DCD. Methods for the synthesis of functionalized nucleic acids. Google Patents; 2014.
6. Wave Life Sciences. Wave Life Sciences – Platform. [Website]. 2016; Accessed August 19, 2016.
7. Wave Life Sciences. Wave Life Science – Pipeline. 2016; Accessed August 19, 2016.
8. WAVE Life Sciences receives orphan drug designation from FDA for its lead candidate designed to treat Huntington’s disease [press release]. June 21, 2016.
9. Pfister EL, Kennington L, Straubhaar J, et al. Five siRNAs targeting three SNPs may provide therapy for three-quarters of Huntington’s disease patients. Curr. Biol. 2009;19(9):774-778.
10. Kordasiewicz Holly B, Stanek Lisa M, Wancewicz Edward V, et al. Sustained therapeutic reversal of Huntington’s disease by transient repression of Huntingtin synthesis. Neuron. 2012 Jun 21;74(6):1031-44. doi: 10.1016/j.neuron.2012.05.009.
11. Carroll JB, Warby SC, Southwell AL, et al. Potent and selective antisense oligonucleotides targeting single-nucleotide polymorphisms in the Huntington disease gene / Allele-specific silencing of mutant huntingtin. Mol Ther. 2011 Dec;19(12):2178-85. doi: 10.1038/mt.2011.201. Epub 2011 Oct 4.
12. Drouet V, Ruiz M, Zala D, et al. Allele-specific silencing of mutant huntingtin in rodent brain and human stem cells. PLoS One. 2014 Jun 13;9(6):e99341.
13. Kay C, Collins JA, Skotte NH, et al. Huntingtin haplotypes provide prioritized target panels for allele-specific silencing in Huntington disease patients of European ancestry. Mol Ther. 2015 Nov;23(11):1759-71.
14. Miniarikova J, Zanella I, Huseinovic A, et al. Design, characterization, and lead selection of therapeutic mirnas targeting huntingtin for development of gene therapy for Huntington’s disease. Mol Ther Nucleic Acids. 2016 Mar 22;5:e297.
15. Pfister EL, Kennington L, Straubhaar J, et al. Five siRNAs targeting three SNPs may provide therapy for three-quarters of Huntington’s disease patients. Curr Biol. 2009 May 12;19(9):774-8.
16. Skotte NH, Southwell AL, Østergaard ME, et al. Allele-specific suppression of mutant huntingtin using antisense oligonucleotides: providing a therapeutic option for all Huntington disease patients. PLoS One. 2014 Sep 10;9(9):e107434.
17. Yu D, Pendergraff H, Liu J, et al. Single-stranded rnas use rnai to potently and allele-selectively inhibit mutant huntingtin expression. Cell. 2012 Aug 31;150(5):895-908.

Meet the Compound: VX15/2503

Image Source: Illustration of antibodies from

Image Source: Illustration of antibodies from

BY: Meredith A. Achey, BM
MOLECULAR FORMULA: Anti-semaphorin 4D (SEMA4D) monoclonal antibody
MECHANISM OF ACTION: VX15/2503 may slow or prevent neurodegeneration in HD by inhibiting SEMA4D, a signaling protein shown to be important in neuroinflammatory processes.1

Animal models of HD and human individuals with HD both exhibit immune dysregulation and increased inflammation in addition to the characteristic neuronal atrophy observed in the disease. Semaphorin 4D (SEMA4D) is a transmembrane signaling protein implicated in several processes that may increase neuroinflammation, including glial cell activation, inhibition of oligodendrocyte and astrocyte migration, inhibition of neurodevelopment, and inducement of apoptosis.2 Given the increased inflammatory response and chronic immune activation observed in HD, SEMA4D inhibition may slow the progression of neurodegenerative processes.

SEMA4D has also been implicated in assisting in the abnormal growth of cancer cells because its high expression at the margins of invasive growths inhibits anti-tumor immune cells from entering the tumor. Strikingly, in metastatic processes, SEMA4D inhibition promotes inflammation and immune activity to encourage rejection of invasive growths,3 in contrast to the inhibitory effect VX15/2503 exhibits on neuroinflammation in mouse models of HD. VX15/2503 was also recently evaluated by Vaccinex in a phase I study in adults with solid tumors.

Vaccinex has developed the anti-SEMA4D monoclonal antibody VX15/2503 using their novel vaccinia virus − based platform for screening human antibodies as therapeutic targets. According to the company’s website, other similar processes that use yeast and bacteriophages to express candidate proteins are limited because the proteins do not undergo the post-translational modifications typical of a mammalian cell, and therefore may be less consistent in their quality and biophysical properties.4,5

In collaboration with the Huntington Study Group, Vaccinex is currently conducting a Phase II clinical trial of VX15/2503 in HD patients, called SIGNAL (NCT02481674), which is designed to evaluate the safety, tolerability, pharmacokinetics, and efficacy of this novel monoclonal antibody in late prodromal and early manifest HD. Secondary endpoints include a number of imaging and biomarker studies, including MRI and PET imaging, as well as measurements of SEMA4D activity in T-cells and in the circulation. Clinical features of HD will be measured using components of the UHDRS, as well as the quantitative motor (Qmotor) assessment system (see HD Insights, Vol. 6), HD-CAB (Cognitive Assessment Battery), and the Problem Behaviors Assessment.6

VX15/2503 showed promise for neuropathology and cognitive symptoms of HD in the YAC12B mouse model, but did not demonstrate motor improvements.2 The SIGNAL trial may help to determine whether SEMA4D inhibition in the early stages of human HD might have similar effects.

1 Smith ES, Jonason A, Reilly C, et al. SEMA4D compromises blood–brain barrier, activates microglia, and inhibits remyelination in neurodegenerative disease. Neurobiol. Dis.2015;73:254-268.
2 Southwell AL, Franciosi S, Villanueva EB, et al. Antisemaphorin 4D immunotherapy ameliorates neuropathology and some cognitive impairment in the YAC128 mouse model of Huntington disease. Neurobiol. Dis. 2015;76:46-56.
3 Evans EE, Jonason AS, Bussler H, et al. Antibody Blockade of Semaphorin 4D Promotes Immune Infiltration into Tumor and Enhances Response to Other Immunomodulatory Therapies. Cancer Immunol. Res. 2015;3(6):689-701.
4 Vaccinex Inc. Vaccinia Technology. [Web page]. 2015;
5 Smith ES, Zauderer M. Antibody library display on a mammalian virus vector: combining the advantages of both phage and yeast display into one technology. Curr Drug Discov Technol. 2014;11(1):48-55.
6 Kingma EM, van Duijn E, Timman R, van der Mast RC, Roos RA. Behavioural problems in Huntington’s disease using the Problem Behaviours Assessment. Gen Hosp Psychiatry. 2008;30(2): 155-161.

Meet the Compound: Laquinimod

By: Ryan E. Korn, BA

Laquinimod Source:


Manufacturer: TEVA Pharmaceutical Industries Ltd. and Active Biotech

Molecular Formula: C19H17ClN2O3

Molecular Weight: 357 g/mol

Mechanism of Action: Laquinimod exhibits both anti-inflammatory and neuroprotective effects. Potential mechanisms of action include its inhibition of cuprizone-induced demyelination; microglial activation; axonal transections; reactive gliosis; oligodendroglial apoptosis; as well as decreasing proinflammatory factors.1, 2

Laquinimod is an experimental immunomodulatory drug that has shown promising neuroprotective effects. The exact mechanism by which laquinimod exerts its neuroprotective effects is not fully understood, but it has been proposed that laquinimod reduces leukocyte migration into the central nervous system. The compound has been shown to modify the innate immune system to promote the differentiation of anti-inflammatory/regulatory T cells, activate microglia cells, increase the expression of brain-derived neurotrophic factor, and prevent inflammation-induced excitotoxicity.

In 2012, a study funded by TEVA Pharmaceutical Industries Ltd. and Active Biotech characterized the impact of laquinimod on CNS-intrinsic inflammation caused by cuprizone-induced demyelination in mice in vivo, and on primary CNS cells in vitro. Results suggest that laquinimod not only prevents cuprizone-induced demyelination but also prevents microglial activation, axonal transections, reactive gliosis, and oligodendroglial apoptoses in wildtype and Rag-1 – deficient mice. Most significantly, laquinimod is believed to inhibit astrocytic NF-κB transcription factor activation, thereby preserving myelin.2

TEVA and Active Biotech have investigated laquinimod as a potential oral treatment for a variety of autoimmune and neurodegenerative diseases. Laquinimod was first investigated for the treatment of relapsing-remitting multiple sclerosis (RRMS), an autoimmune disease that causes inflammation-induced demyelination and axonal degeneration of the CNS, resulting in chronic neurological complications and disability.2 Two of TEVA and Active Biotech’s most recent studies, BRAVO and ALLEGRO, showed that laquinimod decreases the rate of whole-brain atrophy compared to placebo.3 Results in both studies indicate that oral laquinimod is likely to exert a neuroprotective effect resulting in a reduced amount of irreversible brain tissue damage, which is consistent with possible slowing of disability accumulation in RRMS patients.4 These evident neuroprotective effects, reduced inflammatory response, and reduction in brain tissue damage shown in the BRAVO and ALLEGRO studies, could prove effective in other autoimmune and neurodegenerative diseases.

TEVA and Active Biotech recently initiated a Phase II randomized, double-blind, placebo-controlled parallel group study (LEGATO-HD) to evaluate the efficacy and safety of laquinimod as a treatment for HD.5 Laquinimod’s modulation of pathways common to key neurodegenerative disease through the immune cell lineages in the periphery and in the CNS, as well as its evident anti-inflammatory effects, may reduce neuronal death and the harmful inflammatory response seen in HD.4, 6 The HD trial is in the early phase of recruitment and enrollment. The study is expected to be completed in January 2017.5

1 Haggiag S, Ruggieri S, Gasperini C. Efficacy and safety of laquinimod in multiple sclerosis: current status. Ther Adv Neurol Disord. 2013 Nov; 6(6):343-52.

2 Brück W, Pförtner R, Pham T, et al. Reduced astrocytic NF-κB activation by laquinimod protects from cuprizone-induced demyelination. Acta Neuropathol. 2012 Sep; 124(3):411-24.

3 Filippi M, Rocca MA, Pagani E, et al. Placebo-controlled trial of oral laquinimod in multiple sclerosis: MRI evidence of an effect on brain tissue damage. J Neurol Neurosurg Psychiatry 2014; 85:851-858.

4 Mishra MK, Wang J, Keough MB, et al. Laquinimod reduces neuroaxonal injury through inhibiting microglial activation. Ann Clin Transl Neurol. 2014 Jun; 1(6):409-22. doi: 10.1002/acn3.67. Epub 2014 May 26.

5 A service of the U.S. National Institutes of Health [Internet]. A clinical study in subjects with Huntington’s disease to assess the efficacy and safety of three oral doses of laquinimod ( identifier: NCT02215616). [cited Dec 30 2014]. Available from:

6 TEVA Pharmaceutical Industries Ltd [Internet]. Results of Phase III BRAVO trial reinforce unique profile of laquinimod for multiple sclerosis treatment. 2011 August 11 [cited 2014 Dec 30]. Available from:

Meet the Compound: RP103 (cysteamine bitartrate delayed-release)

By: Meredith A. Achey, BM

Figure 1. Cysteamine bitartate Source:

Figure 1. Cysteamine bitartate

Figure 2. Cystamine

Figure 2. Cystamine

Manufacturer: Raptor Pharmaceuticals

Molecular Formula: C6H13NO6S

Molecular Weight: 227 g/mol

Mechanism of Action: Multiple potential mechanisms. Cysteamine (Figure 1) and its metabolic dimer cystamine (Figure 2) are present in an equilibrium in the body and important in many processes, including as antioxidants, radioprotective radical scavengers, 1 and in metabolic pathways leading to mobilization of cysteine.2



Cysteamine and cystamine have been studied as possible pharmacologic interventions for multiple conditions since a 1965 study identified their radioprotective properties,1 and both can protect against acetaminophen poisoning in the liver, and exhibit antiviral activity against influenza A, hepatitis A, and HIV-1.2 In addition, cysteamine can cross the blood-brain barrier and potentially exert neuroprotective and neurorestorative effects in HD.2

Cysteamine shows promise in mouse models of both HD and PD, and several potential mechanisms of action have been identified. First, through cysteine mobilization, cysteamine can potentially address the major deficiency of gamma-lyase cystathionine, the biosynthetic enzyme of cysteine, present in individuals with HD.3 Increased synthesis and mobilization of cysteine results in increased levels of glutathione, improvements in mitochondrial dysfunction, and reduced oxidative stress, all of which are thought to be important in neurodegeneration.4 Second, in a mouse model of HD, cystamine increases the transcription of heat shock proteins that are known to assist in promoting proper protein folding and reduced proteolysis. Increased levels of heat shock proteins have been linked to reduced polyglutamine aggregation and toxicity in a number of neurodegenerative diseases.2, 5 Third, cystamine increases neurotrophins in the brain and in the blood, which may improve HD and PD pathology. Furthermore, because neurotrophins such as brain-derived neurotrophic factor cannot cross the blood-brain barrier, compounds that increase endogenous levels of these factors may be preferable to direct supplementation.2 Finally, inflammation and immune responses have been implicated in the progression of HD and PD. Cystamine up-regulates Nurr1 in a mouse model of HD, a gene that is indirectly responsible for regulating immune response, which may help to explain its neuroprotective effects.2

Raptor Pharmaceuticals’ delayed-release formulation of cysteamine bitartrate is currently approved for use in nephropathic cystinosis. An ongoing phase II/III clinical trial has thus far shown RP103 to be safe and well-tolerated in HD patients compared to placebo, and has demonstrated a small but significant slowing of progression of total motor score over 18 months in patients not taking tetrabenazine. In patients already taking tetrabenazine, the slowing of progression of total motor score announced in February 2014 was not statistically significant.6 The trial is ongoing in France and is scheduled to conclude in 2015.

1 Bacq ZM, Beaumariage ML, Van Caneghem P. Importance for radioprotective effect in mammals of pharmacological and biochemical actions of cysteamine and related substances. Annali dell’Istituto superiore di sanita. 1965; 1(9):639-645.

2 Gibrat C, Cicchetti F. Potential of cystamine and cysteamine in the treatment of neurodegenerative diseases. Prog Neuropsychopharmacol Biol Psychiatry. 2011 Mar 30; 35(2): 380-389.

3 Paul BD, Sbodio JI, Xu R, Vandiver MS, et al. Cystathionine gamma-lyase deficiency mediates neurodegeneration in Huntington’s disease. Nature. 2014 May 1; 509(7498):96-100. doi: 10.1038/nature13136. Epub 2014 Mar 26.

4 Beal MF. Bioenergetic approaches for neuroprotection in Parkinson’s disease. Ann Neurol. 2003;53 Suppl 3:S39-47; discussion S47-38.

5 Borrell-Pagès M, Canals JM, Cordelières FP, Parker JA, et al. Cystamine and cysteamine increase brain levels of BDNF in Huntington disease via HSJ1b and transglutaminase. J Clin Invest. 2006 May; 116(5):1410-24. Epub 2006 Apr 6.

6 Raptor Pharmaceuticals: Raptor announces clinical results with RP103 in Huntington’s disease phase 2/3 trial. 18 month clinical results showed significantly slower progression of total motor score in RP103 treated patients without tetrabenazine [Internet media release]. 2014 [cited 2014 Apr 9]. Available from: http://

Meet the Compound: Olesoxime (TRO19622)


Image source:

Manufacturer: Trophos, S.A.

Molecular Formula: C27H45NO

Molecular Weight: 400 g/mol

Mechanism of Action: Olesoxime is a cholesterol-like compound that exhibits neuroprotective properties. Preclinical studies suggest that olesoxime can promote myelination1 and decrease mitochondrial membrane fluidity in cell and animal models of HD.2


Mitochondrial abnormalities and demyelination are both known features of the pathology of several neurodegenerative conditions. 3, 4 Compounds that address both of these disease processes are promising targets for development of novel pharmaceutical therapies.5

Olesoxime was initially developed for use in amyotrophic lateral sclerosis (ALS), when it was discovered that the compound enhances motor neuron survival in vitro; has neuroprotective properties and promotes regeneration of injured motor neurons in mouse and rat models; and enhances survival and delays disease onset in transgenic SOD1 mice models of familial ALS.In studies conducted through the European MitoTarget initiative, 7 olesoxime showed promise in slowing the progression of spinal muscular atrophy (SMA), 8 but was ineffective in ALS.9

Studies of the use of olesoxime in HD remain in the preclinical phase. Preliminary work in the BACHD rat model of HD demonstrated improvements in psychiatric and behavioral symptoms and cognition, and helped repair mitochondrial impairments, but had no effect on motor symptoms.10

The effects of mutant huntingtin on mitochondria have yet to be fully elucidated, but studies suggest that mitochondrial membrane permeability and fluidity may be increased in HD, leading to defects in mitochondrial respiration.11,12 Compounds that decrease mitochondrial membrane fluidity may slow neurodegenerative processes within mitochondria, and thereby slow the progression of HD.

In a recent study,2 Eckmann and colleagues found that olesoxime successfully decreased mitochondrial membrane fluidity in vitro, and in vivo in mouse and rat models of HD. The researchers posited that the decreased mitochondrial membrane fluidity in BACHD rat brains may be due to increased membrane cholesterol levels. Defects in brain cholesterol metabolism and synthesis have been identified as potential mechanisms for neurodegeneration in HD.13 Dr. Rebecca Pruss, Chief Scientific Officer at Trophos, commented “These results highlight the central role mitochondria play in neurodegenerative diseases…and the need for therapies that restore mitochondrial function in pathophysiologically stressed cells. Olesoxime… could be such a compound; it targets mitochondria and maintains their integrity in stressed cells thus preventing the release of mitochondrial pro-apoptotic factors such as cytochrome c and apoptosis inducing factor… maintaining energy levels and calcium homeostasis. Olesoxime already has a positive clinical track record demonstrating its tolerance, safety and recently its efficacy in spinal muscular atrophy patients; therefore, olesoxime seems to be a promising neuroprotective treatment potentially reducing the effects of huntingtin mutations leading to HD.”table 1


1 Li Y, Zhang Y, Han W, Hu F, et al. TRO19622 promotes myelin repair in a rat model of demyelination. Int J Neurosci. 2013 Nov; 123(11):810-822.

2 Eckmann J, Clemens LE, Eckert SH, Hagl S, et al. Mitochondrial membrane fluidity is consistently increased in different models of Huntington Disease: restorative effects of olesoxime. Mol Neurobiol. 2014 Mar 18. [Epub ahead of print]

3 Chen CM. Mitochondrial dysfunction, metabolic deficits, and increased oxidative stress in Huntington’s disease. Chang Gung Med J. 2011 Mar-Apr; 34(2):135-152.

4 Urrutia PJ, Mena NP, Nunez MT. The interplay between iron accumulation, mitochondrial dysfunction, and inflammation during the execution step of neurodegenerative disorders. Front Pharmacol. 2014; 5:38.

5 Mehrotra A, Sandhir R. Mitochondrial cofactors in experimental Huntington’s disease: behavioral, biochemical and histological evaluation. Behav Brain Research. 2014 Mar 15; 261:345-355.

6 Bordet T, Buisson B, Michaud M, Drouot C, et al. Identification and characterization of cholest-4-en-3-one, oxime (TRO19622), a novel drug candidate for amyotrophic lateral sclerosis. J Pharmacol Exper Ther. 2007 Aug; 322(2):709-720.

7 Trophos announces conclusion of MitoTarget Consortium, achieving advanced understanding of neurodegenerative diseases. Media release. 2012 Jul 31;

8 Trophos will present results of pivotal phase II/III study of olesoxime in spinal muscular atrophy patients at the American Academy of Neurology (AAN). Media release. 2014 Apr 28;

9 Lenglet T, Lacomblez L, Abitbol JL, Ludolph A, et al. A phase II-III trial of olesoxime in subjects with amyotrophic lateral sclerosis. Eur J Neurol. 2014 Mar; 21(3):529-536.

10 Clemens LE, Wlodkowski T, Eckmann J, Eckert S, et al. P06 Olesoxime improves specific features of the HD pathology. J Neurol Neurosurg Psychiatry. 2012 Sep 1; 83(Suppl 1):A53-A54.2013.

11 Quintanilla RA, Jin YN, von Bernhardi R, Johnson GV. Mitochondrial permeability transition pore induces mitochondria injury in Huntington disease. Molecular neurodegeneration. 2013; 8:45.

12 Labbadia J, Morimoto RI. Huntington’s disease: underlying molecular mechanisms and emerging concepts. Trends Biochem Sci. 2013 Aug; 38(8):378-385.

13 Valenza M, Leoni V, Karasinska JM, Patricca L, et al. Cholesterol defect is marked across multiple rodent models of Huntington’s disease and is manifest in astrocytes. J Neurosci. 2010 Aug 11; 30(32):10844-10850.

14 Magalon K, Zimmer C, Cayre M, Khaldi J, et al. Olesoxime accelerates myelination  and promotes repair in models of demyelination. Ann Neurol. 2012 Feb; 71(2):213-226.

15 Sunyach C, Michaud M, Arnoux T, Bernard-Marissal N, et al. Olesoxime delays muscle denervation, astrogliosis, microglial activation and motoneuron death in an ALS mouse model. Neuropharm. 2012 Jun; 62(7):2346-2352. Sci. 2013 Aug; 38(8): 378-385.

16 Gouarné C, Giraudon-Paoli M, Seimandi M, Biscarrat C, et al. Olesoxime protects embryonic cortical neurons from camptothecin intoxication by a mechanism distinct from BDNF. Br J Pharmacol. 2013 Apr; 168(8):1975-88. doi: 10.1111/bph. 12094.Neuropharm. 2012 Jun; 62(7):2346-2352. Sci. 2013 Aug; 38(8):378-385.

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. . Accessed January 21, 2014.

Image source: Auspex Pharmaceuticals, Inc. United States Securities and Exchange Commission Form S-1:
Registration Statement. Filed December 20, 2013. . 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. 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) Accessed Dec. 2, 2013.

10 Long term safety study of SD-809 in patients chorea associated with Huntington disease (ARC-HD). 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.













Meet the Compound: Coenzyme Q10

coq10Molecular Formula: C59H90O4

Molecular Weight: 863.34 g/mol

Mechanism of Action: CoQ10 occurs naturally in the body, an important antioxidant in the mitochondrial electron transport chain1. It has been shown to decrease the abnormally high lactate-pyruvate levels in cerebrospinal fluid in HD2.

CoQ10 has been explored as a neuroprotective in PD and HD (Table 1). Although the QE3 trial of CoQ10 in PD showed no significant benefits,3 studies in HD have shown more promising results. Dr. Flint Beal, Professor of Neurology and Neuroscience at Weill Medical College of Cornell University, told HD Insights that the failure of CoQ10 in PD has an unknown impact on its use in HD. “I am still hoping that the results in HD will be beneficial,” he said. Dr. Karl Kieburtz, Director of the Clinical and Translational Science Institute at the University of Rochester, told HD Insights that the evidence for a modest benefit of CoQ10 in HD is greater than in the case of PD. The CARE-HD study of high dose CoQ10 and remacemide in HD demonstrated a trend toward slowing functional decline4. Dr. Kieburtz suggested that these results may indicate that the benefits of long-term CoQ10 are detectable only in a clinical trial setting. Further exploration of CoQ10 is important, he said, because it is a low-cost, readily available intervention that people at risk for HD can take at low risk for a long time, while some more potent therapies that target specific biological processes may demonstrate high toxicities. This exploration is currently being undertaken in the 2CARE study, a multi-center, randomized, double-blind, placebo-controlled study of high-dose CoQ10, conducted by the Huntington Study Group (HSG) under the direction of Drs. Merit Cudkowicz, Michael McDermott, and Karl Kieburtz. 2CARE aims to identify the effects of CoQ10 on functional decline in HD, as well as its long-term safety and tolerability5.

coq10 table

The PREQUEL study represents the first randomized, controlled trial of CoQ10 in premanifest HD, under the direction of Drs. Christopher Ross of Johns Hopkins University, and Kevin Biglan of the University of Rochester. The results of PREQUEL will be presented at this year’s HD Clinical Research Symposium. Dr. Ralf Reilmann (see “Selected by Chance,” p. 1) said, “I think PREQUEL is one of the most fantastic studies. This was a proof-of-concept study, and I think we are transitioning from a phase where such trials were unrealistic, to a phase where we can actually consider doing challenging, disease-modifying trials in both manifest HD and premanifest HD.”


1 Chaturvedi RK, Beal MF. Mitochondria targeted therapeutic approaches in Parkinson’s and Huntington’s diseases. Mol Cell Neurosci. 2013 Jul; 55:101-14.

2 Koroshetz WJ, Jenkins BG, Rosen BR, Beal MF. Energy metabolism defects in Huntington’s disease and effects of coenzyme Q10. Ann. neurol. 1997;41(2):160-5. Epub 1997/02/01. doi: 10.1002/ana 410410206. PubMed PMID: 9029064.

3 National Institute of Neurological Disorders and Stroke (NINDS). Statement on the termination of QE3 study [Internet]. [Updated 2011 June 2; cited 2013 Sep 19]. Available from

4 Kieburtz K, Koroshetz W, McDermott M, et al. A randomized, placebo-controlled trial of coenzyme Q10 and remacemide in Huntington’s disease. Neurol. 2001 Aug 14; 57(3):397-404.

5 Coenzyme Q10 in Huntington’s Disease (HD) (2CARE) [Internet]. [Cited 2013 Sep 19]. Available from +Huntington&rank=1.

6 Hyson HC, Kieburtz K, Shoulson I, et al. Safety and tolerability of high-dosage coenzyme Q10 in Huntington’s disease and healthy subjects. Mov Disord. 2010;25(12):1924-8.

7 Schults CW, Oakes D, Kieburtz K, et al. Effects of coenzyme Q10 in early Parkinson d isease: Evidence of slowing of the functional decline. Arch Neurol. 2002 Oct; 59(10):1541-50.

8 Kieburtz K, Ravina B, Galpern W, et al. A randomized clinical trial of coenzyme Q10 and GPI-1485 in early Parkinson Disease. Neurol. 2007 Jan 2;68(1):20-28.

9 Beal MF. A phase III clinical trial of coenzyme Q10 (QE3) in early Parkinson’s disease: Parkinson Study Group QE3 Investigators [Abstract]. Mov Disord. 2012 Jun 17-21; 27 Suppl 1:346.

Meet the Compound: PF-02545920




NAME: PF-02545920


MOLECULAR MASS: 392.452 g/mol


MECHANISMS OF ACTION: PDE10A inhibition increases the activity of both the cAMP and cGMP signaling cascades, as well as the MAP kinase pathway, and results in a powerful induction of striatal gene transcription and an overall increase in striatal output.

Meet the Compound: Huntexil


Image courtesy of ChemSpider

Image courtesy of ChemSpider


NAME: Huntexil® (Pridopidine/ACR16)


MOLECULAR MASS: 281.41 g/mol.

TYPE OF COMPOUND: Dopamine stabilizer

MECHANISMS OF ACTION: Functional antagonism of dopamine type 2 receptors and strengthening of cortical glutamate functions in the central nervous system.


Two previous studies that feature Huntexil® are the MermaiHD study and the HART study.

The MermaiHD study was a 26-week, double-blind, controlled trial of 437 HD patients conducted in 2008 through 2009 at 32 centers in Europe1. Study participants were randomized to receive either placebo (n=144) or doses of 45mg (n=148) or 90mg (n=145) of Huntexil per day. The primary outcome measure was the modified motor score, a subset of the Unified Huntington’s Disease Rating Scale (UHDRS) total motor score. The 90 mg per day group improved 1.0 points on the modified motor score compared to placebo from baseline to week 26, but the improvement was not statistically significant. The 90 mg per day group showed a statistically significant improvement of 3.0 points in total motor score compared to placebo. Changes in other motor outcomes were not significant across groups.

The HART study was a 12-week, double-blind, controlled trial of 227 HD patients conducted in 2009 through 2010 at 27 centers in Canada and the United States2. Study participants were randomized to receive placebo (n=58) or doses of 20 mg (n=56), 45 mg (n=55), or 90 mg (n=58) of Huntexil per day. As in the MermaiHD study, the primary outcome measure was the modified motor score, but the improvement of 1.2 points on the modified motor score of the 90mg per day group compared to placebo was not statistically significant. The 90mg per day group showed statistically significant improvement of 2.8 points in total motor score compared to placebo. No significant changes in cognition were observed during this 12- week study. In both studies, Huntexil was safe, and well tolerated by participants2,3.



Justo Garcia de Yebenes, MD

Huntexil is a dopamine stabilizer that was synthesized by Prof. Arvid Carlsson. It can activate dopamine receptors in hypodopaminergic status, and can also block these receptors in cases of dopamine hyperactivity. Huntexil has previously been tested in vitro and in vivo. It showed a good side-effect profile and its pharmacological effect is primarily on extrasynaptic dopamine receptors. Huntexil was first trialed in small groups of Scandinavian HD patients. After four weeks of treatment the results of these studies were primarily an improvement of the modified UHDRS. Following these short-term studies, the MermaiHD trial was organized. Previous studies showed no effect of Huntexil on chorea, dystonia and ocular movements, and so the evaluation of these clinical deficits was thought to ‘dilute’ the significance of the results. For this reason the modified UHDRS was chosen as the primary end-point of the study. That choice eventually proved to be a mistake because the periods of treatment required for improvement of the previously mentioned clinical deficits differ. The results of the study essentially showed no effect of Huntexil treatment at 45 mg per day and a borderline effect of treatment at 90mg per day, using as the defined primary end-point, the modified UHDRS. Additional analysis taking in consideration the number of the patient’s CAG repeats, age, or the total motor score on the UHDRS, showed unequivocal improvement for the group treated with Huntexil at 90 mg per day. Future studies are warranted. With the experience of this study, future studies should be long-term studies, with doses of pridopidine at 90 mg or more per day, using the total UHDRS motor scale as a primary end point, or a more sensitive and global motor scale, if such a rating scale is ever developed.


1 de Yebenes JG, Landwehrmeyer B, Squitieri F, et al. Pridopidine for the treatment of motor function in patients with Huntington’s disease (MermaiHD): a phase 3, randomised, double-blind, placebocontrolled trial. Lancet Neurol 2011 Dec;10(12):1049-57.

2 A randomized, double-blind, placebo-controlled trial of pridopidine in Huntington’s disease. Mov Disord 2013 Feb 28.

3 Squitieri F, Landwehrmeyer B, Reilmann R, et al. One-year safety and tolerability profile of pridopidine in patients with Huntington disease. Neurology 2013 Feb 27.