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HD InsightsMeet the Compound: RP103 (cysteamine bitartrate delayed-release)

By: Meredith A. Achey, BM

Figure 1. Cysteamine bitartate Source: pubchem.ncbi.nlm.nih.gov/summary/summary.cgi?cid=23111531
Figure 1. Cysteamine bitartate
Source: pubchem.ncbi.nlm.nih.gov/summary/summary.cgi?cid=23111531
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:// ir.raptorpharma.com/releasedetail.cfm?ReleaseID=826962.

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