Raptor Pharmaceutical Corp. announced some positive (though preliminary) results from the 18-month review of their CYST-HD Phase 2/3 clinical trial testing a cysteamine drug for Huntington's disease (HD). They reported slower progression of motor impairment in those participants who had received drug compared to those who had received placebo. If these positive results hold up on further analysis and completion of the remaining 18 months of trial, this author believes we have very good reasons to be optimistic about this drug for HD.

What is this Raptor drug? Why try this drug in an HD clinical trial? And -- why might we be optimistic now?

The Drug: The active ingredient in the drug is cysteamine. Cystagon, a first generation cysteamine drug, has been available since 1994 when it was FDA-approved for treatment of cystinosis, a rare genetic disease causing death in childhood. Though Cystagon can effectively treat this disease, it is a hard drug to take for a lifetime due to very unpleasant side effects: stomach upset, nausea, vomiting, bad breath and body odor similar to rotten eggs.

An improved, second generation cysteamine drug, Procysbi was FDA-approved for cystinosis in September 2013. The new drug has the same active ingredient as the original but is "enteric coated" to pass through the stomach before absorption. Though much more expensive, Procysbi greatly improves quality of life and compliance to drug treatment.

The drug being tested for Huntington's is similar to Procysbi and should avoid the side effects of the first generation Cystagon.

Rationale for Cysteamine in HD: Cysteamine has been shown to slow progression in animal models of HD. Dr. M. Karpuj and colleagues reported benefit in terms of motor improvement and lifespan in the R6/2 mouse model [Karpuj MV 2002]. Later in the same year these results were confirmed and reported from the S. Hersch lab [Dedeoglu A 2002]. Others have shown similar results in the YAC128 model [Van Raamsdonk JM 2005]. It has been subsequently shown that cysteamine increases brain-derived neurotrophic factor (BDNF) in animal models of HD [Borrell-Pagès M 2006]. There are multiple other ways in which the drug may impact HD [Gibrat C 2011]. And now, probably most important are the recent results reported in Nature for cysteine benefit in cell and mouse models of HD by Sol Snyder's laboratory [Paul BD 2014].

The CYST-HD Trial for HD: This is a 3-year Phase 2/3 trial which means that safety, tolerance (the Phase 2 part), and efficacy (the Phase 3 part) are being evaluated. The first 18 months was a placebo controlled trial of 96 participants. During the 2nd half of the trial, all participants will receive drug (the open-label part). A portion of participants were also taking tetrabenazine, an important factor in the results for this trial.

The Raptor press release gave information on only the first 18 months, the placebo-controlled part of the trial. What they found was:

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Raptor Press Release

  • Overall slowing of total motor dysfunction by 32% for those who took cysteamine compared to placebo (includes those on or off of tetrabenazine)
  • Slowing of total motor dysfunction was greater (58%) in those participants not taking tetrabenazine
  • Slowing of motor dysfunction was present in all motor testing: eye movements, hand movements, dystonia, and hyperkinetic (chorea) measures
  • Side effects were similar for those receiving drug and those receiving placebo

Why Optimism? Though we would like to have more data than was given in the press release, there are several reasons for optimism:

  • Safety: Remember that cysteamine has a known safety profile with long-term use: more than a decade of use in children with cystinosis -- who now live to adulthood.
  • Positive outcomes in many measures of motor function were reported. We'd be less optimistic if only one measure showed improvement.
  • The level of motor benefit (58%) is substantial for those not on tetrabenazine. The lesser motor benefit (38%) in those on tetrabenazine may have occurred due to masking of cysteamine benefit.

Author's Comments: If the results in the press release are correct, and other data like cognitive readouts, quality of life, and specific motor test results confirm benefit, there is reason to be optimistic about the Raptor drug. No doubt Raptor is busy with this ongoing analysis. If these positive results are confirmed at completion of the 3 year trial, I would push for consideration of expedited approval through the new FDA "Breakthrough" category. I suspect that Raptor is already talking with regulatory agencies regarding the need for another confirmatory trial -- next time with all participants off of tetrabenazine. Getting the HD community behind this small company is vital.


Karpuj MV, Becher MW, Springer JE, Chabas D, Youssef S, Pedotti R, Mitchell D, Steinman L. Prolonged survival and decreased abnormal movements in transgenic model of Huntington disease, with administration of the transglutaminase inhibitor cystamine. Nat Med. 2002 Feb;8(2):143-9. PubMed abstract

Dedeoglu A, Kubilus JK, Jeitner TM, Matson SA, Bogdanov M, Kowall NW, Matson WR, Cooper AJ, Ratan RR, Beal MF, Hersch SM, Ferrante RJ. Therapeutic effects of cystamine in a murine model of Huntington's disease. J Neurosci. 2002 Oct 15;22(20):8942-50. PubMed abstract

Van Raamsdonk JM, Pearson J, Bailey CD, Rogers DA, Johnson GV, Hayden MR, Leavitt BR. Cystamine treatment is neuroprotective in the YAC128 mouse model of Huntington disease. J Neurochem. 2005 Oct;95(1):210-20. PubMed abstract

Borrell-Pagès M, Canals JM, Cordelières FP, Parker JA, Pineda JR, Grange G, Bryson EA, Guillermier M, Hirsch E, Hantraye P, Cheetham ME, Néri C, Alberch J, Brouillet E, Saudou F, Humbert S. 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. PubMed abstract

Gibrat C, Cicchetti F. Potential of cystamine and cysteamine in the treatment of neurodegenerative diseases. Prog Neuropsychopharmacol Biol Psychiatry. 2011 Mar 30;35(2):380-9. doi: 10.1016/j.pnpbp.2010.11.023. Epub 2010 Nov 24. PubMed abstract

Paul BD, Sbodio JI, Xu R, Vandiver MS, Cha JY, Snowman AM, Snyder SH. Cystathionine γ-lyase deficiency mediates neurodegeneration in Huntington's disease. Nature. 2014 May 1;509(7498):96-100. doi: 10.1038/nature13136. Epub 2014 Mar 26. PubMed abstract