NAME: Julie Smith, BS
CURRENT POSITION: President and CEO (designate) of Raptor Pharmaceuticals
EDUCATION: Bachelor of Science in Biological and Nutritional Science, Cornell University
HOBBIES: Spending time with her two little boys, six and eight
Julie Smith came to Raptor Pharmaceuticals in 2012 and currently serves as the company’s President and CEO (designate). Ms. Smith aims to utilize her experience in drug development and commercialization for orphan diseases to bring promising drug therapies to patients with rare diseases around the world. Prior to her current position at Raptor Pharmaceuticals, Ms. Smith served as Chief Commercial Officer of Enobia Pharma, Inc., Vice President of Commercial at Jazz Pharmaceuticals, and led the global marketing efforts for enzyme replacement treatments at Genzyme General. HD Insights recently interviewed Ms. Smith about Raptor Pharmaceuticals’ work with cysteamine bitartrate for HD. Below is an edited transcript of the conversation.
HD INSIGHTS: How did you become interested in HD?
SMITH: I first heard about HD from Abbey Meyers, who was one of the founders of the National Association of Rare Disorders (NORD). NORD was founded with the assistance of Woody Guthrie’s widow, so HD was one of the first rare diseases put forward. Patient advocates came to the forefront and really pushed for policy changes and improvements that would help communities affected by rare diseases. When you hear the story of someone affected by HD, it leaves an indelible imprint on you.
HD INSIGHTS: Can you tell us about the mechanism of action of cysteamine in HD?
SMITH: Cysteamine, a prodrug of cystamine, mobilizes cysteine as it is metabolized. This is believed to have several therapeutic benefits. Firstly, the systemic increase in cysteine has been shown to have both a direct and indirect anti-oxidative effect to cells, while cysteine is rate-liming in the biosynthesis of glutathione, a potent anti-oxidant that has shown protective effects in patients with HD. Secondly, a recent paper published by Solomon Snyder at Johns Hopkins showed that individuals with HD have a major deficit of cystathionine gamma-lyase, which is essential for biosynthesis of cysteine, suggesting another reason that boosting systemic cysteine may be important in HD therapy.1 Thirdly, cysteamine has been shown to up-regulate a number of the cell’s own adaptive stress responses. Mutant huntingtin (mHTT) causes cell stress because the cell must deal with the mutant protein, which it does by forming aggregates. Aggregates of mHTT may trap other normally functioning proteins, and mHTT fragments are difficult for cells to process. Cysteamine up-regulates several heat shock proteins, which may help to normalize protein folding. Mis-folding is indeed a characteristic of mHTT. Finally, it has been observed that cysteamine increases the production and intracellular transport of brain-derived neurotrophic factor, which has also been shown to be deficient in the brains of individuals with HD and other neurodegenerative diseases.
HD INSIGHTS: Please describe the design of your clinical trial.
SMITH: The study was first conceived of and designed in 2010. The French members of the Huntington team had designed a proof-of-concept study, and the more they came to understand the biology of cysteamine, the more excited they became about its potential application in HD. They approached Raptor as we were forming a company, and requested access to RP103, to conduct a prospective placebo-controlled, 36-month trial in early-stage HD patients. The trial consisted of two separate segments: an 18- month placebo-controlled segment, followed immediately by an 18-month open-label, treatment segment with RP103. The primary objective of the trial was to measure the efficacy, safety, and tolerability of RP103 in the treatment of total motor deterioration, compared to placebo, at 18 months, which was the primary endpoint. Secondary endpoints include all components of the UHDRS scale, as well as imaging, quantitative motor assessments, and some additional neuropsychiatric testing.
HD INSIGHTS: Can you tell us briefly about the results?
SMITH: In the data that have been released, total motor score deterioration was approximately 34 percent slower in the RP103- treated patients compared to placebo at 18 months in the 89 patients who completed that phase of the trial. This was not statistically significant. When we received those results we naturally wanted to understand more about individual measures and results in the trial to decide if it was worthwhile to continue. We looked at the other medications that study patients were taking, because some medications, particularly the neuroleptics like tetrabenazine are known to have an effect on patient voluntary movement ability. Total motor score is a collection of 15 different individual tests that measure involuntary and voluntary movements, and involuntary chorea is one component of the total motor score, which comprises approximately ten percent of the overall score. Approximately 33 percent of the study patients were found to be taking tetrabenazine to control their chorea. We looked at the treatment groups of the patients not taking tetrabenazine and other neuroleptics and antipsychotics just to see if those other treatments could have had the effect that we saw – a positive trend – or whether it was directly attributable to RP103. In the 66 patients who did not take tetrabenazine and who were treated with RP103 or placebo, we saw a 57 percent slower progression of total motor score deterioration compared to placebo. This was statistically significant (p=0.03) and clinically significant, and encouraged us to look at the individual measurements and different components of total motor score. The French investigators are working very hard to get all the data assembled and published. In terms of safety, I should also note that there were no unexpected adverse events with RP103.
HD INSIGHTS: What are your plans for cysteamine?
SMITH: We are very positive about cysteamine’s potential in HD. The trial is ongoing, and we look forward to the 36 month results. As the second 18 months is open label with all patients taking RP103, we will not necessarily be able to compare the two arms of placebo treatment and continuous treatment with RP103 in terms of the total motor score, but there are other measurements such as imaging that may provide more insight into cysteamine’s effectiveness over the full course of 36 months. A 36-month trial is pretty challenging to pull off, but patient retention has been strong. All patients who have finished have insisted on staying on open-label extension treatment. We have been able to grant patients access to RP103 for that purpose and we’ll continue to do so until all patients complete their last treatment. We are in the process of speaking with regulators in the USA and Europe in an effort to clarify the path to approval of RP103 for use in HD.
HD INSIGHTS: Thank you very much for your time and for your interest in HD therapeutics.
SMITH: Thank you. It’s our pleasure and our purpose.
1 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.