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Focusing on rare and ultra-rare diseases
November 2015
by Lloyd Dunlap  |  Email the author
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NOVATO, Calif.—Ultragenyx Pharmaceutical Inc., a biopharmaceutical company focused on the development of novel products for rare and ultra-rare diseases, has reported positive interim data on the acute effects of the investigational treatment UX007 (triheptanoin) at the end of the initial 24-week treatment period of the Phase 2 study in long-chain fatty acid oxidation disorder (LC-FAOD) patients.
 
“We are encouraged by these positive exercise tolerance and safety interim results, which add to the growing body of data that support the continued development of UX007 in LC-FAOD,” said Dr. Sunil Agarwal, chief medical officer of Ultragenyx. “We look forward to discussing the data with regulatory authorities to define appropriate next steps.”
 
UX007 is one of several drugs in the Ultragenyx pipeline that share a common characteristic—they have all been in-licensed by the company from various corporate and academic sources. For example, KRN23 resulted from a collaboration and license agreement with Kyowa Hakko Kirin Co., Ltd.; rhGUS, an investigational enzyme replacement therapy for MPS 7, from Saint Louis University; rhPPCA, an investigational enzyme replacement therapy for galactosialidosis, was licensed from St. Jude Children’s Research Hospital; UX007 (triheptanoin) was licensed from Baylor Research Institute, UniQuest and Inserm; and aceneuramic acid, an investigational therapy in development for GNE Myopathy, from Nobelpharma, AAIPharma and the HIBM Research Group.
 
This business model helps explain how the company can be committed to bringing to market novel products for the treatment of rare and ultra-rare diseases, with a focus on serious, debilitating genetic diseases. Founded in 2010, Ultragenyx has rapidly built a diverse portfolio of product candidates with the potential to address diseases for which the unmet medical need is high, the biology for treatment is clear and for which there are no approved therapies.
 
The company is led by a management team experienced in the development and commercialization of rare disease therapeutics. Ultragenyx’s strategy is predicated upon time- and cost-efficient drug development, with the goal of delivering safe and effective therapies to patients with the utmost urgency.
 
The current single-arm, open-label Phase 2 study evaluated 29 pediatric and adult patients across three main symptom groups (musculoskeletal, liver/hypoglycemia and cardiac). Patients needed to have moderate to severe FAOD with significant disease in at least one of these domains or a frequent medical events history in order to enroll. The study began with a four-week run-in period to assess baseline data while on the standard of care therapy including medium-chain triglyceride (MCT) oil, if applicable. The patients were then followed to evaluate the effects of UX007 treatment over 24 weeks on several endpoints, including cycle ergometer performance, 12-minute walk test (12MWT), liver disease/hypoglycemia, cardiac disease and quality of life.
 
The 24-week analysis mainly evaluated the acute effects of UX007 on the musculoskeletal aspects of the disease. The last assessment in this analysis occurred at 18 weeks for the 12MWT and at 24 weeks for the cycle ergometry assessment. The administration of these tests was staggered in order to avoid patient exhaustion during a single visit. Patients who opt to continue will be treated for a total of 78 weeks, and rates of major medical events, such as rhabdomyolysis, hypoglycemia and cardiac events, will be monitored and compared to rates for the two years prior to treatment with UX007. The goal of the study is to evaluate the safety and tolerability of UX007 and to determine both the appropriate patient population as well as endpoints for evaluation in a Phase 3 study. These Phase 2 interim results are based on open-label uncontrolled treatment referenced to baseline run-in period for each patient, which limits definitive conclusions about efficacy and safety.
 
The majority of patients enrolled presented with musculoskeletal disease compared to a limited number who presented with liver and cardiac symptoms. Patients spanned a wide age range from 10 months old to 58 years old. Patients with four LC-FAOD genotypes were enrolled: 12 (41 percent) with VLCAD, 10 (35 percent) with LCHAD, four (14 percent) with CPT-II, and three (10 percent) with TFP. Prior to initiating treatment with UX007, 27 of the 29 patients were on the standard-of-care MCT oil therapy. UX007 was then titrated to a target dose of 25 to 35 percent of total daily caloric intake. The average dose of UX007 through 24 weeks was 30 percent of total daily caloric intake.
 
Four of the 29 enrolled patients discontinued prior to 24 weeks, one of which was attributed to an adverse event (diarrhea) from treatment with UX007. Patients performed only the assessments that were appropriate and valid for their age when they entered the study; therefore not all patients performed all assessments included in the study design.
 
Improvements were observed in both measures of exercise tolerance in patients who performed the tests. Improvements in adult patient-reported quality-of-life scores were also observed in those patients, but no difference was seen in parent-reported scores for pediatric patients.
 
Overall major medical events appeared to decrease in the 25 patients who completed the 24 weeks of treatment when compared to the reported event rate in these patients in the 18 to 24 months prior to treatment with UX007. These data are preliminary and require significantly more time for proper evaluation at the 78 week time-point. The major medical event rate aggregates events related to hypoglycemia, rhabdomyolysis and cardiomyopathy.
 
All 25 patients opted to continue to be treated for a total of 78 weeks. Data after 78 weeks, including rates of major medical events before and after treatment with UX007, are expected to be released in the second half of 2016.
 
Based on these interim Phase 2 data, Ultragenyx intends to begin planning for a Phase 3 study of UX007 in LC-FAOD. An update on the design and timing of the Phase 3 study will be provided after discussions with regulatory authorities in the first half of 2016.
 
LC-FAOD are a group of autosomal recessive genetic disorders characterized by metabolic deficiencies in which the body is unable to convert long-chain fatty acids into energy. The inability to produce energy from fat can lead to severe depletion of glucose in the body, and serious liver, muscle and heart disease, which can lead to hospitalizations or early death. LC-FAOD are included in newborn screening panels across the United States and in certain European countries. LC-FAOD patients are currently treated with the avoidance of fasting, low-fat/high carbohydrate diets, carnitine and MCT oil, a medical food product. Despite current therapy, many patients have significant metabolic events including hospitalizations and mortality due to LC-FAOD.
 
UX007 is a purified, pharmaceutical-grade form of triheptanoin, a specially designed synthetic triglyceride compound, created via a multi-step chemical process. It is an investigational medicine intended to provide patients with medium-length, odd-chain fatty acids that can be metabolized to increase intermediate substrates in the Krebs cycle, a key energy-generating process. Unlike typical even-chain fatty acids, UX007 can be converted to new glucose through the Krebs cycle, potentially providing an important added therapeutic effect, particularly when glucose levels are too low.
 
Code: E111518

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