Date: 2016-07-14
Type of information: Presentation of results at a congress
phase: 3
Announcement: presentation of results at the 14th International Symposium on MPS and Related Diseases in Bonn, Germany
Company: Ultragenyx Pharmaceutical (USA - CA)
Product: recombinant human beta-glucuronidase (rhGUS, UX003)
Action
mechanism: enzyme replacement therapy. Mucopolysaccharidosis 7 is caused by a deficiency of the lysosomal enzyme beta-glucuronidase, which is required for the breakdown of certain complex carbohydrates known as glycosaminoglycans (GAGs). The inability to break down GAGs leads to their accumulation in many tissues, resulting in serious disease. Patients with MPS 7 may have abnormal coarsened facial features, enlargement of the liver and spleen, airway obstruction, lung disease, cardiovascular complications, joint stiffness, short stature, and skeletal disease. Glucuronidase (GUS) is an enzyme found in the lysosome that when taken up into cells efficiently by a particular receptor results in the delivery of the GUS enzyme into the lysosomes and clearance of stored GAGs. Preclinical studies of the chronic administration of rhGUS results in a reduction of tissue pathology in the liver, spleen, lung, heart, kidney, muscle, bone and brain.
Disease: mucopolysaccharidosis 7 (MPS 7, Sly syndrome)
Therapeutic area: Rare diseases - Genetic diseases - Metabolic diseases
Country: USA
Trial
details: The Phase 3 study will use a novel randomized, intra-subject placebo-controlled, single crossover design, referred to as Blind Start, to evaluate the safety and efficacy of UX003 (NCT02230566)
Latest
news: * On July 14, 2016, Ultragenyx Pharmaceutical announced topline data from the pivotal Phase 3 study of recombinant human beta-glucuronidase (rhGUS, UX003), an investigational therapy for the treatment of Mucopolysaccharidosis 7 (MPS 7, Sly syndrome). The study met its primary endpoint of reducing urinary GAG (dermatan sulfate) excretion after 24 weeks of treatment, demonstrating a reduction from baseline of 64.8 percent (p<0.0001). The data are being presented at the 14th International Symposium on MPS and Related Diseases. * On June 8, 2015, Ultragenyx Pharmaceutical, a biopharmaceutical company focused on the development of novel products for rare and ultra-rare diseases, announced it has completed patient enrollment in the pivotal Phase 3 study of recombinant human beta-glucuronidase (rhGUS, UX003), an investigational therapy for the treatment of Mucopolysaccharidosis 7 (MPS 7, Sly syndrome). The study was initiated in December 2014 and the company looks forward to completing the study and announcing results in 2016. The Phase 3 randomized, placebo-controlled, blind-start clinical study being conducted at five sites in the U.S. is designed to assess the efficacy and safety of rhGUS in 12 patients between 5 and 35 years of age. Patients are randomized to one of four groups. One cohort begins rhGUS therapy immediately, while the other three start on placebo and cross over to rhGUS at different predefined time points in a blinded manner. The primary objective of the study is to determine the efficacy of rhGUS as determined by the reduction in urinary GAG excretion after 24 weeks of treatment. Secondary efficacy objectives include a multi-domain responder index and an individualized clinical response measure, as well as other clinical outcomes including pulmonary function, walking, shoulder flexion, fine and gross motor function, visual acuity, and fatigue. The safety and tolerability of rhGUS will also be assessed. * On December 15, 2014, Ultragenyx Pharmaceutical announced the dosing of the first patient in the pivotal Phase 3 study of recombinant human beta-glucuronidase (rhGUS, UX003), an investigational therapy for the treatment of mucopolysaccharidosis 7 (MPS 7, Sly syndrome). The Phase 3 global, randomized, placebo-controlled, blind-start clinical study will assess the efficacy and safety of rhGUS in 12 patients between 5 and 35 years of age. Patients will be randomized to one of four groups. One cohort begins rhGUS therapy immediately, while the other three start on placebo and cross over to rhGUS at different predefined time points in a blinded manner. This novel trial design generates treatment data from all 12 patients, improving the statistical power of the study relative to a traditional parallel-group design. Based on data from the Phase 1/2 study, patients will be dosed with 4 mg/kg of rhGUS every other week for up to a total of 48 weeks, and all groups will receive a minimum of 24 weeks of treatment with rhGUS. The primary objective of the study is to determine the efficacy of rhGUS as determined by the reduction in urinary GAG excretion after 24 weeks of treatment. The Phase 3 study will also evaluate the safety and tolerability of rhGUS, pulmonary function, walking, stair climb, shoulder flexion, fine and gross motor function, hepatosplenomegaly, cardiac size and function, visual acuity, patient and caregiver assessment of most significant clinical problems, global impressions of change, a multi-domain responder index, and other endpoints. Agreement with the FDA was reached that their evaluation of the pivotal Phase 3 study will be based on the totality of the data on a patient-by-patient basis. FDA advised against the declaration of a primary clinical endpoint in order to allow for more flexibility in the overall efficacy evaluation, appreciating the heterogeneous and rare nature of this disease. The European Medicines Agency (EMA) has already agreed that approval under exceptional circumstances could be possible based upon a single positive Phase 3 study using urinary GAG excretion as the primary endpoint with a trend toward improvement in the most important clinical endpoints (six-minute walk test, forced expiratory volume, spleen/liver volume). Data from the Phase 3 study is expected in the first half of 2016. Longer-term 36-week data from the Phase 1/2 study is expected to be presented at the Lysosomal Disease Network's 11th Annual World Symposium in February 2015. Two additional patients continue to be treated under emergency Investigational New Drug (eIND) applications.
The study provides evidence of clinical improvement with rhGUS treatment. The Multi-domain Responder Index (MDRI) score at 24 weeks of treatment, a secondary endpoint, demonstrated an overall mean improvement (±SD) of +0.5 domains (±0.80) (p=0.0527). Six of the 12 patients had an improvement in their MDRI score of +1 or more. Five patients demonstrated no worsening of this progressive disease, or an MDRI score of 0. One patient had an MDRI score of -1. The MDRI is a summation of scores from each of the following domains: the six-minute walk test (6MWT), forced vital capacity (FVC), shoulder flexion, visual acuity, and the Bruininks-Oseretsky Test of Motor Proficiency (BOT-2) fine motor and gross motor function. For each domain, patients received a score of +1 when they demonstrated improvement of a magnitude equal or greater than a pre-defined minimally important difference (MID), -1 for worsening of one MID or greater, and 0 for any change that was less than 1 MID. As expected, many patients were unable to perform one or more tests due to physical or cognitive limitations and were not evaluated on those tests.
For the 6MWT, the improvement (±SE) was 20.8 (±16.75) meters at 24 weeks of treatment based on the estimates from 9 patients who had any change from baseline data. Three of these patients demonstrated an improvement of a magnitude equal or greater than the MID with increases of 65 meters, 80 meters and 83 meters at 24 weeks compared to baseline. For the fatigue scores, four patients improved at or above the MID level after 24 weeks of treatment and nine of 12 showed improvement at some point during the study.
All patients experienced treatment emergent adverse events, which were generally mild to moderate in severity. Six of the eight patients with infusion associated reactions (IARs) on rhGUS treatment had events involving the IV catheter. There were two patients that each had a single hypersensitivity-type IAR, including one Grade 3 treatment-related anaphylactoid serious adverse event (SAE) that resulted from an infusion rate error. The second patient had mild fever and diaphoresis that resolved without treatment. No patients demonstrated recurring hypersensitivity reactions to infusions. There was a second SAE that was a Grade 2 unrelated event from an accidental injury. There were no deaths and no treatment discontinuations or missed infusions due to AEs. Seven of the 12 patients developed anti-rhGUS antibodies, which were not associated with immune-mediated AEs.
Based on these data, Ultragenyx plans to meet with the FDA and EMA this year to discuss plans to submit regulatory filings in the first half of 2017.
