The clinical development of Aldurazyme was initiated in December 1997, and it represented the first industry-sponsored ERT study in any MPS disorder. However, investigator-initiated clinical studies and reports on the result of BMT did not adequately establish the clinical variation or quantitative clinical endpoints that might be of use in the study of a novel therapeutic. The lack of significant quantitative information on both the disease and clinical measures, and the rarity and variability of disease expression made the establishment of a clinical development program particularly difficult.
To establish the possible clinical problems appropriate for study, MPS I disease and known clinical evaluations used in MPS I were reviewed. The potential medical problems that seemed most appropriate for study included the enlarged liver and spleen, the joint stiffness, the airway problems with associated sleep apnea, respiratory insufficiency, the diverse cardiac problems, recurrent infections, and the eye disease. Other compound clinical problems that were studied, but with more difficulty, included the fatigue/malaise, severe headaches, the enlarged tongue, and signs of cord compression. Besides clinical measures, the elevated level of GAG in the urine, which reflects excessive renal distal tubular storage, is commonly used as a screen for MPS disease as well.
To establish the possible treatment effects that could be measured in the initial clinical study, the data from the preclinical studies in the MPS I dog with rhIDU, the reports of BMT in MPS I, and the first published clinical study of Ceredase in Gaucher's disease were reviewed. Based on the data from the MPS I dogs undergoing enzyme therapy, both liver storage and urinary GAG were found to be effective measures of lysosomal storage that did accurately reflected the storage in diverse tissues. These measures of storage did decline sharply within weeks of initiating enzyme therapy, suggesting that even a few doses of rhIDU were sufficient to reduce storage in vivo. These data were corroborated by the data from MPS I patients posttransplantation that showed a quantitative result in one patient and other qualitative clinical reports of liver-size reduction. Urinary GAG excretion did decrease after BMT, although the actual published clinical data were limited. The data from MPS I dog studies also showed substantial clearance of the synovial engorgement consistent with apparent effects of improved mobility in an MPS I dog after therapy for 1 year. The improvement in joint mobility was also qualitatively noted in BMT. The improvement in lymphoid storage in dogs suggested that the soft tissues storage that blocks the airway might improve, and data from BMT showed improvement in sleep apnea. The changes in cardiac disease in the dog were limited and the long time frame for cardiac disease progression and its irre-versibility, especially for valve disease, made this measure less useful for clinical studies. Based on these and other information, the first clinical endpoints were established.
Business, regulatory, and clinical strategy also shaped the design of the first clinical study. The program focused on achieving a significant clinical efficacy and safety result in the first study. Given that the enzyme was a recombinant form of the natural human protein, it was potentially reasonable to treat the compound differently from a new chemical entity. Given the rarity of the disorder (an incidence of ~1:80 to 100,000 births), the young age of the patients, and the intravenous infusions required per week, it was initially thought that a small open-label study comparable to that used for the approval of Ceredase (12 patients, open label) was possible. Given that Ceredase was approved on that single open-label study, the regulatory strategy was to replicate this strategy for the use of rhIDU to treat MPS I.
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