The efficacy of XURIDEN was evaluated in a 6-week open-label study in 4 patients with hereditary orotic aciduria (3 male, 1 female; age range from 3 to 19 years). Three patients were previously treated with uridine and were switched at study entry to XURIDEN. All patients were administered XURIDEN orally at a daily dosage of 60 mg/kg once daily. Following the initial 6-weeks, all 4 patients continued to receive XURIDEN daily in the extension phase of the study at dosages of 60 to 120 mg/kg for a total duration of 24 months.

The study assessed changes in the patients' pre-specified hematologic parameters during the initial 6-week period and the extension phase. The pre-specified hematologic parameters were: neutrophil count and percent neutrophils (Patient 1), white blood cell count (Patient 2), and mean corpuscular volume (Patients 3 and 4). For patients switched from oral uridine to oral XURIDEN (Patients 1, 2, and 3), the primary endpoint was stability of the hematologic parameter; for the treatment-naïve patient (Patient 4), the primary endpoint was improvement of the hematologic parameter.

Secondary endpoints were urine orotic acid and orotidine levels, and growth (height and weight) for all patients.

Table 4 summarizes the changes in the patients' pre-specified hematologic parameters at Week 6 and 24 Months compared to baseline. After 6 weeks of treatment, Patients 1 and 3 met the pre-specified criteria for stability of the hematologic parameter. When Patient 2 was switched from uridine to XURIDEN treatment, the pre-specified parameter of white blood cell count remained stable; however, documentation of a low white blood cell count prior to uridine initiation was not available. Patient 4 did not meet the pre-specified endpoint of improvement of the hematologic parameter.

By 24 months of treatment with XURIDEN, the pre-specified hematologic parameter for Patient 1 worsened, but the assessment was confounded by Cohen syndrome with associated neutropenia, which was diagnosed after the patient completed the study. The pre-specified hematologic parameters for Patients 2, 3, and 4 remained essentially unchanged.

At baseline, Patients 1, 2, and 3, previously treated with uridine, had normal urine orotic acid levels, and those remained stable after 6 weeks of treatment with XURIDEN. All four patients had normal urine orotidine levels at baseline which remained stable after 6 weeks of treatment with XURIDEN. After 24 months of treatment, urine orotic acid and orotidine levels remained stable in all four patients.

The treatment effect of XURIDEN on growth was assessed in the three pediatric patients (Patients 1, 3, and 4). At baseline, weight and height were at or below the lower limit of normal for age for all three patients. After 24 months of treatment, each patient's growth parameters remained essentially unchanged.

Case reports

Nineteen (19) case reports of patients with hereditary orotic aciduria have been documented in published literature. Eighteen (18) patients were diagnosed as infants or children between the ages of 2 months and 12 years and were treated with exogenous sources of uridine. One patient, diagnosed at age 28, was not treated with exogenous uridine.

All 19 patients presented with significantly elevated levels of urinary orotic acid. Fifteen of 19 had abnormal hematologic parameters at presentation, including 15 with megaloblastic anemia, 8 with leukopenia and at least 2 with neutropenia. Oral administration of exogenous sources of uridine was reported to significantly improve hematologic abnormalities (megaloblastic anemia, leukopenia and neutropenia) within 2 to 3 weeks in almost all documented cases when administered in sufficient amounts. Concentrations of urinary orotic acid were significantly reduced within 1 to 2 weeks of initiating uridine replacement therapy. Some fluctuation in levels of urinary orotic acid were observed, but always at much lower levels than those reported prior to treatment. Improvements in body weight were also documented over time with continued uridine replacement therapy.

The effects of exogenous uridine were maintained over months and years, as long as treatment continued at sufficient doses (with appropriate dose increases based on body weight increases). Most hematologic abnormalities and orotic aciduria reappeared within days up to 2 or 3 weeks when administration of uridine was stopped or the dose was reduced. If treatment was interrupted for longer periods, body weight growth receded. If absolute dosages were not adjusted adequately to compensate for body weight gains, signs and symptoms of hereditary orotic aciduria recurred.