Date: 2017-09-11
Type of
information: Presentation of results at a congress
phase: 2
Announcement: presentation of results at the American Society for Bone and Mineral Research (ASBMR) 2017 Annual Meeting
Company: Ultragenyx Pharmaceutical (USA - CA)
Product: burosumab - KRN23 (UX023)
Action
mechanism:
- monoclonal antibody. KRN23 is an investigational recombinant fully human monoclonal IgG1 antibody against the phosphaturic hormone FGF23 being developed to treat TIO and XLH, both of which are characterized by excess activity of FGF23. FGF23 is a hormone that reduces serum levels of phosphorus and vitamin D by regulating phosphate excretion and vitamin D production by the kidney. KRN23 is designed to bind to and thereby inhibit the excessive biological activity of FGF23. By blocking excess FGF23, KRN23 is intended to restore normal phosphate reabsorption from the kidney and increase the production of vitamin D, which enhances intestinal absorption of phosphate and calcium. Ultragenyx and Kyowa Hakko Kirin Co., Ltd. entered into a collaboration and license agreement in August 2013 to develop and commercialize KRN23.
Disease: tumor-induced osteomalacia (TIO)
Therapeutic
area: Rare diseases
Country:
Trial
details:
- The open-label, dose-finding Phase 2 clinical study is evaluating the safety and efficacy of KRN23 in 17 adult patients. The primary objectives of the study are to establish the dose, and assess the safety profile and efficacy of treatment with KRN23 in adults with TIO and ENS whose tumors or lesions cannot be resected. Patients receive subcutaneous injections of KRN23 once every four weeks for 48 weeks. All patients begin treatment with KRN23 at a starting dose of 0.3 mg/kg. Doses are then titrated in an effort to achieve a target fasting serum phosphorus range of 2.5 to 4.0 mg/dL. After completing the initial 48-week treatment period of the study, patients may continue into a planned treatment extension period in which they receive KRN23 treatment for up to an additional 96 weeks. The co-primary endpoints include: the proportion of patients achieving mean peak serum phosphorus levels above the lower limit of normal (LLN; 2.5 mg/dL), as averaged between baseline and week 24; and the percent change from baseline in excess osteoid after 48 weeks of treatment. Preliminary clinical effects of KRN23 treatment will be evaluated by radiographic assessments, muscle strength, walking ability, and by patient-reported measures of pain, disability, and quality of life. Markers of bone health and changes in serum phosphorus and other biochemical measures are also followed.
- Ultragenyx is conducting the Phase 2 study under a collaboration and license agreement with Kyowa Hakko Kirin to develop and commercialize KRN23. The japanese group is conducting a separate Phase 2 study evaluating the safety and efficacy of KRN23 in 12 adult patients in Japan.
Latest
news:
- • On September 11, 2017, Ultragenyx Pharmaceutical and Kyowa Hakko Kirin announced 24 week data from the phase 2 study of burosumab in adult tumor-induced osteomalacia patients. These data have been presented at the American Society for Bone and Mineral Research (ASBMR) 2017 Annual Meeting. The co-primary endpoints in this 48 week study are change in serum phosphorus and key biopsy parameters of osteomalacia. In 16 patients with baseline and week 24 data, mean serum phosphorus, renal phosphate reabsorption (TmP/GFR) and serum 1,25 dihydroxy vitamin D levels increased after the first dose and over 24 weeks of treatment. The baseline mean serum phosphorus level of 1.6 mg/dL was well below the lower limit of normal of 2.5 mg/dL. The mean serum phosphorus level entered the normal range within two weeks of treatment, and was maintained in the low normal range through week 24 of treatment. At week 24 there was a statistically significant increase in mean percent change from baseline levels (51% and 38% respectively) of the bone turnover markers, Procollagen type 1 N-terminal propeptide (P1NP) and collagen type 1 cross-linked C-telopeptide of type I collagen (CTx).
- All patients had moderate to severe osteomalacia at baseline as assessed by histomorphometric indices of osteomalacia. Four patients who completed 48 weeks of treatment had bone biopsy data. In three of these patients burosumab treatment was associated with improvements in histomorphometric indices of osteomalacia. One patient did not receive burosumab consistently. Burosumab demonstrated a clinically meaningful improvement in patient reported outcomes. At 24 weeks, patients experienced a statistically significant reduction in all four fatigue parameters as assessed by the Brief Fatigue Inventory. Burosumab also demonstrated a statistically significant increase in lower limb strength as seen with the increase in repetitions at 24 weeks in the Sit-to-Stand test. Adverse events occurred in all patients (n=16). Treatment-related adverse events were observed in seven patients (44%), and included, as previously disclosed, Vitamin D deficiency and rash, and dysgeusia, all mild in grade. Most adverse events were grade 1 or 2 and included two patients with injection site reactions and two patients with restless leg syndrome that were previously disclosed. Three patients had a serious adverse event (previously disclosed tumor progression, thoracic epidural tumor compression, and a mesenchymal tumor progression). None of the serious adverse events were considered treatment related and all of these patients had a history of tumor progression at baseline and one patient discontinued to treat their tumor progression. No clinically meaningful changes were observed in mean serum calcium, urinary calcium and in serum intact parathyroid hormone.
- • On September 18, 2016, Ultragenyx Pharmaceutical announced the presentation of positive interim data from the Phase 2 study of KRN23 for the treatment of tumor-induced osteomalacia (TIO) at the American Society for Bone and Mineral Research (ASBMR) 2016 Annual Meeting. Interim data at 24 weeks from the first eight patients, including one patient with epidermal nevus syndrome (ENS), demonstrated that KRN23 improved serum phosphorus levels and bone metabolism measures. Mean serum phosphorus, renal phosphate reabsorption (TmP/GFR) and serum 1,25 dihydroxy vitamin D levels increased over 24 weeks of treatment. Before KRN23 treatment and after washout with any oral phosphate treatment, the mean serum phosphorus level was 1.7 mg/dL, well below the lower limit of normal of 2.5 mg/dL. The mean serum phosphorus level entered the normal range within one week of treatment, and was maintained in the low normal range from week 10 to week 24 of treatment. Overall, the improvement in serum phosphorus and other bone mineral metabolism measures observed in this study to date is generally consistent with what has been observed in studies of KRN23 in pediatric and adult patients with X-linked hypophosphatemia.
- Of the seven patients who responded, six patients showed an improvement in bone mineral density at 24 weeks of treatment. Bone turnover markers, including Procollagen type 1 N-terminal propeptide (P1NP) and C-telopeptide of type I collagen (CTX-1), showed a statistically significant increase. One patient completed 48 weeks of treatment, at which time bone biopsies indicated an improvement from severe osteomalacia at baseline to mild osteomalacia at 48 weeks. The same patient showed resolution of four fractures at 24 weeks of treatment, determined by bone scan as previously disclosed. Bone mineral density for this patient improved 2% and 3% in the lumber spine and total hip, respectively. Bone biopsy and bone scan data for additional patients will be available at a later date.
Adverse events occurred in all patients. Treatment-related adverse events were observed in three patients (38%), and included Vitamin D deficiency and rash as previously disclosed, and dysgeusia, all mild in grade. There was one serious adverse event of neoplasm progression, which occurred in one patient with pre-existing metastatic spindle sarcoma who did not respond and has discontinued treatment. No injection site reactions were observed. Two patients had restless leg syndrome, one of whom had symptoms suggestive of worsening pre-existing restless leg syndrome. No clinically meaningful changes were observed in mean serum calcium, urinary calcium and in serum intact parathyroid hormone.
• On January 6, 2015, Ultragenyx Pharmaceutical announced the initiation of a new development program for KRN23 (UX023) in tumor-induced osteomalacia (TIO). The company intends to initiate a Phase 2 study in six adult TIO patients in the first half of 2015. The study will consist of a 16-week individual dose-titration period followed by a 28-week treatment period. The goal of the dose-titration period is to identify the individualized dose of KRN23 required to achieve stable serum phosphorus levels in the target range. Patients will receive subcutaneous injections of KRN23 once every four weeks.
Is
general: Yes
