Clinical Trials

Date: 2017-04-18

Type of information: Results

phase: 3

Announcement: results

Company: Ultragenyx Pharmaceutical (USA - CA) Kyowa Hakko Kirin (Japan)

Product: burosumab - recombinant human monoclonal IgG1 antibody for fibroblast growth factor 23/KRN23

Action mechanism:

• monoclonal antibody. KRN23 is an investigational recombinant fully human monoclonal IgG1 antibody, discovered by Kyowa Hakko Kirin, against the phosphaturic hormone fibroblast growth factor 23 (FGF23). It is being developed to treat X- linked hypophosphataemia, a disease 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. Phosphate wasting in XLH is caused by excessive levels and activity of FGF23. KRN23 is designed to bind to and thereby inhibit the excessive biological activity of FGF23. By blocking excess FGF23 in patients with XLH, 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 entered into a collaboration and license agreement in August 2013 to develop and commercialize KRN23.

Disease: X-linked Hypophosphatemia

Therapeutic area: Rare diseases - Genetic diseases - Metabolic diseases

Country: Canada, Denmark, France, Ireland, Italy, Japan, Republic of Korea, UK, USA

Trial details:

• UX023-CL303 is a phase 3 multicenter, randomized, double-blind, placebo-controlled study to evaluate the efficacy and safety of KRN23 in adult subjects with XLH. Approximately 120 subjects with a diagnosis of XLH supported by clinical and biochemical features consistent with XLH and/or a confirmed PHEX mutation (self or family member consistent with X-linked inheritance) and with bone or joint pain at baseline will be enrolled. Subjects not receiving supplementation therapy with oral phosphate and active vitamin D metabolites or those willing to discontinue supplementation therapy are eligible. (NCT02526160) Ultragenyx is conducting a second, fully-enrolled open-label bone quality Phase 3 study in 14 adult XLH patients evaluating the improvement in osteomalacia, the underlying bone pathology of XLH, via bone biopsy. The bone quality study complements the phosphate and patient symptom data from the larger Phase 3 XLH study by evaluating the effect of burosumab more directly on the bone.

Latest news:

• • On April 18, 2017, Ultragenyx Pharmaceutical, Kyowa Hakko Kirin and Kyowa Kirin International announced positive 24-week data from the randomized, double-blind, placebo-controlled Phase 3 study of burosumab in adults with X-linked hypophosphatemia. Patients treated with burosumab demonstrated a statistically significant improvement in serum phosphorus levels, with 94% of patients achieving normal levels compared to 8% on placebo. Patients treated with burosumab also achieved a statistically significant improvement in stiffness and strong trends in improvements in physical function and pain. Adverse events were consistent with what has been previously observed in open label studies in adults and children. Efficacy Results: The study enrolled 134 patients, randomized 1:1 to burosumab at a dose of 1 mg/kg or placebo every four weeks for 24 weeks. The study met the primary endpoint of increasing serum phosphorus levels as 94% of patients treated with burosumab (n=68) achieved serum phosphorus levels above the lower limit of normal and maintained levels in the low normal range through 24 weeks, compared to 8% in the placebo arm (n=66). There were three pre-specified key secondary endpoints, including stiffness and physical function, both measured by the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC®), and pain measured by the Brief Pain Inventory Question 3 (BPI Q3; pain at its worst in the last 24 hours). At week 24 stiffness improved by a mean score of 7.87 points for patients treated with burosumab compared to a 0.25 point worsening among patients in the placebo group (mean difference of 8.12; p=0.0122). Physical function improved by 3.11 points for patients treated with burosumab compared to a 1.79 point worsening among patients in the placebo group (mean difference of 4.90 points; p=0.0478). Pain score improved by 0.79 for patients treated with burosumab compared to a 0.32 improvement among patients in the placebo group (mean score difference of 0.46 points; p=0.0919). Results were directionally consistent towards improvement across all three key secondary endpoints. After pre-planned multiplicity adjustment, the improvement in stiffness among patients treated with burosumab remained statistically significant at the less than the 0.0167 threshold, while physical function and pain scores demonstrated strong trends. Safety Results: There was no difference in the overall frequency of treatment emergent adverse events, treatment related adverse events and serious adverse events between the two treatment groups. The most common (>10%) adverse events in patients treated with either burosumab or placebo were back pain (burosumab 15%, placebo 9%), nasopharyngitis (burosumab 13%, placebo 9%), tooth abscess (burosumab 13%, placebo 8%), injection site reactions (burosumab 12%, placebo 12%), headache (burosumab 12%, placebo 8%), restless legs syndrome (burosumab 12%, placebo 8%), dizziness (burosumab 10%, placebo 6%), nausea (burosumab 10%, placebo 9%), arthralgia (burosumab 9%, placebo 24%), pain in extremity (burosumab 7%, placebo 15%) and oropharyngeal pain (burosumab 2%, placebo 11%). There was no evidence of hypersensitivity reactions to injections. There were two serious adverse events in each treatment group, none of which were considered treatment-related. No differences between groups were observed in serum intact parathyroid hormone levels or ectopic mineralization as assessed by renal ultrasounds or echocardiograms. Of the 134 patients enrolled in the study, one patient in the burosumab arm discontinued treatment during the 24-week double-blind treatment period due to consent withdrawal. There have been no deaths in the study.
• • On July 28, 2016, Ultragenyx Pharmaceutical announced that it has completed patient enrollment in the Phase 3 study of KRN23 for the treatment of adults with X-linked hypophosphatemia (XLH). Data from the study are expected in 2017.
• •  On December 3, 2015, Ultragenyx Pharmaceutical announced the initiation of the Phase 3 study of KRN23 for the treatment of adults with XLH (X-linked hypophosphatemia).  The primary endpoint of the study will be serum phosphorus levels through 24 weeks and the key secondary endpoint is the Brief Pain Inventory Question 3 (pain at its worst in the last 24 hours) at Week 24. Other secondary endpoints include patient reported outcomes assessing skeletal pain, stiffness, fatigue, motor function, and quality of life in these patients.

Is general: Yes