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Item Burosumab Provides Sustained Improvement in Phosphorus Homeostasis and Heals Rickets in Children Aged 1 to 4 Years With X-Linked Hypophosphatemia (XLH)(Oxford University Press, 2021) Gottesman, Gary; Imel, Erik Allen; Carpenter, Thomas O.; Chen, Angel; Skrinar, Alison; Roberts, Mary Scott; Whyte, Michael P.; Medicine, School of MedicineXLH is the most common heritable rickets. Affected children have high levels of circulating FGF23 that cause hypophosphatemia with consequent rickets and lower limb deformity. Burosumab, a fully human monoclonal antibody that binds FGF23, is FDA-approved for the treatment of XLH in children ≥6 months old and adults. Herein, we report final, 3-year safety and efficacy data from an open-label, phase 2 study of burosumab in children 1 to <5 years old at baseline (NCT02750618). Eligibility required hypophosphatemia and radiographic evidence of rickets. The primary efficacy endpoint was change from baseline in fasting serum phosphorus (Pi). Secondary endpoints included Rickets Severity Score (RSS) and Radiographic Global Impression of Change (RGI-C). Patients received burosumab subcutaneous Q2W starting at 0.8 mg/kg for 160 weeks (64-week treatment + 96-week treatment extension periods). All 13 enrolled patients completed the 64-week treatment period; 1 left the study to transition to commercially available burosumab, and 12 completed all 160 weeks. Baseline mean (SD) age was 2.9 (1.1) years; 69% were boys; all had previously received oral phosphate salts and active vitamin D. Burosumab rapidly corrected fasting serum Pi with mean (SD) levels of 2.5 (0.3) mg/dL at Baseline, 3.7 (0.5) mg/dL at Week 1 (W1), 3.4 (0.5) mg/dL at W64, and 3.4 (0.5) mg/dL at W160 (normal range: 3.2–6.1 mg/dL). Lower RSS indicated improved rickets. Total RSS decreased from 2.9 (1.4) at Baseline to 1.2 (0.5) at W40 and to 0.9 (0.5) at W64 and was maintained through W160 [1.0 (0.6)]. Positive RGI-C scores indicate healing rickets relative to Baseline. Global RGI-C scores indicating substantial healing (≥+2) at W40 [+2.2 (0.3)] and W64 [+2.2 (0.4)] were maintained through W160 [+2.2 (0.4)]. Similarly, lower limb deformity RGI-C scores were +1.2 (0.6) at W40 and +1.5 (0.5) at W64, and sustained healing was evident at W160 [+2.0 (0.3)]. Wrist and knee RSSs and RGI-C scores similarly improved. The upper limit of normal for serum ALP ranged from 297 to 345 U/L depending on the child’s age and sex. Mean ALP was 549 (194) U/L at Baseline, normalized by W40 [335 (88) U/L], and was sustained through W160 [302 (71) U/L]. The burosumab safety profile over 160 weeks resembled previous pediatric studies; no new safety concerns emerged. All patients had ≥1 treatment-emergent adverse event (TEAE). All TEAEs were mild (Grade 1) or moderate (Grade 2) except for one patient with a grade 3 TEAE (food allergy) and one with a grade 3 TEAE (increased serum amylase, 92% salivary/8% pancreatic). One patient had a serious TEAE (dental abscess leading to hospitalization). These grade 3 and serious TEAEs were considered unrelated to study drug. Burosumab rapidly restored Pi homeostasis, improved rickets, and normalized serum ALP in children with XLH aged 1 to <5 years with no new safety concerns. Improvements were maintained during the 3 years of treatment.Item Burosumab vs Phosphate/Active Vitamin D in Pediatric X-Linked Hypophosphatemia: A Subgroup Analysis by Dose Level(The Endocrine Society, 2023) Imel, Erik A.; Glorieux, Francis H.; Whyte, Michael P.; Portale, Anthony A.; Munns, Craig F.; Nilsson, Ola; Simmons, Jill H.; Padidela, Raja; Namba, Noriyuki; Cheong, Hae Il; Pitukcheewanont, Pisit; Sochett, Etienne; Högler, Wolfgang; Muroya, Koji; Tanaka, Hiroyuki; Gottesman, Gary S.; Biggin, Andrew; Perwad, Farzana; Chen, Angel; Scott Roberts, Mary; Ward, Leanne M.; Medicine, School of MedicineContext: In an open-label, randomized, controlled, phase 3 trial in 61 children aged 1 to 12 years with X-linked hypophosphatemia (XLH), burosumab improved rickets vs continuing conventional therapy with active vitamin D and phosphate. Objective: We conducted an analysis to determine whether skeletal responses differed when switching to burosumab vs continuing higher or lower doses of conventional therapy. Methods: Conventional therapy dose groups were defined as higher-dose phosphate [greater than 40 mg/kg] (HPi), lower-dose phosphate [40 mg/kg or less] (LPi), higher-dose alfacalcidol [greater than 60 ng/kg] or calcitriol [greater than 30 ng/kg] (HD), and lower-dose alfacalcidol [60 ng/kg or less] or calcitriol [30 ng/kg or less] (LD). Results: At week 64, the Radiographic Global Impression of Change (RGI-C) for rickets was higher (better) in children randomly assigned to burosumab vs conventional therapy for all prebaseline dose groups: HPi (+1.72 vs +0.67), LPi (+2.14 vs +1.08), HD (+1.90 vs +0.94), LD (+2.11 vs +1.06). At week 64, the RGI-C for rickets was also higher in children randomly assigned to burosumab (+2.06) vs conventional therapy for all on-study dose groups: HPi (+1.03), LPi (+1.05), HD (+1.45), LD (+0.72). Serum alkaline phosphatase (ALP) also decreased in the burosumab-treated patients more than in the conventional therapy group, regardless of on-study phosphate and active vitamin D doses. Conclusion: Prior phosphate or active vitamin D doses did not influence treatment response after switching to burosumab among children with XLH and active radiographic rickets. Switching from conventional therapy to burosumab improved rickets and serum ALP more than continuing either higher or lower doses of phosphate or active vitamin D.Item Conditional Deletion of Murine Fgf23: Interruption of the Normal Skeletal Responses to Phosphate Challenge and Rescue of Genetic Hypophosphatemia(Wiley, 2016-06) Clinkenbeard, Erica L.; Cass, Taryn A.; Ni, Pu; Hum, Julia M.; Bellido, Teresita; Allen, Matthew R.; White, Kenneth E.; Department of Medical and Molecular Genetics, School of MedicineThe transgenic and knockout (KO) animals involving Fgf23 have been highly informative in defining novel aspects of mineral metabolism, but are limited by shortened lifespan, inability of spatial/temporal FGF23 control, and infertility of the global KO. To more finely test the role of systemic and genetic influences in FGF23 production, a mouse was developed that carried a floxed ("f")-Fgf23 allele (exon 2 floxed) which demonstrated in vivo recombination when bred to global-Cre transgenic mice (eIIa-cre). Mice homozygous for the recombined allele ("Δ") had undetectable serum intact FGF23, elevated serum phosphate (p < 0.05), and increased kidney Cyp27b1 mRNA (p < 0.05), similar to global Fgf23-KO mice. To isolate cellular FGF23 responses during phosphate challenge, Fgf23(Δ/f) mice were mated with early osteoblast type Iα1 collagen 2.3-kb promoter-cre mice (Col2.3-cre) and the late osteoblast/early osteocyte Dentin matrix protein-1-cre (Dmp1-cre). Fgf23(Δ/f) /Col2.3-cre(+) and Fgf23(Δ/f) /Dmp1-cre(+) exhibited reduced baseline serum intact FGF23 versus controls. After challenge with high-phosphate diet Cre(-) mice had 2.1-fold to 2.5-fold increased serum FGF23 (p < 0.01), but Col2.3-cre(+) mice had no significant increase, and Dmp1-cre(+) mice had only a 37% increase (p < 0.01) despite prevailing hyperphosphatemia in both models. The Fgf23(Δ/f) /Col2.3-cre was bred onto the Hyp (murine X-linked hypophosphatemia [XLH] model) genetic background to test the contribution of osteoblasts and osteocytes to elevated FGF23 and Hyp disease phenotypes. Whereas Hyp mice maintained inappropriately elevated FGF23 considering their marked hypophosphatemia, Hyp/Fgf23(Δ/f) /Col2.3-cre(+) mice had serum FGF23 <4% of Hyp (p < 0.01), and this targeted restriction normalized serum phosphorus and ricketic bone disease. In summary, deleting FGF23 within early osteoblasts and osteocytes demonstrated that both cell types contribute to baseline circulating FGF23 concentrations, and that targeting osteoblasts/osteocytes for FGF23 production can modify systemic responses to changes in serum phosphate concentrations and rescue the Hyp genetic syndrome.Item FGF23 and Associated Disorders of Phosphate Wasting(YS Medical Media, 2019-09-01) Gohil, Anisha; Imel, Erik A.; Pediatrics, School of MedicineFibroblast growth factor 23 (FGF23), one of the endocrine fibroblast growth factors, is a principal regulator in the maintenance of serum phosphorus concentration. Binding to its cofactor αKlotho and a fibroblast growth factor receptor is essential for its activity. Its regulation and interaction with other factors in the bone-parathyroid-kidney axis is complex. FGF23 reduces serum phosphorus concentration through decreased reabsorption of phosphorus in the kidney and by decreasing 1,25 dihydroxyvitamin D (1,25(OH)2D) concentrations. Various FGF23-mediated disorders of renal phosphate wasting share similar clinical and biochemical features. The most common of these is X-linked hypophosphatemia (XLH). Additional disorders of FGF23 excess include autosomal dominant hypophosphatemic rickets, autosomal recessive hypophosphatemic rickets, fibrous dysplasia, and tumor-induced osteomalacia. Treatment is challenging, requiring careful monitoring and titration of dosages to optimize effectiveness and to balance side effects. Conventional therapy for XLH and other disorders of FGF23-mediated hypophosphatemia involves multiple daily doses of oral phosphate salts and active vitamin D analogs, such as calcitriol or alfacalcidol. Additional treatments may be used to help address side effects of conventional therapy such as thiazides to address hypercalciuria or nephrocalcinosis, and calcimimetics to manage hyperparathyroidism. The recent development and approval of an anti-FGF23 antibody, burosumab, for use in XLH provides a novel treatment option.Item Long-term Burosumab Administration Is Safe and Effective in Adults With X-linked Hypophosphatemia(Oxford University Press, 2022) Weber, Thomas J.; Imel, Erik A.; Carpenter, Thomas O.; Peacock, Munro; Portale, Anthony A.; Hetzer, Joel; Merritt, J. Lawrence, II; Insogna, Karl; Medicine, School of MedicineContext: Burosumab was developed as a treatment option for patients with the rare, lifelong, chronically debilitating, genetic bone disease X-linked hypophosphatemia (XLH). Objective: Collect additional information on the safety, immunogenicity, and clinical response to long-term administration of burosumab. Methods: UX023-CL203 (NCT02312687) was a Phase 2b, open-label, single-arm, long-term extension study of adult subjects with XLH who participated in KRN23-INT-001 or KRN23-INT-002 studies. The long-term UX023-CL203 study (January 5, 2015 through November 30, 2018) provided data up to 184 weeks. Participants in UX023-CL203 received burosumab based on the last dose in the prior KRN23-INT-001 or KRN23-INT-002 studies (0.3, 0.6, or 1.0 mg/kg given by subcutaneous injection every 4 weeks). At Week 12, burosumab could be titrated upward/downward to achieve fasting serum phosphate levels within the normal range. Primary objectives included long-term safety, the proportion of subjects achieving fasting serum phosphate in the normal range, changes in bone turnover markers, patient-reported outcomes for pain and stiffness, and measures of mobility. Results: Fasting serum phosphate levels at the midpoint of the dosing interval (2 weeks postdose, the time of peak effect) were within the normal range in 85% to 100% of subjects. Measures of phosphate metabolism and bone biomarkers generally improved with burosumab therapy, approaching or reaching their respective normal ranges by study end. Improvements in patient-reported outcomes and mobility were sustained throughout the observation period. No new safety findings emerged with longer-term burosumab treatment. Conclusion: These data support the conclusion that burosumab therapy may be a safe and effective long-term treatment option for adult patients with XLH.Item OR13-2 Burosumab Resulted in Greater Improvement in Rickets Than Conventional Therapy in Children with X-Linked Hypophosphatemia (XLH)(Oxford University Press, 2019-04-15) Imel, Erik; Whyte, Michael; Munns, Craig; Portale, Anthony; Ward, Leanne; Nilsson, Ola; Simmons, Jill; Padidela, Raja; Namba, Noriyuki; Cheong, Hae Il; Mao, Meng; Chen, Chao-Yin; Skrinar, Alison; San Martin, Javier; Glorieux, Francis; Medicine, School of MedicineXLH is characterized by excess FGF23, hypophosphatemia, skeletal deformities, and growth impairment. For the last 40 years, XLH has been treated with multiple daily doses of oral phosphate and active vitamin D (Pi/D). Burosumab, a fully human monoclonal antibody to FGF23, has been approved by the FDA for the treatment of XLH in patients ≥1 year-old. In this Phase 3 trial (NCT02915705), 61 children with XLH (1-12 years old) were randomized (1:1) to receive subcutaneous burosumab starting at 0.8 mg/kg every 2 weeks or continue Pi/D titrated and individualized for each subject by investigators. Eligibility criteria included a Total Rickets Severity Score (RSS) ≥2.0 despite prior treatment with Pi/D (>7-day washout before baseline). The primary endpoint was healing of rickets at Week 40 assessed by radiologists blinded to treatment using the Radiographic Global Impression of Change (RGI-C). The mean ± SE daily oral phosphate dose from baseline to Week 40 was 37.8 ± 3.2 mg/kg, with >99% compliance reported based on days of dosing. Compared with Pi/D, 40 weeks of burosumab resulted in a greater LS mean ± SE increase in serum phosphorus (0.92 ± 0.08 vs 0.20 ± 0.06 mg/dL), TmP/GFR (1.19 ± 0.11 vs -0.16 ± 0.05 mg/dL), and 1,25(OH)2D (30 ± 4 vs 19 ± 4 pg/mL). At Week 40, rickets improved in both groups; RGI-C global score was significantly higher in burosumab subjects than in Pi/D subjects (LS mean ± SE: +1.9 ± 0.1 vs +0.8 ± 0.1; p<0.0001). More burosumab subjects had substantial healing (RGI-C ≥+2.0), compared with Pi/D subjects (21/29, 72% vs 2/32, 6%; odds ratio of 39.1, p<0.0001). Improvement in the RGI-C lower limb deformity score was greater with burosumab than with Pi/D (+0.62 ± 0.12 vs +0.21 ± 0.12; p=0.02). Alkaline phosphatase decreased more with burosumab compared with Pi/D (-131 ± 13 vs 35 ± 19; p<0.0001). Consistent with decreases in rickets severity, burosumab improved growth and mobility. Standing height Z-score increased by a LS mean change (95% CI) of +0.15 (0.05, 0.25) for burosumab and +0.08 (-0.02, 0.19) for Pi/D. The 6 Minute Walk Test percent predicted distance increased with burosumab (Baseline to Week 40: 62% to 72%) and was unchanged with Pi/D (76% to 75%). Nephrocalcinosis score (range 0-4) shifted 0 in 20 Pi/D and 24 burosumab subjects; +1 in 3 Pi/D and 0 burosumab subjects; and -1 in 3 Pi/D and 2 burosumab subjects. Pre-defined adverse events (AEs) of interest, including hypersensitivity and injection site reactions, were higher in the burosumab group and were mild to moderate in severity overall. There were 4 serious AEs (3 burosumab, 1 Pi/D); none were treatment-related and all resolved. No subject discontinued study drug in either group. Data after 64 weeks of treatment will be available at the time of presentation. In this randomized Phase 3 trial, burosumab resulted in increases in growth and mobility, and significantly greater improvements in rickets than Pi/D in 1-12 year-old children with XLH.