Roberts, Mary Scott

Abstract Disclosure: S.W. Ing: Advisory Board Member; Self; Ultragenyx, Amolyt. Grant Recipient; Self; Alexion Pharmaceuticals, Inc.. Research Investigator; Self; BridgeBio Pharma, Takeda, Amolyt, Radius Health, Inc, Ultragenyx. P. Harmatz: Research Investigator; Self; BridgeBio Pharma. S. Mora: Research Investigator; Self; BridgeBio Pharma. E.A. Imel: Research Investigator; Self; BridgeBio Pharma. P.J. Tebben: Research Investigator; Self; BridgeBio Pharma. M.L. Warren: Research Investigator; Self; BridgeBio Pharma, Ascendis, Amolyt. Speaker; Self; Ascendis. N. Ma: Research Investigator; Self; Calcilytix Therapeutics, Ultragenyx, Inozyme. Other; Self; Up To Date. A.A. Khan: Research Investigator; Self; BridgeBio Pharma, Ascendis. A. Palermo: Research Investigator; Self; BridgeBio Pharma. B. Decallonne: Research Investigator; Self; BridgeBio Pharma. S. Lemoine: Research Investigator; Self; BridgeBio Pharma, Kyowa Kirin. G. Mantovani: Research Investigator; Self; BridgeBio Pharma. A. Linglart: Consulting Fee; Self; Alexion, Novo Nordisk, Merck, Pfizer, Inc.. Research Investigator; Self; BridgeBio Pharma, Kyowa Kirin. H. Wasserman: Research Investigator; Self; BridgeBio Pharma. A.P. Barbosa: Research Investigator; Self; BridgeBio Pharma. C. Cardot-bauters: Research Investigator; Self; BridgeBio Pharma. M. Roberts: Employee; Self; BridgeBio Pharma. A. Mathew: Employee; Self; BridgeBio Pharma. S. Adler: Employee; Self; BridgeBio Pharma. M.C. Zillikens: Research Investigator; Self; BridgeBio Pharma. R.J. Clifton-Bligh: Consulting Fee; Self; Ipsen, Kyowa Kirin, Amgen Inc, Eisai. Research Investigator; Self; BridgeBio Pharma. L. Rejnmark: Research Investigator; Self; BridgeBio Pharma, Ascendis, Amolyt, Takeda, Kyowa Kirin. Autosomal dominant hypocalcemia type 1 (ADH1), caused by gain-of-function calcium-sensing receptor gene (CASR) variants, is characterized by low parathyroid hormone (PTH) concentrations, hypocalcemia, hypercalciuria, hyperphosphatemia and hypomagnesemia. While a rare disease, ADH1 is one of the more frequently identified causes of genetic hypoparathyroidism. Conventional therapy includes calcium (Ca) and/or active vitamin D, but this regimen incompletely corrects the hypocalcemia and is associated with persistent hypercalciuria, which may result in renal complications including nephrocalcinosis (NC), nephrolithiasis (NL), and chronic kidney disease (CKD). The CLARIFY disease monitoring study [NCT05227287] is a global, multicenter, longitudinal study to understand disease burden, management, and progression in children and adults with ADH1 over a 5-year period. Here we report data on the characteristics of adult participants at study entry. As of November 2023, 45 adults (≥18 years) with ADH1 were enrolled, with a mean±SD age of 42.1±16.5 years (range 18-80). The mean±SD age of a hypocalcemia diagnosis was 19.1±19.1 years, while the mean±SD age for a diagnosis of ADH1 was 28.2±20.6 years. As reported on medical history, in decreasing order of prevalence, 36% (16) had NC, 22% (10) had intracranial calcifications, 11% (5) had history of seizures, 11% (5) had CKD, 9% (4) had cataracts, 7% (3) had NL, and 4% (2) had undergone renal transplant. Treatment data were available for 43 participants and included the following: 74% (32) Ca and active vitamin D, 9% (4) Ca alone, 9% (4) active vitamin D alone, 37% (16) magnesium, 33% (14) thiazide diuretics, 26% (11) potassium, 7% (3) phosphate binder, 7% (3) PTH, and 5% (2) no treatment. Mean±SD fasting values collected prior to conventional therapy dose are presented. PTH concentrations (10.1±8.2 pg/mL [nl 15-65]) and albumin-corrected calcium ([cCa]=7.5±1.0 mg/dL [nl 8.5-10.5]) were low. Despite the low mean cCa, the mean 24-hr urine calcium was elevated (268±183 mg/d, [nl <250 women, <300 men]). Blood phosphate was 4.8±0.8 mg/dL [nl 2.5-4.8] while blood magnesium was 1.8±0.2 mg/dL [nl 1.8-2.4]. 25-OH vitamin D was 35.0±13.5 ng/mL [nl 30-80]. Renal function as assessed by CKD-EPIcr_R showed eGFR of 86±23 mL/min/1.73m² (range 36-123). This study represents the largest cohort of adults with ADH1 described to date. These data highlight variability in therapeutic approaches in a real-world setting with some participants receiving up to 6 different medications/supplements. Despite being followed in expert centers, and treated with available therapies, patients on average have low cCa with relatively high 24-hr urine calcium excretion. The CLARIFY study provides an opportunity to better understand the progression and burden of disease in participants with ADH1. Presentation: 6/3/2024

Abstract Disclosure: S.W. Ing: Research Investigator; Self; BridgeBio Pharma. P. Harmatz: Research Investigator; Self; BridgeBio Pharma. S. Mora: Research Investigator; Self; BridgeBio Pharma. E.A. Imel: Research Investigator; Self; BridgeBio Pharma. P.J. Tebben: Research Investigator; Self; BridgeBio Pharma. M.L. Warren: Research Investigator; Self; BridgeBio Pharma, Ascendis, Amolyt. Speaker; Self; Ascendis. N. Ma: Research Investigator; Self; Calcilytix Therapeutics, Ultragenyx, Inozyme. Other; Self; Up To Date. A.A. Khan: Research Investigator; Self; BridgeBio Pharma, Ascendis. A. Palermo: Research Investigator; Self; BridgeBio Pharma. B. Decallonne: Research Investigator; Self; BridgeBio Pharma. S. Lemoine: Research Investigator; Self; BridgeBio Pharma, Kyowa Kirin. G. Mantovani: Research Investigator; Self; BridgeBio Pharma. A. Linglart: Consulting Fee; Self; Alexion, Novo Nordisk, Merck, Pfizer, Inc.. Research Investigator; Self; BridgeBio Pharma, Kyowa Kirin. H. Wasserman: Research Investigator; Self; BridgeBio Pharma. A.P. Barbosa: Research Investigator; Self; BridgeBio Pharma. C. Cardot-bauters: Research Investigator; Self; BridgeBio Pharma. M. Roberts: Employee; Self; BridgeBio Pharma. A. Mathew: Employee; Self; BridgeBio Pharma. S. Adler: Employee; Self; BridgeBio Pharma. M.C. Zillikens: Research Investigator; Self; BridgeBio Pharma. R.J. Clifton-Bligh: Consulting Fee; Self; Ipsen, Kyowa Kirin, Amgen Inc, Eisai. Research Investigator; Self; BridgeBio Pharma. L. Rejnmark: Research Investigator; Self; BridgeBio Pharma, Ascendis, Amolyt, Takeda, Kyowa Kirin. Autosomal dominant hypocalcemia type 1 (ADH1), caused by gain-of-function calcium-sensing receptor gene (CASR) variants, is characterized by low parathyroid hormone (PTH) concentrations, hypocalcemia, hypercalciuria, hyperphosphatemia and hypomagnesemia. While a rare disease, ADH1 is one of the more frequently identified causes of genetic hypoparathyroidism. Conventional therapy includes calcium (Ca) and/or active vitamin D, but this regimen incompletely corrects the hypocalcemia and is associated with persistent hypercalciuria, which may result in renal complications including nephrocalcinosis (NC), nephrolithiasis (NL), and chronic kidney disease (CKD). The CLARIFY disease monitoring study [NCT05227287] is a global, multicenter, longitudinal study to understand disease burden, management, and progression in children and adults with ADH1 over a 5-year period. Here we report data on the characteristics of adult participants at study entry. As of November 2023, 45 adults (≥18 years) with ADH1 were enrolled, with a mean±SD age of 42.1±16.5 years (range 18-80). The mean±SD age of a hypocalcemia diagnosis was 19.1±19.1 years, while the mean±SD age for a diagnosis of ADH1 was 28.2±20.6 years. As reported on medical history, in decreasing order of prevalence, 36% (16) had NC, 22% (10) had intracranial calcifications, 11% (5) had history of seizures, 11% (5) had CKD, 9% (4) had cataracts, 7% (3) had NL, and 4% (2) had undergone renal transplant. Treatment data were available for 43 participants and included the following: 74% (32) Ca and active vitamin D, 9% (4) Ca alone, 9% (4) active vitamin D alone, 37% (16) magnesium, 33% (14) thiazide diuretics, 26% (11) potassium, 7% (3) phosphate binder, 7% (3) PTH, and 5% (2) no treatment. Mean±SD fasting values collected prior to conventional therapy dose are presented. PTH concentrations (10.1±8.2 pg/mL [nl 15-65]) and albumin-corrected calcium ([cCa]=7.5±1.0 mg/dL [nl 8.5-10.5]) were low. Despite the low mean cCa, the mean 24-hr urine calcium was elevated (268±183 mg/d, [nl <250 women, <300 men]). Blood phosphate was 4.8±0.8 mg/dL [nl 2.5-4.8] while blood magnesium was 1.8±0.2 mg/dL [nl 1.8-2.4]. 25-OH vitamin D was 35.0±13.5 ng/mL [nl 30-80]. Renal function as assessed by CKD-EPIcr_R showed eGFR of 86±23 mL/min/1.73m² (range 36-123). This study represents the largest cohort of adults with ADH1 described to date. These data highlight variability in therapeutic approaches in a real-world setting with some participants receiving up to 6 different medications/supplements. Despite being followed in expert centers, and treated with available therapies, patients on average have low cCa with relatively high 24-hr urine calcium excretion. The CLARIFY study provides an opportunity to better understand the progression and burden of disease in participants with ADH1. Presentation: 6/3/2024

ABSTRACT Tumor-induced osteomalacia (TIO) is caused by phosphaturic mesenchymal tumors producing fibroblast growth factor 23 (FGF23) and is characterized by impaired phosphate metabolism, skeletal health, and quality of life. UX023T-CL201 is an ongoing, open-label, phase 2 study investigating the safety and efficacy of burosumab, a fully human monoclonal antibody that inhibits FGF23, in adults with TIO or cutaneous skeletal hypophosphatemia syndrome (CSHS). Key endpoints were changes in serum phosphorus and osteomalacia assessed by transiliac bone biopsies at week 48. This report focuses on 14 patients with TIO, excluding two diagnosed with X-linked hypophosphatemia post-enrollment and one with CSHS. Serum phosphorus increased from baseline (0.52 mmol/L) and was maintained after dose titration from week 22 (0.91 mmol/L) to week 144 (0.82 mmol/L, p < 0.0001). Most measures of osteomalacia were improved at week 48: osteoid volume/bone, osteoid thickness, and mineralization lag time decreased; osteoid surface/bone surface showed no change. Of 249 fractures/pseudofractures detected across 14 patients at baseline, 33% were fully healed and 13% were partially healed at week 144. Patients reported a reduction in pain and fatigue and an increase in physical health. Two patients discontinued: one to treat an adverse event (AE) of neoplasm progression and one failed to meet dosing criteria (receiving minimal burosumab). Sixteen serious AEs occurred in seven patients, and there was one death; all serious AEs were considered unrelated to treatment. Nine patients had 16 treatment-related AEs; all were mild to moderate in severity. In adults with TIO, burosumab exhibited an acceptable safety profile and was associated with improvements in phosphate metabolism and osteomalacia. © 2020 The Authors. Journal of Bone and Mineral Research published by American Society for Bone and Mineral Research..

Abstract Tumor-induced Osteomalacia (TIO) is a rare condition in which excess FGF23 produced by a tumor leads to renal phosphate wasting, impaired 1,25(OH)2D synthesis, osteomalacia, fractures, weakness, fatigue, and decreased mobility. In an ongoing open-label Phase 2 study (NCT02304367), 17 adults with TIO or cutaneous skeletal hypophosphatemia syndrome (CSHS) were enrolled and received burosumab, a fully human monoclonal antibody against FGF23. Key endpoints were changes in serum phosphorus and osteomalacia as assessed from trans-iliac crest bone biopsies. This report excludes 3/17 subjects who did not have TIO: 2 subjects diagnosed with X-linked hypophosphatemia post-enrollment and 1 subject with CSHS. Serum phosphorus increased from baseline (BL; 1.60 mg/dL) and was maintained after titration, from Week (W) 22 (2.85 mg/dL, dosing cycle midpoint) to W144 (2.56 mg/dL, dosing cycle endpoint, p<0.0001). Serum TmP/GFR and 1,25(OH)2D also increased with burosumab. Eleven subjects underwent paired bone biopsies at BL and W48. Osteoid volume/bone volume decreased from a mean ± SE of 17.6% ± 5.9% at BL to 12.1% ± 4.7% at W48 (p=0.086). Mean ± SE osteoid thickness decreased from 16.5 ± 3.6 µm to 11.3 ± 2.8 µm (p<0.05). Using imputation (Dempster et al. 2012), mineralization lag time decreased from a mean ± SE of 1598 ± 420 days to 1032 ± 712 days (p=0.41). Osteoid surface/bone surface showed no change from BL (mean ± SE BL: 57% ± 9%, W48: 57% ± 7%). Of 249 areas identified with increased uptake on bone scan at BL, 68 (27%) and 81 (33%) were fully healed at W96 and W144, respectively; 56 (23%) and 32 (13%) were partially healed at W96 and W144, respectively. Mean (SD) Global Fatigue Score decreased from 5.6 (2.5) at BL to 3.5 (3.0) at W48, and to 3.8 (2.2) at W144 (both p<0.01). All 3 domains of the Brief Pain Inventory decreased with burosumab (W144 Pain Severity and Pain Interference p<0.05), indicating reduced pain. The SF-36 mean (SD) physical component summary score increased from 33 (10) at BL to 39 (10) at W48 (p<0.05) and to 41 (12) at W144 (p<0.01), indicating improved physical functioning. The mean (SD) number of sit-to-stand repetitions, an assessment of proximal muscle function, increased from 6.7 (4.2) at BL to 8.5 (4.2) at W48 (n=10; p<0.01). All subjects had ≥1 adverse event (AE). Two subjects discontinued: 1 to undergo chemotherapy to treat an AE of neoplasm progression and 1 failed to meet serum phosphorus dosing criteria and therefore received minimal burosumab dosing. There were 16 serious AEs in 7 subjects, all unrelated to drug. Of the 6 subjects with a serious AE of tumor progression/compression, 5 had a history of tumor progression prior to enrollment. There was 1 death, considered unrelated to treatment. In adults with TIO Syndrome, burosumab was associated with improvements in phosphate metabolism, osteomalacia, skeletal metabolism/fracture healing, physical functioning, fatigue, pain, and quality of life.