Browsing by Author "Carpenter, Thomas"

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    OR13-1 Burosumab Improves the Biochemical, Skeletal, and Clinical Symptoms of Tumor-Induced Osteomalacia Syndrome
    (Oxford University Press, 2019-04-15) Jan De Beur, Suzanne; Miller, Paul; Weber, Thomas; Peacock, Munro; Insogna, Karl; Kumar, Rajiv; Luca, Diana; Theodore-Oklota, Christina; Lampl, Kathy; San Martin, Javier; Carpenter, Thomas; Medicine, School of Medicine
    Tumor-induced Osteomalacia (TIO) and Epidermal Nevus Syndrome with osteomalacia (ENS) are rare conditions in which ectopic production of FGF23 by tumor (TIO) and bone (ENS) lead 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 were enrolled and treated with burosumab, a fully human monoclonal antibody against FGF23. Key endpoints were change in serum phosphorus and osteomalacia as assessed from trans-iliac crest bone biopsies. The per protocol (PP) analysis included 14/17 subjects who received 0.3-2.0 mg/kg burosumab every 4 weeks (W). Three subjects were excluded: 1 received subthreshold dosing (0.3 mg/kg at Day 0 and 0.15 mg/kg at W8, W32, and W72); 2 were diagnosed with X-linked hypophosphatemia post-enrollment. Ten subjects in the PP group had paired bone biopsies at baseline and W48. Mean ± SE histomorphometric values for the 8/10 subjects with osteomalacia at baseline were 20.4 ± 4.2 µm for osteoid thickness (OT), 23.0 ± 7.2% for osteoid volume/bone volume (OV/BV), and 66.1 ± 10.6% for osteoid surface/bone surface (OS/BS); baseline median (Q1, Q3) for mineralization lag time (MLT) was 1672 (1102, 2929) days. At W48, histomorphometric indices improved as shown by mean percentage changes in OT (37%), OV/BV (40%), OS/BS (-5%), and MLT (median percentage change -78%). Serum phosphorus, fatigue, and physical functioning are reported for the PP group. Mean (SD) serum phosphorus was 1.5 (0.3) mg/dL at baseline and 2.6 (0.8) mg/dL when averaged across the mid-point of the dose interval through W24. After W24, serum phosphorus, assessed only at the end of the dose interval, maintained this increase through W72. Mean (SD) Global Fatigue Score decreased from 5.3 (2.8) at baseline to 3.6 (2.9) at W48 (p=0.020) and to 3.3 (2.7) at W72 (p=0.004). The SF-36 mean (SD) physical component summary score increased from 34 (11) at baseline to 39 (10) at W48 (p=0.059) and to 42 (10) at W72 (p=0.003). Mean (SD) vitality score increased from 41 (14) to 47 (12) at W48 (p=0.075) and to 49 (12) at W72 (p=0.012). The mean (SD) number of sit-to-stand repetitions increased from 6.9 (4.0) at baseline to 8.6 (4.2) at W48 (n=10; p=0.004). By W72, all 17 subjects had ≥1 adverse event (AE). There were 13 serious AEs in 6 subjects, none were considered drug-related. Tumor progression occurred only in subjects with a history of tumor progression prior to enrollment. One subject discontinued treatment prior to W48 to treat tumor progression with chemotherapy. There was 1 death, considered unrelated to treatment. In adults with TIO Syndrome, burosumab was associated with improvements in serum phosphorus, osteomalacia, mobility, quality of life, and reductions in fatigue.
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    OR13-3 Effects of Iron Isomaltoside versus Ferric Carboxymaltose on Hormonal Control of Phosphate Homeostasis: The PHOSPHARE-IDA04/05 Randomized Controlled Trials
    (Oxford University Press, 2019-04-15) Wolf, Myles; Rubin, Janet; Achebe, Maureen; Econs, Michael; Peacock, Munro; Imel, Erik; Thomsen, Lars; Carpenter, Thomas; Weber, Thomas; Zoller, Heinz; Medicine, School of Medicine
    Iron isomaltoside (IIM) and ferric carboxymaltose (FCM) are newer intravenous iron preparations that can be administered in high-doses to rapidly correct iron deficiency anemia (IDA). FCM can cause hypophosphatemia due to fibroblast growth factor 23 (FGF23) mediated renal phosphate wasting, which has been associated with osteomalacia, but the comparative effects of IIM are unknown. In two separate, identically designed, open label randomized controlled trials, we 1:1 randomized 245 adults with IDA to receive IIM (single infusion of 1000 mg) or FCM (FDA-approved dosing schedule: 2 infusions of 750 mg administered 1 week apart). We compared the incidence, severity and duration of hypophosphatemia, and effects on renal phosphate excretion, FGF23, PTH, vitamin D, and biomarkers of bone turnover measured in blood and urine samples collected at study visits at baseline (day 0) and on days 1, 7, 8, 14, 21, and 35. In pooled analyses of both trials, the incidence of hypophosphatemia <2 mg/dL was higher in the FCM versus IIM group (74.4% versus 8.0%, p<0.0001). Hypophosphatemia persisted at day 35 in 43.0% of FCM-treated patients compared to 0.9% of IIM-treated patients (p<0.0001). Severe hypophosphatemia ≤1 mg/dL occurred in 11.3% of FCM-treated patients compared to 0.0% of IIM-treated patients (p<0.0001). FCM significantly increased intact FGF23 compared to IIM (p<0.0001): on day 1, which was one day after the first infusion, FCM increased mean intact FGF23 from 49.9 pg/mL at baseline to 149.5 pg/mL; by day 8, which was one day after the second infusion, FCM increased intact FGF23 to 327.9 pg/mL; the corresponding figures for IIM were 59.9 pg/mL at baseline, 58.3 pg/mL by day 1 and 66.9 pg/mL by day 8. Compared to treatment with IIM, FCM significantly: increased urinary fractional phosphate excretion; decreased serum 1,25-(OH)2 vitamin D; decreased ionized calcium; and increased PTH, which persisted through day 35. These changes after FCM treatment were accompanied by significant increases in both total and bone specific alkaline phosphatase that also persisted through day 35. Correction of IDA was comparable between the two treatments. Serious or severe hypersensitivity reactions occurred in 0.8% in the IIM group and 1.7% in the FCM group. Compared to IIM, FCM induced high rates of FGF23-mediated hypophosphatemia, which was frequently severe and often persisted for >35 days. FCM but not IIM also induced changes in vitamin D and calcium homeostasis that triggered secondary hyperparathyroidism, which likely contributed to persistence of hypophosphatemia. Consistent with case reports of pathological fractures following FCM use, FCM also induced significant elevations of biomarkers of bone turnover that are associated with osteomalacia.