Browsing by Author "Carpenter, Thomas O."
Now showing 1 - 10 of 20
Results Per Page
Sort Options
Item 12605 Two Systematic Reviews Of Treatment Efficacy On Patient Important Outcomes In Children X-linked Hypophosphatemia(Oxford University Press, 2024-10-05) Ali, Dalal S.; Mirza, Reza; Hussein, Salma; Alsarraf, Farah; Alexander, R. Todd; AbuAlrob, Hajar; Brandi, Maria Luisa; Carpenter, Thomas O.; Dandurand, Karel; Filler, Guido; Florenzano, Pablo F.; Fukumoto, Seiji; Grasemann, Corinna; Imel, Erik A.; De Beur, Suzanne Marie Jan; Morgante, Emmett; Ward, Leanne M.; Aziz Khan, Aliya; Guyatt, Gordon; Medicine, School of MedicineObjective: We sought to examine the highest certainty evidence on managing X-linked hypophosphatemia (XLH) in children, aiming to inform treatment recommendations of XLH international guidelines. Data Sources: We searched Embase, MEDLINE, Web of Science, and Cochrane Central from inception to March 2023. We also reviewed reference lists of eligible studies and pertinent review articles. Study eligibility criteria: Eligible studies included randomized controlled trials (RCTs) and observational studies enrolling individuals younger than 18 years old with XLH diagnosed on clinical grounds or with a confirmed pathogenic variant in PHEX. Articles were selected according to specific criteria evaluating the effectiveness of burosumab compared to either no treatment or conventional therapy (phosphate salts and active vitamin D) or evaluating conventional therapy compared to no treatment. Methods: Two reviewers independently determined eligibility, conducted data extraction, and assessed the risk of bias (RoB) in eligible articles. We employed the GRADE methodology to evaluate the certainty of the evidence. Results: After removing duplicates from 7,043 citations, we screened 4,114 records and assessed 254 full texts, of which in the systematic review (SR) addressing burosumab one RCT and one post-Hoc study proved eligible. Being open-label design, the RoB was high, with certainty of evidence on individual outcomes ranging from moderate to very low. Burosumab, compared to conventional therapy, probably prevents lower limb deformity, and improves physical health quality of life (QoL) (moderate certainty). It might also increase height and possibly improve the burden of symptoms related to chronic hypophosphatemia (low certainty). Conversely, burosumab probably increases Treatment-Emergent adverse events after the first administration (moderate certainty), and it may increase dental abscesses (low certainty). In the second SR, one observational study assessing conventional therapy versus no treatment was at high RoB providing very low certainty of evidence regarding the impact of conventional therapy compared to no treatment on final height. Conclusion: Our review indicates that burosumab likely offers benefits in preventing lower limb deformity and improving physical health QoL, while potentially increasing height and improving the burden of symptoms related to chronic hypophosphatemia (low certainty). However, it may also increase adverse events, including dental abscesses. Additionally, our review found limited evidence regarding the impact of conventional therapy compared to no treatment on final height in children. These findings highlight the need for further research to better understand the long-term impact of conventional therapy and burosumab in children.Item Burosumab for the Treatment of Tumor‐Induced Osteomalacia(Wiley, 2021-04) Jan de Beur, Suzanne M.; Miller, Paul D.; Weber, Thomas J.; Peacock, Munro; Insogna, Karl; Kumar, Rajiv; Rauch, Frank; Luca, Diana; Cimms, Tricia; Scott Roberts, Mary; Martin, Javier San; Carpenter, Thomas O.; Medicine, School of MedicineTumor-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.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 Therapy in Children with X-Linked Hypophosphatemia(Massachusetts Medical Society, 2018-05) Carpenter, Thomas O.; Whyte, Michael P.; Imel, Erik A.; Boot, Annemieke M.; Högler, Wolfgang; Linglart, Agnès; Padidela, Raja; van't Hoff, William; Mao, Meng; Chen, Chao-Yin; Skrinar, Alison; Kakkis, Emil; San Martin, Javier; Portale, Anthony A.; Medicine, School of MedicineBACKGROUND X-linked hypophosphatemia is characterized by increased secretion of fibroblast growth factor 23 (FGF-23), which leads to hypophosphatemia and consequently rickets, osteomalacia, and skeletal deformities. We investigated burosumab, a monoclonal antibody that targets FGF-23, in patients with X-linked hypophosphatemia. METHODS In an open-label, phase 2 trial, we randomly assigned 52 children with X-linked hypophosphatemia, in a 1:1 ratio, to receive subcutaneous burosumab either every 2 weeks or every 4 weeks; the dose was adjusted to achieve a serum phosphorus level at the low end of the normal range. The primary end point was the change from baseline to weeks 40 and 64 in the Thacher rickets severity total score (ranging from 0 to 10, with higher scores indicating greater disease severity). In addition, the Radiographic Global Impression of Change was used to evaluate rachitic changes from baseline to week 40 and to week 64. Additional end points were changes in pharmacodynamic markers, linear growth, physical ability, and patient-reported outcomes and the incidence of adverse events. RESULTS The mean Thacher rickets severity total score decreased from 1.9 at baseline to 0.8 at week 40 with every-2-week dosing and from 1.7 at baseline to 1.1 at week 40 with every-4-week dosing (P<0.001 for both comparisons); these improvements persisted at week 64. The mean serum phosphorus level increased after the first dose in both groups, and more than half the patients in both groups had levels within the normal range (3.2 to 6.1 mg per deciliter [1.0 to 2.0 mmol per liter]) by week 6. Stable serum phosphorus levels were maintained through week 64 with every-2-week dosing. Renal tubular phosphate reabsorption increased from baseline in both groups, with an overall mean increase of 0.98 mg per deciliter (0.32 mmol per liter). The mean dose of burosumab at week 40 was 0.98 mg per kilogram of body weight with every-2-week dosing and 1.50 mg per kilogram with every-4-week dosing. Across both groups, the mean serum alkaline phosphatase level decreased from 459 U per liter at baseline to 369 U per liter at week 64. The mean standing-height z score increased in both groups, with greater improvement seen at all time points with every-2-week dosing (an increase from baseline of 0.19 at week 64) than with every-4-week dosing (an increase from baseline of 0.12 at week 64). Physical ability improved and pain decreased. Nearly all the adverse events were mild or moderate in severity. CONCLUSIONS In children with X-linked hypophosphatemia, treatment with burosumab improved renal tubular phosphate reabsorption, serum phosphorus levels, linear growth, and physical function and reduced pain and the severity of rickets.Item Burosumab treatment in adults with X-linked hypophosphataemia: 96-week patient-reported outcomes and ambulatory function from a randomised phase 3 trial and open-label extension(BMJ, 2021) Briot, Karine; Portale, Anthony A.; Brandi, Maria Luisa; Carpenter, Thomas O.; Cheong, Hae Ii; Cohen-Solal, Martine; Crowley, Rachel K.; Eastell, Richard; Imanishi, Yasuo; Ing, Steven; Insogna, Karl; Ito, Nobuaki; de Beur, Suzanne Jan; Javaid, Muhammad K.; Kamenicky, Peter; Keen, Richard; Kubota, Takuo; Lachmann, Robin H.; Perwad, Farzana; Pitukcheewanont, Pisit; Ralston, Stuart H.; Takeuchi, Yasuhiro; Tanaka, Hiroyuki; Weber, Thomas J.; Yoo, Han-Wook; Nixon, Annabel; Nixon, Mark; Sun, Wei; Williams, Angela; Imel, Erik A.; Medicine, School of MedicineObjectives: To report the impact of burosumab on patient-reported outcomes (PROs) and ambulatory function in adults with X-linked hypophosphataemia (XLH) through 96 weeks. Methods: Adults diagnosed with XLH were randomised 1:1 in a double-blinded trial to receive subcutaneous burosumab 1 mg/kg or placebo every 4 weeks for 24 weeks (NCT02526160). Thereafter, all subjects received burosumab every 4 weeks until week 96. PROs were measured using the Western Ontario and the McMaster Universities Osteoarthritis Index (WOMAC), Brief Pain Inventory-Short Form (BPI-SF) and Brief Fatigue Inventory (BFI), and ambulatory function was measured with the 6 min walk test (6MWT). Results: Subjects (N=134) were randomised to burosumab (n=68) or placebo (n=66) for 24 weeks. At baseline, subjects experienced pain, stiffness, and impaired physical and ambulatory function. At week 24, subjects receiving burosumab achieved statistically significant improvement in some BPI-SF scores, BFI worst fatigue (average and greatest) and WOMAC stiffness. At week 48, all WOMAC and BPI-SF scores achieved statistically significant improvement, with some WOMAC and BFI scores achieving meaningful and significant change from baseline. At week 96, all WOMAC, BPI-SF and BFI achieved statistically significant improvement, with selected scores in all measures also achieving meaningful change. Improvement in 6MWT distance and percent predicted were statistically significant at all time points from 24 weeks. Conclusions: Adults with XLH have substantial burden of disease as assessed by PROs and 6MWT. Burosumab treatment improved phosphate homoeostasis and was associated with a steady and consistent improvement in PROs and ambulatory function.Item Continued Beneficial Effects of Burosumab in Adults with X-Linked Hypophosphatemia: Results from a 24-Week Treatment Continuation Period After a 24-Week Double-Blind Placebo-Controlled Period(Springer, 2019-09-01) Portale, Anthony A.; Carpenter, Thomas O.; Brandi, Maria Luisa; Briot, Karine; Cheong, Hae II; Cohen-Solal, Martine; Crowley, Rachel; Jan De Beur, Suzanne; Eastell, Richard; Imanishi, Yasuo; Imel, Erik A.; Ing, Steven; Ito, Nobuaki; Javaid, Muhammad; Kamenicky, Peter; Keen, Richard; Kubota, Takuo; Lachmann, Robin; Perwad, Farzana; Pitukcheewanont, Pisit; Ralston, Stuart H.; Takeuchi, Yasuhiro; Tanaka, Hiroyuki; Weber, Thomas J.; Yoo, Han-Wook; Zhang, Lin; Theodore-Oklota, Christina; Mealiffe, Matt; San Martin, Javier; Insogna, Karl; Medicine, School of MedicineBurosumab, a fully human monoclonal antibody to FGF23, is the only approved treatment for X-linked hypophosphatemia (XLH), a rare genetic disorder characterized by renal phosphate wasting and substantial cumulative musculoskeletal morbidity. During an initial 24-week randomized, controlled trial, 134 adults with XLH received burosumab 1 mg/kg (n = 68) or placebo (n = 66) every 4 weeks. After 24 weeks, all subjects received open-label burosumab until week 48. This report describes the efficacy and safety of burosumab during the open-label treatment period. From weeks 24–48, serum phosphorus concentrations remained normal in 83.8% of participants who received burosumab throughout and were normalized in 89.4% who received burosumab after placebo. By week 48, 63.1% of baseline fractures/pseudofractures healed fully with burosumab, compared with 35.2% with burosumab after placebo. In both groups, burosumab was associated with clinically significant and sustained improvement from baseline to week 48 in scores for patient-reported outcomes of stiffness, pain, physical function, and total distance walked in 6 min. Rates of adverse events were similar for burosumab and placebo. There were no fatal adverse events or treatment-related serious adverse events. Nephrocalcinosis scores did not change from baseline by more than one grade at either week 24 or 48. These data demonstrate that in participants with XLH, continued treatment with burosumab is well tolerated and leads to sustained correction of serum phosphorus levels, continued healing of fractures and pseudofractures, and sustained improvement in key musculoskeletal impairments.Item Cover, Volume 43, Issue 2(Wiley, 2022) Sarafrazi, Soodabeh; Daugherty, Sean C.; Miller, Nicole; Boada, Patrick; Carpenter, Thomas O.; Chunn, Lauren; Dill, Kariena; Econs, Michael J.; Eisenbeis, Scott; Imel, Erik A.; Johnson, Britt; Kiel, Mark J.; Krolczyk, Stan; Ramesan, Prameela; Truty, Rebecca; Sabbagh, Yves; Medicine, School of MedicineThe cover image is based on the Research Article Novel PHEX gene locus-specific database: Comprehensive characterization of vast number of variants associated with X-linked hypophosphatemia (XLH) by Yves Sabbagh et al., https://doi.org/10.1002/humu.24296.Item Effect of four monthly doses of a human monoclonal anti-FGF23 antibody (KRN23) on quality of life in X-linked hypophosphatemia(Elsevier, 2016-12) Ruppe, Mary D.; Zhang, Xiaoping; Imel, Erik A.; Weber, Thomas J.; Klausner, Mark A.; Ito, Takahiro; Vergeire, Maria; Humphrey, Jeffrey S.; Glorieux, Francis H.; Portale, Anthony A.; Insogna, Karl; Peacock, Munro; Carpenter, Thomas O.; Department of Medicine, IU School of MedicineX-linked hypophosphatemia (XLH) is characterized by lower extremity deformities that lead to bone and/or joint pain that result from decreased renal tubular reabsorption leading to hypophosphatemia caused by elevated levels of fibroblast growth factor 23 (FGF23). Objective Validate the use of SF-36v2 Health Survey (SF-36v2) and the Western Ontario and McMaster Osteoarthritis Index (WOMAC) to measure previously unstudied health-related quality of life (HRQoL) in XLH patients and determine the change in HRQoL before and after treatment with KRN23, a human monoclonal anti-FGF23 antibody. Methods Twenty-eight adult outpatients with XLH received up to four doses of KRN23 administered subcutaneously every 28 days. General HRQoL was measured with the SF-36v2 and condition-related HRQoL with the WOMAC at baseline and study endpoint as a secondary outcome of a Phase 1/2, open-label, multicenter, dose-escalation trial. Results Testing for scale discriminant validity and convergent-divergent validity supported the use of these scales in the assessment of HRQoL in XLH. Both instruments indicated impairment of physical function at baseline with all mean scores showing a trend to improved health at study endpoint compared to baseline. When corrected for multiple comparisons, the score for Role Limitations due to physical health on the SF-36v2 which measures the patient's perception of their own chronic functional impairments due to poor physical health remained significantly improved (P < 0.05), increasing to the mean score of US adults. For the WOMAC, Physical Functioning and Stiffness scores were significantly improved (P < 0.05). Conclusion KRN23 administration was associated with significantly improved patient perception of their Physical Functioning and Stiffness due to their disease. This study demonstrates that the SF-36v2 and WOMAC are valid tools for assessing HRQoL in XLH.Item Effects of Iron Isomaltoside vs Ferric Carboxymaltose on Hypophosphatemia in Iron-Deficiency Anemia: Two Randomized Clinical Trials(American Medical Association, 2020-02-04) Wolf, Myles; Rubin, Janet; Achebe, Maureen; Econs, Michael J.; Peacock, Munro; Imel, Erik A.; Thomsen, Lars L.; Carpenter, Thomas O.; Weber, Thomas; Brandenburg, Vincent; Zoller, Heinz; Medicine, School of MedicineImportance Intravenous iron enables rapid correction of iron-deficiency anemia, but certain formulations induce fibroblast growth factor 23–mediated hypophosphatemia. Objective To compare risks of hypophosphatemia and effects on biomarkers of mineral and bone homeostasis of intravenous iron isomaltoside (now known as ferric derisomaltose) vs ferric carboxymaltose. Design, Setting, and Participants Between October 2017 and June 2018, 245 patients aged 18 years and older with iron-deficiency anemia (hemoglobin level ≤11 g/dL; serum ferritin level ≤100 ng/mL) and intolerance or unresponsiveness to 1 month or more of oral iron were recruited from 30 outpatient clinic sites in the United States into 2 identically designed, open-label, randomized clinical trials. Patients with reduced kidney function were excluded. Serum phosphate and 12 additional biomarkers of mineral and bone homeostasis were measured on days 0, 1, 7, 8, 14, 21, and 35. The date of final follow-up was June 19, 2018, for trial A and May 29, 2018, for trial B. Interventions Intravenous administration of iron isomaltoside, 1000 mg, on day 0 or ferric carboxymaltose, 750 mg, infused on days 0 and 7. Main Outcomes and Measures The primary end point was the incidence of hypophosphatemia (serum phosphate level <2.0 mg/dL) between baseline and day 35. Results In trial A, 123 patients were randomized (mean [SD] age, 45.1 [11.0] years; 95.9% women), including 62 to iron isomaltoside and 61 to ferric carboxymaltose; 95.1% completed the trial. In trial B, 122 patients were randomized (mean [SD] age, 42.6 [12.2] years; 94.1% women), including 61 to iron isomaltoside and 61 to ferric carboxymaltose; 93.4% completed the trial. The incidence of hypophosphatemia was significantly lower following iron isomaltoside vs ferric carboxymaltose (trial A: 7.9% vs 75.0% [adjusted rate difference, –67.0% {95% CI, –77.4% to –51.5%}], P < .001; trial B: 8.1% vs 73.7% [adjusted rate difference, –65.8% {95% CI, –76.6% to –49.8%}], P < .001). Beyond hypophosphatemia and increased parathyroid hormone, the most common adverse drug reactions (No./total No.) were nausea (iron isomaltoside: 1/125; ferric carboxymaltose: 8/117) and headache (iron isomaltoside: 4/125; ferric carboxymaltose: 5/117). Conclusions and Relevance In 2 randomized trials of patients with iron-deficiency anemia who were intolerant of or unresponsive to oral iron, iron isomaltoside (now called ferric derisomaltose), compared with ferric carboxymaltose, resulted in lower incidence of hypophosphatemia over 35 days. However, further research is needed to determine the clinical importance of this difference.Item Healthcare Resource Use Associated With Tumor-Induced Osteomalacia: A Literature Review(Oxford University Press, 2024) Jan de Beur, Suzanne M.; Dahir, Kathryn M.; Imel, Erik A.; Zanchetta, María Belén; Williams, Angela; Li, Zhiyi; Webb, Neil; Crowe, Victoria; Johnson, Ben; Carpenter, Thomas O.; Medicine, School of MedicineContext: Tumor-induced osteomalacia (TIO) is an ultra-rare, paraneoplastic syndrome caused by tumors that secrete fibroblast growth factor 23 (FGF23). Initial signs and musculoskeletal symptoms can be nonspecific and unrecognized, leading to long delays in diagnosis and treatment, and resulting in severe and progressive disability in patients with TIO. Objective: This review aimed to identify published evidence on healthcare resource use in TIO to better understand the burden of the disease. Evidence acquisition: A targeted literature review was conducted to identify publications reporting on disease characteristics and healthcare resource use associated with TIO. Evidence synthesis: In total, 414 publications were included in the review, of which 376 were case reports. From the case reports, data on 621 patients were extracted. These patients had a mean (SD) age of 46.3 (15.8) years; 57.6% were male. Mean time from first symptoms to diagnosis of TIO was 4.6 (4.7) years and, in cases where imaging tests were reported, patients underwent a mean of 4.1 (2.7) procedures. Tumor resection was attempted in 81.0% of patients and successful in 67.0%. Fracture was reported in 49.3% of patients. Results from association analyses demonstrated that longer time to diagnosis was associated with poorer tumor resection outcomes and a higher probability of tumor recurrence. Unfavorable tumor resection outcomes were associated with greater use of pharmacologic treatment and a greater likelihood of orthopedic surgery. Conclusion: TIO is associated with a substantial healthcare resource burden. Improvements in the diagnostic process could lead to better management of TIO, thereby benefiting patients and reducing that burden.