Burosumab 30mg/1ml solution for injection pre-filled syringes

PurposeAn international working group (IWG) consisting of experts in X-linked hypophosphatemia (XLH) developed global guidelines providing a comprehensive, evidence-based approach to XLH diagnosis, management, and monitoring.MethodsThe IWG, consisting of 43 members as well as methodologists and a patient partner, conducted 2 systematic reviews (SRs) and narrative reviews to address key areas. The SRs addressed the impact of burosumab compared to conventional therapy (phosphate and active vitamin D) or no therapy on patient-important outcomes in adults. They also evaluated conventional therapy compared to no therapy. GRADE methodology was applied to evaluate the certainty of evidence. Non-GRADED recommendations were made in the presence of insufficient evidence to conduct SRs. These guidelines have been reviewed and endorsed by several medical and patient societies and organizations.ResultsThe diagnosis of XLH is based on integrating clinical evaluation, laboratory findings confirming renal phosphate wasting (following exclusion of conditions mimicking XLH), and skeletal imaging. Fibroblast growth factor 23 measurement and DNA analysis are of value in the diagnosis, if available. Pathogenic or likely pathogenic variants in the PHEX gene are confirmatory but not necessary for the diagnosis. Management requires a multidisciplinary team knowledgeable and experienced in XLH. Effective medical therapy with burosumab can improve fracture and pseudofracture healing.Main conclusionIn adults with XLH and fractures or pseudofractures, burosumab is recommended over no therapy (strong recommendation, GRADEd). Additionally, burosumab is suggested as the preferred treatment compared to conventional therapy (conditional recommendation, GRADEd) in the absence of fractures or pseudofractures. If burosumab is not available, symptomatic adults should be treated with conventional therapy (Non-GRADEd recommendation).

Abstract licence: CC BY-NC-ND

ContextUnderstanding the effects of burosumab compared to conventional therapy or no treatment on patient-important outcomes in adults with X-linked hypophosphatemia (XLH) is essential to guide evidence-based treatment recommendations.ObjectiveTo examine the highest certainty evidence addressing the management of XLH in adults to inform treatment recommendations.MethodsWe searched Embase, MEDLINE, Web of Science, and Cochrane Central up to May 2023. Eligible studies included randomized controlled trials (RCTs) and observational studies of individuals aged 18+ with clinically or genetically confirmed XLH. Manuscripts comparing burosumab to no treatment or conventional therapy (phosphate and active vitamin D) and conventional therapy to no treatment were included. Two reviewers independently determined eligibility, extracted data, and assessed risk of bias (RoB). GRADE methodology was used to assess evidence certainty.ResultsWe screened 4114 records, after removing duplicates, and assessed 254 full texts. One RCT and 2 observational studies were eligible. The RCT of burosumab vs no treatment had low RoB. Burosumab probably improves pain from fracture/pseudofracture healing (moderate certainty) but has little or no impact on direct pain measures (moderate certainty). Burosumab may reduce the need for parathyroidectomy (low certainty) but has little or no impact on fatigue (high certainty), stiffness (moderate certainty), and mobility (low certainty) over 24 weeks. Burosumab may increase dental abscess risk (low certainty). Indirect evidence comparing burosumab to conventional therapy provided low certainty regarding burosumab vs conventional therapy. Two observational studies on conventional therapy vs no treatment had high RoB and very low certainty regarding the impact of conventional therapy on patient-important outcomes.ConclusionNo formal comparisons between burosumab and conventional therapy in adults exist. Evidence for conventional therapy vs no treatment is very uncertain. Our review highlights the need for more data on the long-term effects of burosumab and conventional therapy on patient-important outcomes in adult patients with XLH.

Abstract licence: CC BY-NC-ND

ObjectiveTo examine the evidence addressing the management of X-linked hypophosphatemia (XLH) in children to inform treatment recommendations.MethodsWe searched Embase, MEDLINE, Web of Science, and Cochrane Central up to May 2023. Eligible studies included randomized controlled trials (RCTs) and observational studies of individuals younger than 18 years with clinically or genetically confirmed XLH. Manuscripts comparing burosumab to either no treatment or conventional therapy (phosphate and active vitamin D) or evaluating conventional therapy to no treatment were included. Two reviewers independently determined eligibility, extracted data, and assessed risk of bias (RoB). GRADE methodology was used to assess evidence certainty.ResultsWe screened 4114 records and assessed 254 full texts. One RCT and one post hoc study proved eligible when comparing burosumab to conventional therapy or no treatment. The open-label RCT was at high RoB, with certainty of evidence 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). Burosumab may increase height and enhance the burden of symptoms related to chronic hypophosphatemia (low certainty). Burosumab probably increases treatment-emergent adverse events (moderate certainty) and may increase dental abscesses (low certainty). One observational study assessing conventional therapy vs no treatment was at high RoB, providing very low certainty evidence regarding the impact of conventional therapy on final height.ConclusionOur review indicates that burosumab likely provides benefits to children by preventing lower limb deformity and improving physical health QoL while potentially increasing height. However, burosumab may also increase adverse events. Our review found limited evidence regarding the impact of conventional therapy compared to no treatment on final height. Further research is required to understand the long-term effect of medical therapy in children.

Abstract licence: CC BY-NC-ND

IntroductionTumor-induced osteomalacia is a rare paraneoplastic syndrome characterized by defective bone mineralization due to excessive fibroblast growth factor 23 production, leading to hypophosphatemia, phosphaturia, and osteomalacia. Burosumab, a monoclonal antibody that targets fibroblast growth factor 23, has emerged as a promising therapeutic option for patients with tumor-induced osteomalacia. This systematic review and meta-analysis assesses the efficacy and safety profile of Burosumab in managing tumor-induced osteomalacia, particularly in cases refractory to conventional treatments or when surgical resection of the tumor is not feasible.MethodsThis systematic review and meta-analysis adhered to the PRISMA guidelines and the Cochrane Handbook. Eligible studies included clinical trials evaluating Burosumab against placebo or standard care in patients with tumor-induced osteomalacia. Key outcomes encompassed serum phosphate levels, histomorphometric osteoid parameters, worst pain scale scores, and safety endpoints. Data extraction and quality appraisal were undertaken independently by two reviewers. Pooled means and events per 100 observations were derived using an inverse-variance random-effects model.ResultsFour studies met the eligibility criteria, encompassing 44 patients treated with Burosumab. Burosumab effectively stabilized serum phosphate levels (MD = 0.99; IC 95% 0.77-1.21; I2 = 0%). Histomorphometric parameters of osteoid tissue demonstrated marked improvements following Burosumab treatment, including reductions in thickness (MD = -4.56; IC 95% -6.72 to -2.40; I2 = 29.6%), volume (MD = -5.45; IC 95% -6.91 to -3.99; I2 = 0%), however, no significant change was observed in surface area (MD = -0.56; IC95% -3.63 - 2.50; I2 = 0%). Burosumab also significantly reduced pain score (MD = -1.11; IC95% -2.27 - 0.04; I2 = 0%). Safety analyses revealed that 79.33% (IC 95% 15, 84-98,74; I2 = 80.7%) of patients experienced adverse events, which were predominantly mild and seldom necessitated treatment discontinuation.ConclusionBurosumab was associated with improvements in serum phosphate and bone histomorphometric parameters. A trend toward pain reduction was observed. The safety profile appeared acceptable, although adverse events were frequent. Findings should be interpreted considering the limited evidence base.

Abstract licence: CC BY