APEG 2021: X-linked hypophosphataemia – an update on treatment approaches


The human monoclonal antibody burosumab (Crysvita®) was registered in Australia in September 2021 for the treatment of patients with X-linked hypophosphataemia1 (XLH; the most common genetic cause of rickets)2. It offers an effective alternative treatment option to the conventional therapy used over the past 40 years, oral phosphate supplements and calcitriol.3

Paediatric endocrinologist Professor Craig Munns presented an overview of the clinical efficacy and safety of burosumab in paediatric XLH at the Australasian Paediatric Endocrine Group (APEG) Annual Scientific Meeting in November 2021.4

XLH: a rare genetic phosphate-wasting disease

XLH is a rare, genetic life-long phosphate-wasting disease. “It is the most common form of genetic hypophosphataemia,” explained Prof. Munns. Mutations in the PHEX gene (phosphate-regulating endopeptidase homologue, X-linked) result in elevated circulating fibroblast growth factor 23 (FGF23) levels, which in turn leads to reduced renal phosphate reabsorption and decreased production of active Vitamin D (1,25[OH]2D). The result is chronic hypophosphataemia, impaired mineralisation of bones and teeth, and muscle weakness.3

Prof. Munns described the clinical manifestations of XLH: “It’s a multisystem disorder. In children you can get incomplete healing of rickets and osteomalacia with cholecalciferol; you get lower limb deformities and short stature, [children can have] craniosynostosis, Chiari malformation, and there is poor fracture healing. There’s muscle weakness that seems to be independent of the osteomalacia, [muscle and bone] pain, dental abscesses, and periodontal disease. In adults, there is a continuation of these features, with enthesopathy (ligament, tendon, joint capsule calcification), osteophytes, and arthritis, often requiring joint replacement. Adults often have fractures and pseudofractures, and hearing impairment. In time there can be [problems with] optic atrophy, and spinal stenosis.”5

Conventional medical treatment for XLH is usually titrated to minimise gastrointestinal side effects.2However, outcome is variable with significant complications of therapy,” explained Prof Munns. Other complications of conventional treatment may include hyperparathyroidism, nephrocalcinosis, renal failure, and hypertension.5 “These are very common and debilitating,” said Prof. Munns.

Paediatric XLH prevalence in Australia

Prof. Munns presented the results of a study conducted by the Australian Paediatric Surveillance Unit (APSU) showing the minimum estimated national prevalence of paediatric XLH. The study also looked at demographics, family history of XLH, biochemistry, clinical features, complications, and therapies used to treat children with XLH.

The data was collected via a once-off survey sent to the APSU mailing list. The survey identified 74 confirmed cases of XLH, equating to a national prevalence of 1.31 per 100,000 children under 18 years (CI 1.02–1.64). The current median age of children with XLH was 11 years (range 1–18 years), the median age at diagnosis was 2 years (range 0.1–17), and the majority (59%) were female. There was a family history supporting X-linked inheritance in 48 (67%) children and PHEX gene mutation testing was undertaken in 49 (66%) children, with 47 of the 49 (96%) found to be positive for the mutation.

The most common clinical features reported in the study cohort were lower limb bowing, bone or joint pain, gross motor delay, abnormal gait, myalgia, and short stature (<3rd centile). Additionally, 28% experienced tooth abscess and 11% had craniosynostosis. Males tended to have a more severe phenotype of the disease, which Prof. Munns noted differed from the results from other studies and needs to be confirmed in future investigations.

The survey found that management involved burosumab in just over half the patients (55%) and phosphate and calcitriol supplementation in the remainder (45%). Complications of phosphate and calcitriol therapy involved nephrocalcinosis, hyperparathyroidism, and renal impairment. Prof Munns noted that similar complications were not seen in patients following burosumab treatment.

Improved outcomes with burosumab in children with XLH compared to conventional therapy6

Prof Munns presented the results of the phase 3 study of burosumab in children with XLH.6

This was a randomised, active-controlled, open-label trial that compared the efficacy and safety of continued conventional therapy (oral phosphate and active vitamin D) versus  burosumab in children aged 1–12 years with XLH. Patients received either burosumab (0.8 mg/kg every 2 weeks delivered subcutaneously; n=29) or conventional therapy for 64 weeks (n=32). The primary endpoint was change in rickets severity at Week 40 assessed by the Radiographic Global Impression of Change (RGIC) score.6

Patients in the burosumab group had significantly greater improvement in RGIC score than those in the conventional group (least squares mean +1.9 [SE 0.1] with burosumab vs +0.8 [SE 0.1] with conventional therapy; difference 1.1, 95% CI 0.8 – 1.5; p<0.0001).6

There was also a significantly greater increase in length and height Z score at Week 64 in the burosumab group than in the conventional therapy group (least squares mean change 0.17 with burosumab [SE 0.07] versus 0.02 [SE 0.04]; difference 0.14, 95% CI 0.0 – 0.29; p=0.0490).6

After adjusting for baseline differences, patients in the burosumab group had a significantly greater improvement in distance walked compared to patients in the conventional therapy group at 64 weeks (least squares mean change 9% [SE 2] for burosumab versus 2% [SE 3] for conventional therapy; difference 7%, 95% CI 0.01 – 14.52; p – 0.0496).6

Dental abscesses occurred more frequently in the burosumab group, which the authors suggested could be due to patient variability or a possible direct dental benefit of conventional therapy.6 Commenting on these results, Prof Munns noted, “tooth abscesses are a reflection of abnormal tooth development so it may be that if we start treating children young enough that their secondary teeth and later primary teeth will have an improvement in their morphology, which will make abscess less likely.

Treatment emergent adverse events considered possibly, probably or definitely related to treatment occurred more frequently with burosumab (59% versus 22% for conventional therapy). “Most treatment emergent adverse events in the burosumab group related to injection site reactions, were mild in severity and resolved within a few days,” the study authors explained.6

By inhibiting excess FGF23 activity and normalizing renal phosphate excretion, burosumab induced clinically meaningful improvements within 64 weeks and has the potential to prevent long-term complications associated with X-linked hypophosphataemia,” the study authors concluded.6

Pain and other patient-related outcome measures improved with burosumab compared to continued conventional therapy3

Patient-reported outcomes were also measured in children aged over 5 years at screening (n=35) using a Patient-Reported Outcomes Measurement Information System (PROMIS).3

Pain interference scores differed significantly between groups at Week 40 (-5.02, 95% CI -9.29 to -0.75; p = 0.0212) but not at Week 64.  Reductions in pain interference and fatigue scores from baseline were clinically meaningful with burosumab at Weeks 40 and 64 but not with conventional therapy. Between-group differences were not significant for physical function mobility or fatigue; conversely, physical health scores (PHS) improved significantly with burosumab at week 40 and week 64, but not with conventional therapy (between-treatment differences were nonsignificant). “In conclusion, changing to burosumab improved PRO measures, with statistically significant differences in PROMIS pain interference at week 40 versus continuing with conventional therapy and in PHS-10 at weeks 40 and 64,” said the study authors.3

Prof Munns explained the possible reasons underlying these results: “Osteomalacia is painful, and rickets is painful, so it’s an improvement in both of these that leads to a reduction in pain. But it also might be a primary muscle effect of hypophosphataemia or some other FGF23-mediated effect.”

Crysvita® (burosumab): now registered in Australia for the treatment of XLH

Burosumab is a recombinant human IgG monoclonal antibody that binds to and inhibits the biological activity of fibroblast growth factor 23 (FGF23), which is present in excess in XLH.1 Neutralisation of FGF23 increases renal tubular reabsorption of phosphate and the serum concentration of 1,25 dihydroxy-Vitamin D.1 In Australia, it is indicated for the treatment of XLH in adults, adolescents and children 1 year of age and older.1

Disclosure

This article was sponsored by Kyowa Kirin Australia. Before prescribing, please review the CRYSVITA product information via the TGA website. Treatment decisions based on the information in this article are the responsibility of the prescribing physician.

 References

  1. Australian Product Information for Crysvita® (burosumab) approved 10 September 2021. CRYSVITA product information. Last accessed: Jan 2022.
  2. Carpenter TO, Imel EA, Holm IA, et al. A clinician’s guide to X-linked hypophosphatemia. J Bone Miner Res. 2011;26:1381-8.
  3. Padidela R. et al Calcif Tissue Int 2021;108(5):622-633 https://doi.org/10.1007/s00223-020-00797-x
  4. Munns, CJ. 2021 Oral presentation entitled “XLH – novel insights and therapies”, as presented at the APEG 2021 Annual Scientific Meeting, Tuesday 23rd of November 2021, Virtual Meeting.
  5. Imel E et al. JBMRPlus 2019;3(8): e10190 https://asbmr.onlinelibrary.wiley.com/doi/10.1002/jbm4.10190  
  6. Imel E et al. Lancet 2019; 393(10189):2416–2427. http://dx.doi.org/10.1016/S0140-6736(19)30654-3

Already a member?

Login to keep reading.

OR
Email me a login link
logo

© 2022 the limbic