Diagnosis and Management of X-linked Hypophosphatemia (XLH)

Transcription

1 Diagnosis and Management of X-linked Hypophosphatemia (XLH) August 10, 2018 Eric T. Rush, MD, FAAP, FACMG Clinical Geneticist Children s Mercy Hospital Associate Professor of Pediatrics UMKC School of Medicine

2 Disclosures Consultant/ Speaking Research funding Alexion Pharmaceuticals (Consultant/Speaker) Biomarin Pharmaceuticals (Consultant/Speaker) Ultragenyx Pharmaceuticals (Speaker) Alexion Pharmaceuticals Stock ownership/corporate boards-employment Off-label uses None None 2

3 Agenda Pathology, Diagnosis and Natural history of XLH Historical standard of care for XLH Innovations in care of patients with XLH 3

4 History of XLH Albright provided the classical description of the disease now known as XLH in , although rachitis tarda was described much earlier in cases resistance to treatments such as cod-liver oil This paper describes a 16 year old patient with 15 years of rickets resistance to physiologic vitamin D and heliotherapy Individual fractures were assisted in healing by extremely high vitamin D dosages 4

5 History of XLH Winters described in 1958 a family from North Carolina with chronic hypophosphatemia and rickets 2 and important observations were made: Rickets were worse in males than in females No instances of male-to-male transmission Renal phosphate absorption 50% of normal Rickets were resistant to vitamin D effects on phosphorus, but not on calcium 5 possible mechanisms were proposed, one of which #4 turned out to be essentially correct 5

6 History of XLH Glorieux and colleagues reported in 1972 the treatment of 8 patients with XLH with phosphate salts and Vitamin D 3 and were observed to have improvements in growth and resolution of rickets Improvement in serum phosphorus was noted With some refinements, this treatment modality has been our standard of care for the past forty-plus years 6

7 XLH at birth Patients with XLH tend to be normal at birth and have a rather variable phenotype Hypophosphatemia is present from birth, but obvious signs and symptoms will develop over the first year of life Patients without known family history will typically escape detection somewhat longer than those with a family history 7

8 Pediatric Disease Bowing and Short Stature Short stature is not universal, but is common and more significant in males as compared to females Bowing often develops as children grow and begin to walk in the first two years of life, and severity can be estimated by medial knee distance or by radiographic measurements 4 8

9 Pediatric Diseases Metaphyseal Changes Widened and frayed metaphyses are common findings of XLH The distal femur, proximal tibia, and the distal aspect of the radius and ulna are locations which are frequently affected by rickets 5 Carpenter et al,

10 Pediatric Disease Dental Dental manifestations in XLH are common and include: 6,7 Enamel hypoplasia and discoloration Thinning of dentin with enlargement of pulp chambers Chronic or recurrent dental abscesses Foster et al, 2014 Souza et al,

11 Pediatric Disease - Skull Craniosynostosis Sagittal suture appears most common 22 Frontal Bossing with dolichocephaly Flattened Cranial Base Decreased depth of posterior fossa Chiari I Malformation 44% of patients 23 11

12 Pediatric Disease - Other Motor delay Stiffness and pain Alteration to walking and running gait 12

13 Adult Disease - Osteomalacia Osteomalacia can be seen in adults with XLH 8, and can contribute to: Carpenter et al, 2011 Fractures Bone Pain Stiffness Early-onset Arthritis 13

14 Adult Disease - Enthesopathy Enthesopathy is a common finding (30-84%) in patients with XLH and is the result of excessive mineralization of the enthesis fibrocartilage 9 These lesions are frequently painful and can limit mobility Liang et al,

15 Adult Disease Additional Findings Dental Abscess 86% of patients Hearing Loss Joint Pain 82% of patients Muscle pain and weakness, can occur due to hypophosphatemia for any reason Poor exercise and activity tolerance 15

16 What are Rickets? Any condition which results in the failure of bone mineral (hydroxyapatite) to accumulate properly into the bone Historically, have occurred for nutritional reasons, but now this is uncommon in the United States London during the Industrial Revolution 16

17 Physiology of Rickets 17

18 Phosphate Utilization Diets are generally rich in phosphate, of which approximately 60-70% is absorbed by the small intestine Process regulated by 1,25-hydroxyvitamin D Phosphate is filtered by the glomerulus and then reabsorbed by sodium phosphate transporters in the proximal tubule These transporters can be downregulated by FGF23 and PTH 18

19 Function of FGF23 Predominantly produced by the osteocytes Two main mechanisms of action 26 Inhibit renal tubular phosphate reabsorption Suppress 1-alpha hydroxylase activity Requires FGFR And Klotho coreceptors for activity 19

20 Nature of Renal Phosphate Wasting Pathogenic PHEX variant Upregulation Effect on Sodium/Phosphate Effect Increases Phosphate Excretion FGF23 20 Effect on 1 alpha hydroxylase Decreases Phosphate Absorption

21 Genetics of XLH There are several different types of hypophosphatemic rickets, which can differ in phenotype and inheritance pattern Today, we are discussing X-linked hypophosphatemic rickets X-linked dominant disorder, which is uncommon Caused by loss of function pathogenic variants in the PHEX gene, which is a phosphate-regulating endopeptidase 21

22 PHEX Variants Between 57%-78% of the variants detected have been on sequencing analysis This leaves 22%-43% of variants detected on deletion/duplication analysis Studies vary on total yield of PHEX analysis, but suffice to say it is substantially below 100% 10 Normal testing does NOT rule out XLH in a patient with appropriate clinical and biochemical findings 22

23 Epidemiology and Prevalence of XLH XLH is a rare disease, which means that it affects fewer than 200,000 Americans 11 The incidence of XLH is generally believed to be approximately 1 in 20,000 to 1 in 25,000 which makes it approximately as common as osteogenesis imperfecta 23

24 Diagnosis of XLH Personal history of Rickets Can get murky pretty quickly; patients may have been told that they had nutritional rickets or another skeletal disorder Family history Helpful if present, but about 30% are new dominant mutations 12 24

25 Diagnosis of XLH Serum phosphorus Low Urine phosphorus - High Serum calcium Normal Urine calcium Normal Alkaline phosphatase High 25-OH Vitamin D Normal PTH Can be elevated or normal FGF23 Typically elevated 25

26 Conventional Treatment in XLH Conventional medical treatment has been administration of: oral phosphate supplementation and calcitriol supplementation Phosphorus mg/kg/day Will be ineffective unless calcitriol is coadministered Calcitriol ng/kg/day 26

27 Conventional Treatment in XLH Phosphate supplements generally must be divided into several (3-5) doses a day Calcitriol supplements generally can be given two times per day In both cases, it pays to start at doses much lower than target doses and slowly move up 27

28 Monitoring Conventional Therapy Safety Serum phosphorus, serum and urine calcium, renal ultrasound, PTH Do not attempt to normalize phosphorus Avoid hypercalcemia, hypercalciuria, nephrocalcinosis Avoid hyperparathyroidism 28

29 Monitoring Conventional Therapy Efficacy Alkaline phosphatase, radiology Decrease in alkaline phosphatase level into high normal range suggests healing of rickets For pediatric patients, rickets survey will show improvement in metaphyseal changes and bowing over time Improvement in growth for children, reduction in pain for children and adults 29

30 Rationale for Treatment Renal phosphate wasting due to increased phosphate excretion and decreased absorption Decreased absorption related to 1-alpha hydroxylase downregulation targeted by calcitriol supplementation Increased phosphate excretion has historically been difficult to address, but has been indirectly supported by exogenous phosphate administration 30

31 Additional Treatment of XLH Surgical Treatment is sometimes required, and can be much more conservative with good medical therapy For children, this may be mean leg straightening surgeries or craniosynostosis surgeries For adults, rodding after fracture, arthroplasty, and dental procedures may be necessary 31

32 Benefits of Conventional Treatment in Children Consistent treatment during growth results in 5,13 Correction of rickets Partial correction of skeletal abnormalities Decrease in need for surgical intervention Improved final height 32

33 Benefits of Conventional Treatment in Children Additional study has also suggested 14 Increase in growth velocity, especially during early phase of treatment Improvement (but not normalization) of serum phosphorus levels 33

34 Benefits of Conventional Treatment in Adults Adults with XLH can have: Osteomalacia Fractures Enthesopathy Dental Disease Pain Decreased mobility 34

35 Benefits of Conventional Treatment in Adults Sullivan and colleagues 15 found that supplementation improved Experience in musculoskeletal symptoms Biochemical parameters related to XLH Osteoid volume and mineral apposition rates Adverse events including hyperpara and renal insufficiency were noted 35

36 Benefits of Conventional Treatment in Adults Conner and colleagues 16 found additionally that extent of therapy did not predict the extent of enthesopathy, but that the extent of therapy was correlated with the extent of dental disease Treatment in adulthood may not promote or prevent enthesopathy; however, it may be associated with a lower risk of experiencing severe dental disease 36

37 Limitations of Treatment Mechanistically, treatment with phosphorus and calcitriol is only a partial treatment Doesn t address central PHEX problem of FGF23-driven phosphaturia As a practical matter, adherence is really difficult for this disorder Phosphate supplementation required between three and five times per day and calcitriol twice per day which is difficult to remember Phosphate supplementation causes stomach upset and diarrhea, which can further impact adherence 37

38 Limitations of Treatment Conventional therapy can improve growth, but patients still do not catch up completely 24 XLH patients in one study had decreased stature (-3.3 SDS), which Leg length (-3.8 SDS) was most impaired Sitting height (-1.7 SDS) was relatively more normal Overtreatment can cause hyperpara, nephrocalcinosis, chronic kidney disease 38

39 Rational Approaches to Treatment of XLH Conventional treatment of XLH has been incomplete Ideal treatment would address underlying mechanism of disease Restoration of PHEX activity HARD Inhibition of FGF23 activity EASIER? 39

40 Burosemab for treatment of XLH KRN23 is a monoclonal antibody that binds to and inactivates FGF23 Phase 1 study in humans showed 17 Increase in serum phosphorus Increase in serum 1,25- dihydroxyvitamin D Increase in TmP/GFR Carpenter et al, 2014 Biochemical responses were quicker in the IV group, but longer lasting in the SC groupgroup 40

41 Burosemab for treatment of XLH Sequential Phase 1/2 trial involving 28 adults with XLH for 4-month dose escalation % had normal serum phosphorus at baseline 88.5% had normal serum phosphorus by day 7 after fourth dose 22 patients continued to 12 month extension study 19 Mean peak phosphorus mg/dl Mean trough phosphorus mg/dl 41 Imel et al, 2015

42 Burosemab for treatment of Pediatric XLH Open-label Phase 2 trial, 52 children with XLH randomly assigned to receive SC burosemab either every 2 weeks or 4 weeks 19 Dose adjusted to achieve serum phosphorus at lower end of normal range Primary endpoint was improvement in Thacher Rickets Severity Score Radiographic Global Impression of Change was used to compare radiographic appearance at weeks 40 and 64 to baseline 42

43 Burosemab for treatment of Pediatric XLH Increases in serum phosphorus seen in both groups, but more stable in every two week group Renal tubular phosphate reabsorption increases in both groups 43 Increased 1,25- dihydroxyvitamin D and decreased ALP seen

44 Burosemab for treatment of Pediatric XLH Significant reduction in RSS, denoting overall improvement in rickets RGI-C noted improvement in entire cohort, but more marked in subcohort of patients with higher RSS 44

45 Burosemab for treatment of Adult XLH 133 Patients completed 24 week double-blinded, placebo-controlled Phase 3 RCT % had previous orthopedic surgery 63.4% had history of osteoarthritis 99.3% had evidence of enthesopathy 69.4% had previous conventional therapy 71.6% had severe pain 45

46 Burosemab for treatment of Adult XLH Patients who received burosemab had a significantly higher rate of normal serum phosphate both at midpoint of dosing (94.1% vs. 7.6%, p<0.001) and at the end of the dosing interval (67.6% vs. 6.1%) -5 patients required dose reduction due to Phos level greater than 4.5 TmP/GFR also increased significantly in the burosemab group (1.7+/- 0.4 to 2.7 +/- 0.75), but very little change was seen in the placebo group 46

47 Burosemab for treatment of Adult XLH 32 (47.1%) subjects in the burosumab group had 65 active fractures at baseline 38 (57.6%) subjects in the placebo group had 91 active fractures at baseline By week 24, 43.1% of patients in the burosemab group had fracture healing compared with 7.7% in the control group 47

48 Burosemab for treatment of Adult XLH Trend toward improvement in pain for adults with XLH Significant improvement in WOMAC physical function and stiffness scores 48

49 Dosing of Burosemab 25 Burosemab should not be coadministered with phosphate and/or calcitriol supplementation Do not use if hypophosphatemia is not present Only use if chronic kidney disease is not present Pediatric dosage is 0.8 mg/kg SC every two weeks Adult dosage is 1 mg/kg SC every four weeks 49

50 Surveillance of Burosemab In children, serum phosphorus every 4 weeks for the first 3 months of treatment If serum phosphorus is greater than 5 mg/dl, dose should be reduced and reassessed in four weeks If serum phosphorus is below LLN, can be increased If serum phosphorus is normal, continue present dose Specific recommendations for dosage adjustment provided in burosemab PI 50

51 Surveillance of Burosemab In adults, the maximum dose is 90mg Serum phosphorus should be measured on a monthly basis, measured 2 weeks post-dose, for the first 3 months of treatment If serum phosphorus is above the normal range, withhold the next dose and reassess the serum phosphorus level after 4 weeks The patient must have serum phosphorus below the normal range to be able to reinitiate 51

52 Adverse Events seen with burosemab therapy Pediatric Patients Headache Injection site reaction Vomiting Fever Pain in arms and legs Decreased vitamin D levels Rash Toothache or infection Adult Patients Back pain Headache Tooth infection Restless leg syndrome Decreased vitamin D levels Dizziness Constipation Hyperphosphatemia Muscle pain Dizziness 52

53 Conclusions XLH is a rare, but significant disease which has multiple impacts on health throughout the lifespan Standard treatments have been suboptimal and difficult to comply with Burosemab offers therapy which targets hyperphosphaturia and shows efficacy for 53

54 THANK YOU!

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