Hypophosphatemic rickets: new treatments · 2018-06-11 · Valld'HebronBarcelona Hospital Campus...
Transcript of Hypophosphatemic rickets: new treatments · 2018-06-11 · Valld'HebronBarcelona Hospital Campus...
![Page 1: Hypophosphatemic rickets: new treatments · 2018-06-11 · Valld'HebronBarcelona Hospital Campus Sempre, el pacientprimer 5 X-Linked Hypophosphatemia •It is the most common inherited](https://reader033.fdocuments.us/reader033/viewer/2022042412/5f2b8f79bac65b404570aa6f/html5/thumbnails/1.jpg)
Vall d'Hebron Barcelona Hospital Campus1Sempre, el pacient primer
Hypophosphatemic rickets: new treatments
11.06.18 Tubulopathies
Gema AricetaPediatric Nephrology, University Hospital Vall d‘ Hebron, Barcelona
![Page 2: Hypophosphatemic rickets: new treatments · 2018-06-11 · Valld'HebronBarcelona Hospital Campus Sempre, el pacientprimer 5 X-Linked Hypophosphatemia •It is the most common inherited](https://reader033.fdocuments.us/reader033/viewer/2022042412/5f2b8f79bac65b404570aa6f/html5/thumbnails/2.jpg)
Vall d'Hebron Barcelona Hospital Campus2Sempre, el pacient primer
Disclosures
• Lectures and educational activities sponsored by Kyowa Kirim• Advisory meetings for Kyowa Kirin
![Page 3: Hypophosphatemic rickets: new treatments · 2018-06-11 · Valld'HebronBarcelona Hospital Campus Sempre, el pacientprimer 5 X-Linked Hypophosphatemia •It is the most common inherited](https://reader033.fdocuments.us/reader033/viewer/2022042412/5f2b8f79bac65b404570aa6f/html5/thumbnails/3.jpg)
Vall d'Hebron Barcelona Hospital Campus3Sempre, el pacient primer
Primary Hypophosphatemic rickets: a group of diseases
Disease Abbreviation Gene FGF23 levels Hypo-phosphatemia
X-Linked Hypophosphatemia
XLH PHEX ↑ Y
Autosomal dominant hypophosphatemic rickets
ADHR FGF23 ↑ Y
Autosomal recessive hypophosphatemic rickets 1
ARHR1 DMP1 ↑ Y
Autosomal recessive hypophosphatemic rickets 2
ARHR2 ENPP1 ↑ Y
Autosomal recessive hypophosphatemic rickets 3
(Raine Syndrome)ARHR3 FAM20C ↑ Y
Hypophosphatemic rickets with hypercalciuria
HHRH SLC34A3 (NPT2C) - Y
![Page 4: Hypophosphatemic rickets: new treatments · 2018-06-11 · Valld'HebronBarcelona Hospital Campus Sempre, el pacientprimer 5 X-Linked Hypophosphatemia •It is the most common inherited](https://reader033.fdocuments.us/reader033/viewer/2022042412/5f2b8f79bac65b404570aa6f/html5/thumbnails/4.jpg)
Vall d'Hebron Barcelona Hospital Campus4Sempre, el pacient primer
FGF23
• FGF23 is a 32-D protein mainly produced by osteocytes in bone, (and less by osteoblasts and chondrocytes, and other organs (thymus, brain, spleen)
• FGF23 promotes phosphate excretion in the urine by suppressing the expression of sodium-phosphate co-transporters, NaPi-2a and NaPi-2c, in the proximal tubule
• FGF23 acts as a counter-regulatory hormone for vitamin D through inhibition of the renal 1α-hydroxylase, and stimulation of the 24-hydroxylase
• FGF23 also regulates PTH production by the parathyroid gland
JR Stubbs, S Egwuonwu. Pediatr Nephrol, 2011; Sharma A et, Pediatric Nephrology Avner eds, 2016
![Page 5: Hypophosphatemic rickets: new treatments · 2018-06-11 · Valld'HebronBarcelona Hospital Campus Sempre, el pacientprimer 5 X-Linked Hypophosphatemia •It is the most common inherited](https://reader033.fdocuments.us/reader033/viewer/2022042412/5f2b8f79bac65b404570aa6f/html5/thumbnails/5.jpg)
Vall d'Hebron Barcelona Hospital Campus5Sempre, el pacient primer
X-Linked Hypophosphatemia
• It is the most common inherited form of rickets / osteomalacia
• Incidence 3.9/100.000 live newborns, prevalence 4.8/100.000
• It is caused by loss of function mutations in the PHEX gene that encodes for an endopeptidase which is expressed predominantly in bones and teeth, in osteoblasts, osteocytes, and odontoblasts.
• Loss of function pathogenic variants in PHEX lead to increased serum levels of FGF23 which results in:
• high serum levels of FGF23 • Renal phosphate wasting • Hypophosphatemia• Decreased 1-α hydroxylation of 25(OH) vit D
![Page 6: Hypophosphatemic rickets: new treatments · 2018-06-11 · Valld'HebronBarcelona Hospital Campus Sempre, el pacientprimer 5 X-Linked Hypophosphatemia •It is the most common inherited](https://reader033.fdocuments.us/reader033/viewer/2022042412/5f2b8f79bac65b404570aa6f/html5/thumbnails/6.jpg)
Vall d'Hebron Barcelona Hospital Campus6Sempre, el pacient primer
“Traditional” treatment of XLH rickets
Children: from diagnosis until the end of longitudinal growth (at least)
• Oral phosphate supplements
20-40 mg/kg/day (≤ 100 mg/Kg/d in infants) divided in 3-5 daily doses
• Oral Calcitriol (1α vit D) different recommendations
20-30 ng/Kg/day (in 2-3 daily doses) 50-70 ng/kg/day (≤ 3 ug per day)
A. Linglart , endocrine conections, 2014; Ruppe MD, GeneReviews, 2017
Adults: indications not well defined (bone pain, fractures, trauma surgery)
• Oral phosphate supplements: 750-1000 mg/day divided in 3 daily doses
• Oral Calcitriol: 0.5-0.75 ug/day
![Page 7: Hypophosphatemic rickets: new treatments · 2018-06-11 · Valld'HebronBarcelona Hospital Campus Sempre, el pacientprimer 5 X-Linked Hypophosphatemia •It is the most common inherited](https://reader033.fdocuments.us/reader033/viewer/2022042412/5f2b8f79bac65b404570aa6f/html5/thumbnails/7.jpg)
Vall d'Hebron Barcelona Hospital Campus7Sempre, el pacient primer
XLH rickets treatment aims and limitations
Aims
Healing ricketsLeg deformities correction(± orthopedic surgery)Growth improvement
Limitations
Hypophosphatemia persistsSystemic manifestationsSide effects: GI disturbancesand risk of nephrocalcinosisIt is not focused on diseasepathogenesis, and evenincreases FGF23 levels!
![Page 8: Hypophosphatemic rickets: new treatments · 2018-06-11 · Valld'HebronBarcelona Hospital Campus Sempre, el pacientprimer 5 X-Linked Hypophosphatemia •It is the most common inherited](https://reader033.fdocuments.us/reader033/viewer/2022042412/5f2b8f79bac65b404570aa6f/html5/thumbnails/8.jpg)
Vall d'Hebron Barcelona Hospital Campus8Sempre, el pacient primer
Growth hormone in XLHROpen randomized controlled clinical trial in children 10y old
(16 treated with P + calcitriol + rhGH vs. 66 treated with P + calcitriol)
Zivicnjack M et al, J Clin Endocrinol Metab 96: E2097–E2105, 2011
![Page 9: Hypophosphatemic rickets: new treatments · 2018-06-11 · Valld'HebronBarcelona Hospital Campus Sempre, el pacientprimer 5 X-Linked Hypophosphatemia •It is the most common inherited](https://reader033.fdocuments.us/reader033/viewer/2022042412/5f2b8f79bac65b404570aa6f/html5/thumbnails/9.jpg)
Vall d'Hebron Barcelona Hospital Campus9Sempre, el pacient primer
Limited effect of rhGH on growth impairment in children with XHR
Rafaelsen S, et al.Eur J Endocrinol. 2016 Feb;174(2):125-36.
n = 22
![Page 10: Hypophosphatemic rickets: new treatments · 2018-06-11 · Valld'HebronBarcelona Hospital Campus Sempre, el pacientprimer 5 X-Linked Hypophosphatemia •It is the most common inherited](https://reader033.fdocuments.us/reader033/viewer/2022042412/5f2b8f79bac65b404570aa6f/html5/thumbnails/10.jpg)
Vall d'Hebron Barcelona Hospital Campus10Sempre, el pacient primer
![Page 11: Hypophosphatemic rickets: new treatments · 2018-06-11 · Valld'HebronBarcelona Hospital Campus Sempre, el pacientprimer 5 X-Linked Hypophosphatemia •It is the most common inherited](https://reader033.fdocuments.us/reader033/viewer/2022042412/5f2b8f79bac65b404570aa6f/html5/thumbnails/11.jpg)
Vall d'Hebron Barcelona Hospital Campus11Sempre, el pacient primer
Limitations for measuring treatment efficacy in XLHR
• Phenotype variability even within same family affected members
• Impact of the age of diagnosis and treatment initiation on outcome
• Gender effect: affected females and carries vs affected males
• Adherence
• Adverse effects: GI intolerance
• Evaluation of bone mineral pattern
![Page 12: Hypophosphatemic rickets: new treatments · 2018-06-11 · Valld'HebronBarcelona Hospital Campus Sempre, el pacientprimer 5 X-Linked Hypophosphatemia •It is the most common inherited](https://reader033.fdocuments.us/reader033/viewer/2022042412/5f2b8f79bac65b404570aa6f/html5/thumbnails/12.jpg)
Vall d'Hebron Barcelona Hospital Campus12Sempre, el pacient primer
New treatments for Hypophosphatemic rickets
• Calcimimetics
• anti-FGF23 ab (KRN23)
![Page 13: Hypophosphatemic rickets: new treatments · 2018-06-11 · Valld'HebronBarcelona Hospital Campus Sempre, el pacientprimer 5 X-Linked Hypophosphatemia •It is the most common inherited](https://reader033.fdocuments.us/reader033/viewer/2022042412/5f2b8f79bac65b404570aa6f/html5/thumbnails/13.jpg)
Vall d'Hebron Barcelona Hospital Campus13Sempre, el pacient primer
Cinacalcet in XLHR: case reports
5 y. old boy with XLH treated since 4 months age
Active rickets and 2nd. hyperparathyroidismdue P intolerance
Good outcome and rickets healing treated with calcitriol + cinacalcet combination
JS VanSickle, et al. Pediatric Nephrology, 2018
![Page 14: Hypophosphatemic rickets: new treatments · 2018-06-11 · Valld'HebronBarcelona Hospital Campus Sempre, el pacientprimer 5 X-Linked Hypophosphatemia •It is the most common inherited](https://reader033.fdocuments.us/reader033/viewer/2022042412/5f2b8f79bac65b404570aa6f/html5/thumbnails/14.jpg)
Vall d'Hebron Barcelona Hospital Campus14Sempre, el pacient primer
020406080
100120140160
baseline 3 months 12 months
pg/mL PTH
6 XLHR patients with PHEX mutations treated with reduced P dose and cinacalcet
Cinacalcet in XLHR: own data
0
0,5
1
1,5
2
2,5
3
3,5
4
baseline 3 months 12 months
mg/dL Serum P
![Page 15: Hypophosphatemic rickets: new treatments · 2018-06-11 · Valld'HebronBarcelona Hospital Campus Sempre, el pacientprimer 5 X-Linked Hypophosphatemia •It is the most common inherited](https://reader033.fdocuments.us/reader033/viewer/2022042412/5f2b8f79bac65b404570aa6f/html5/thumbnails/15.jpg)
Vall d'Hebron Barcelona Hospital Campus15Sempre, el pacient primer
6 XLHR patients with PHEX mutations treated with reduced P dose and cinacalcet
Cinacalcet in XLHR: own data
Parameter Baseline 3 months 12 months effectSerum P (mg/dL)
(p)
2.48 2.5
(0.46)
2.35
(0.34)no change
PTH (pg/mL)
(p)
78.71 51.23
(0.067)
40
(0.039)decrease
FGF23 (RU/ml)
(p)
255 165.91
(0.034)
156.8
(0.09)decrease
TRP (%)
(p)
55.66 72.39
(0.023)
77.4
(0.03)increase
TmP/GFR (mg/dL)
(p)
1.37 1.76
(0.014)
1.67
(0.03)
increase
![Page 16: Hypophosphatemic rickets: new treatments · 2018-06-11 · Valld'HebronBarcelona Hospital Campus Sempre, el pacientprimer 5 X-Linked Hypophosphatemia •It is the most common inherited](https://reader033.fdocuments.us/reader033/viewer/2022042412/5f2b8f79bac65b404570aa6f/html5/thumbnails/16.jpg)
Vall d'Hebron Barcelona Hospital Campus16Sempre, el pacient primer
. anti-FGF23 ab (KRN23)
Carpenter T et al. J Clin Invest 2014
Effects of IV and sc KRN23 vs placebo on TmP/GFR, serum P and 1,25OH2D levels
![Page 17: Hypophosphatemic rickets: new treatments · 2018-06-11 · Valld'HebronBarcelona Hospital Campus Sempre, el pacientprimer 5 X-Linked Hypophosphatemia •It is the most common inherited](https://reader033.fdocuments.us/reader033/viewer/2022042412/5f2b8f79bac65b404570aa6f/html5/thumbnails/17.jpg)
Vall d'Hebron Barcelona Hospital Campus17Sempre, el pacient primer
. Effect of repeated doses of anti-FGF23 ab (KRN23) in adults
Zhang X. J Clin Pharmacol 2016
![Page 18: Hypophosphatemic rickets: new treatments · 2018-06-11 · Valld'HebronBarcelona Hospital Campus Sempre, el pacientprimer 5 X-Linked Hypophosphatemia •It is the most common inherited](https://reader033.fdocuments.us/reader033/viewer/2022042412/5f2b8f79bac65b404570aa6f/html5/thumbnails/18.jpg)
Vall d'Hebron Barcelona Hospital Campus18Sempre, el pacient primer
. anti-FGF23 ab (KRN23) in adults with XLHA randomised, double-blind, placebo controlled, Phase III study (UX023-CL303) with open-label extension to assess the efficacy and safety of KRN23
Courtesy of Kyowa Kirin
![Page 19: Hypophosphatemic rickets: new treatments · 2018-06-11 · Valld'HebronBarcelona Hospital Campus Sempre, el pacientprimer 5 X-Linked Hypophosphatemia •It is the most common inherited](https://reader033.fdocuments.us/reader033/viewer/2022042412/5f2b8f79bac65b404570aa6f/html5/thumbnails/19.jpg)
Vall d'Hebron Barcelona Hospital Campus19Sempre, el pacient primer
. anti-FGF23 ab (KRN23) in adults with XLHA randomised, double-blind, placebo controlled, Phase III study (UX023-CL303) with open-label extension to assess the efficacy and safety of KRN23
Courtesy of Kyowa Kirin
![Page 20: Hypophosphatemic rickets: new treatments · 2018-06-11 · Valld'HebronBarcelona Hospital Campus Sempre, el pacientprimer 5 X-Linked Hypophosphatemia •It is the most common inherited](https://reader033.fdocuments.us/reader033/viewer/2022042412/5f2b8f79bac65b404570aa6f/html5/thumbnails/20.jpg)
Vall d'Hebron Barcelona Hospital Campus20Sempre, el pacient primer
A randomised, open-blind, Phase II study (UX023-CL201) in 52 children with XLH
anti-FGF23 ab (KRN23) in children
Courtesy of Kyowa Kirin
![Page 21: Hypophosphatemic rickets: new treatments · 2018-06-11 · Valld'HebronBarcelona Hospital Campus Sempre, el pacientprimer 5 X-Linked Hypophosphatemia •It is the most common inherited](https://reader033.fdocuments.us/reader033/viewer/2022042412/5f2b8f79bac65b404570aa6f/html5/thumbnails/21.jpg)
Vall d'Hebron Barcelona Hospital Campus21Sempre, el pacient primer
A randomised, open-blind, Phase II study (UX023-CL201) in 52 children with XLH
anti-FGF23 ab (KRN23) in children
Courtesy of Kyowa Kirin
![Page 22: Hypophosphatemic rickets: new treatments · 2018-06-11 · Valld'HebronBarcelona Hospital Campus Sempre, el pacientprimer 5 X-Linked Hypophosphatemia •It is the most common inherited](https://reader033.fdocuments.us/reader033/viewer/2022042412/5f2b8f79bac65b404570aa6f/html5/thumbnails/22.jpg)
Vall d'Hebron Barcelona Hospital Campus22Sempre, el pacient primer
Study of the safety, pharmacodynamics and efficacy of KRN23 in children 1-4 y old (UX023-CL205) in 13 children with XLH
anti-FGF23 ab (KRN23) in children
Courtesy of Kyowa Kirin
![Page 23: Hypophosphatemic rickets: new treatments · 2018-06-11 · Valld'HebronBarcelona Hospital Campus Sempre, el pacientprimer 5 X-Linked Hypophosphatemia •It is the most common inherited](https://reader033.fdocuments.us/reader033/viewer/2022042412/5f2b8f79bac65b404570aa6f/html5/thumbnails/23.jpg)
Vall d'Hebron Barcelona Hospital Campus23Sempre, el pacient primer
Study of the safety, pharmacodynamics and efficacy of KRN23 in children 1-4 y old (UX023-CL205) in 13 children with XLH
anti-FGF23 ab (KRN23) in children
Courtesy of Kyowa Kirin
![Page 24: Hypophosphatemic rickets: new treatments · 2018-06-11 · Valld'HebronBarcelona Hospital Campus Sempre, el pacientprimer 5 X-Linked Hypophosphatemia •It is the most common inherited](https://reader033.fdocuments.us/reader033/viewer/2022042412/5f2b8f79bac65b404570aa6f/html5/thumbnails/24.jpg)
Vall d'Hebron Barcelona Hospital Campus24Sempre, el pacient primer
anti-FGF23 ab (KRN23)
Courtesy of Kyowa Kirin
• Very promising results
• Questions
• Long term outcome and safety• Indication and prescription• Treatment assesment: FGF23 monitoring,
bone indicators?• Access and cost
![Page 25: Hypophosphatemic rickets: new treatments · 2018-06-11 · Valld'HebronBarcelona Hospital Campus Sempre, el pacientprimer 5 X-Linked Hypophosphatemia •It is the most common inherited](https://reader033.fdocuments.us/reader033/viewer/2022042412/5f2b8f79bac65b404570aa6f/html5/thumbnails/25.jpg)
Vall d'Hebron Barcelona Hospital Campus25Sempre, el pacient primer
Thank you for your attention