CKD-MBD in 2017 What s new? Focus on Sec Hyperparathyroidism

CKD-MBD in 2017 What s new? Focus on Sec Hyperparathyroidism Pieter Evenepoel Nephrology, Dialysis, and Transplantation University Hospitals Leuven April 2017, FMC Herbeumont

Disclosures Research support: Amgen, Tecomedical, Diasorin Advisory Board/Consulting: Sanofi, Amgen, Shire Speakers bureau: Amgen, VIFOR Fresenius

CKD-MBD

CKD-MBD - Calcium - Phosphorus - 1,25(OH)2D Lab - FGF-23 Abnormalities - Alkaline phosphatase Secondary HPT Bone Disease Abnormal bone morphology - Turnover - Mineralization - Volume - Linear growth - Strength FRACTURES Vascular Calcification Vascular calcification Soft-tissue calcification Arterial stiffness FGF-23 = fibroblast growth factor-23. Kidney Disease: Improving Global Outcomes (KDIGO) CKD MBD Work Group. Kidney Int. 2009;76 (Suppl 113):S1 S130. MORTALITY

Secondary hyperparathyroidism Epidemiology Pathogenesis Consequences Treatment options Challenges

PTH: temporal trends in Flanders Flanders, Renal transplant recipients (2006-2013), at time of Tx: n=518 Parathyroidectomy (%)

PTH: temporal trends in the world phase 1, 1996 2001; phase 2, 2002 2004; phase 3, 2005 2008; phase 4, 2009 2011; phase 5, 2012- Tentori F et al. CJASN 2015;10:98-109

Parathyroidectomy rate (per 1000 patient years) PTX: temporal trends in the world phase 1, 1996 2001; phase 2, 2002 2004; phase 3, 2005 2008; phase 4, 2009 2011; phase 5, 2012- PTX rate shows a declining trend: Less stringent PTH target range Increased uses of acitve Vitamin D/Cinacalcet Francesca Tentori et al. CJASN 2015;10:98-109

Secondary hyperparathyroidism Epidemiology Pathogenesis Consequences Treatment options Challenges

Pathogenesis of shpt: evolving concepts 2000 calcium-centric paradigm adapted from Isakova and Wolf Kidney Int 2010

Pathogenesis of shpt: evolving concepts FGF23 increases precede PTH Chronic Renal Insufficiency Cohort (CRIC), n=3879, CKD stage 2-4 Prevalence rates Cubic spline functions Isakova et al. Kidney Int 2011 Evenepoel et al. CJASN 2010

Pathogenesis of shpt: evolving concepts 2000 2010 calcium-centric paradigm phosphate-centric paradigm adapted from Isakova and Wolf Kidney Int 2010

Pathogenesis of shpt: evolving concepts PTH increases precede FGF23 and calcitriol changes SKIPOGH study, n=1128, general population, Switserland Dhayat et al. Kidney Int 2016

Pathogenesis of shpt: evolving concepts shpt is universal despite normal active vitamin D levels Flanders, Renal transplant recipients (2006-2013), at time of Tx: n=518 USA, HD, ArMORR, n=825 France, Renal transplant recipients (2004-2006), at time of Tx: n=143 11 ± 10 pg/ml 9.3 ± 8.9 pg/ml

Vitamin D metabolism in CKD Seatle Kidney Study Decreased production Decreased catabolism Bosworth et al. Kidney Int 2012 CKD is a state of stagnant Vitamin D metabolism

Pathogenesis of shpt: evolving concepts 2000 2010 2020? adapted from Isakova and Wolf Kidney Int 2010

Secondary hyperparathyroidism Pathogenesis Epidemiology Consequences Treatment options Challenges

PTH and bone phenotype(s)

Fracture risk in CKD RR Fracture risk 4 3 2 1 CKD1-2 CKD3 CKD4-5 CKD5D Tx Yr1 Yr10 Nickolas et al. JASN 2006; Jadoul et al. Kidney Int 2006; Alem et al. Kidney Int 2000; Chen et al. Osteoporosis int 2014 Vautour et al. Osteop Int 2004; Abbott et al. Ann Epidemiol 2001; Ball et al. JAMA 2002

PTH & fractures in CKD Author Population Size Main finding(s) Stehman-Breen et al. KI 2000 Coco et al. AJKD 2000 Fishbane et al. CJASN 2016 CKD5D, USRDS (1993-1996) 4.952 NO association between PTH and hip fracture CKD5D (1988-89) 1.272 Low PTH (<195 pg/ml) associates with hip fractures CKD5D FMC (2000-2013) 955.341 Low PTH (and Ca) associates with hip and femur fractures Jadoul et al. KI 2006 CKD5D (HD) DOPPS (2002-2004) 12.782 High PTH (>900 pg/ml) associates with incident (all) fractures Goldmith et al. AJKD 2009 CKD5D Systematic review High PTH ( >900 pg/ml RR 1,7) associates with fractures Perin et al. AJT 2013 Danese et al. AJKD 2006 Atusumi et al. AJKD 1999 CKD-T 143 High PTH associates with fractures CKD5D, DMMS (1993-1997) 9.007 U-shaped relationship between PTH and (hip/vertebral/pelvic) fractures CKD5D 178 U-shaped relationship between PTH and fractures, with low PTH significantly associated with vertebral fractures

PTH & fractures in CKD 5 Fishbane et al. CJASN 2016

PTH & fractures in CKD-T High PTH levels are associated with an increased vertebral fracture risk in RTRs (n=125) Persistent Hyperparathyroidism (PTH > 130 ng/l at 3 months) is a Major Risk Factor for Fractures in the 5 Years After Kidney Transplantation (n=143) Giannini et al. JBMR 2010 Perrin et al. AJT 2013

Pathophysiology Low PTH High PTH Low bone turnover High bone turnover Microstructural abnormalities Low cancellous bone volume Reduced trabecular thickness Reduced toughness Bone Quality Fracture Material and nanomechanical abnormalities (low mineral-to-matrix ratio) Malluche et al. JASN 2012; Ng et al. JBMR 2015; Moorthi and Moe Kidney Int 2013

Thoughness The toughness of bone is at least partly related to the ability of its microstructure to dissipate deformation energy without propagation of the crack

PTH and vascular phenotype(s)

Vascular calcification progression in CKD controversy Fox et al. KI 2004 (Framingham Heart Study) Budoff et al. AJKD 2011 (CRIC) Temmar et al. J Hypertension 2010 Russo et al. KI 2007 Shroff et al. Circulation 2008 Evenepoel et al. JCEM 2015 CKD1-2 CKD3 CKD4-5 CKD5D Tx Yr1 Yr10

PTH & calcification progression Higher CAC progression in patients with parathyroid hormone (PTH) levels greater than 450 pg/ml. Malluche et al. JASN 2015 (epub)

PTH & mortality Francesca Tentori et al. CJASN 2015;10:98-109

Outcome PTH and outcomes: summary KDIGO KDOQI 2 150 300 9 PTH (X UNL) PTH (ng/ml)

Secondary hyperparathyroidism Epidemiology Pathogenesis Consequences Treatment options Challenges

? Which target? Commercial influences RCTs Observational (conflicting) data Pharmaco-economical aspects (bundled payment plans, reimbursement restrictions..) Guidelines Which PTH level to target? Soomo and Goldfarb CJASN 2015 Tentori et al. CJASN 2015

How? Suppress PTH Calcimimetics Vitamin D(analogs) Parathyroidectomy PTH Systemic Toxicity Ca PTH Bone Disease Control Calcium Control intake Adjust dialysate calcium Use calcium supplements or vitamin D therapy Vit D P Increase Vitamin D Levels Nutritional/active VitD Lower Elevated Serum Phosphate Control dietary intake (additives!) Use phosphate binders a Treatment approach = vitamin D + phosphate binders used as first-line therapy; cinacalcet used later in the course of therapy. Tomasello S. Diabetes Spectrum. 2008;21:19-25

How?

Calcimimetics Ca ++ Parathyroid Gland Chief Cell CaSR AMG 416 Cinacalcet Cinacalcet 1,2 Calcimimetic Small organic molecule; molecular weight = 393.9 g/mol Interacts with membrane-spanning segments of CaSR and enhances signal transduction, thereby reducing PTH secretion AMG 416 3,4,8 Calcimimetic Synthetic 7-amino acid peptide linked to L-cysteine; molecular weight =1048.3 g/mol Peptide agonist of the CaSR that interacts with and activates the receptor thereby reducing PTH secretion G Proteins Daily oral IV at the end of dialysis Increased Intracellular Signaling Cartoon representation. Nucleus IV = intravenous; CaSR = calcium-sensing receptor; Da = Dalton; ESRD = end-stage renal disease; PTH = parathyroid hormone Regulation and Decreased Secretion of PTH 1. Cinacalcet product label. 2. Goodman WG. Adv Ren Replace Ther. 2002;9:200-208. 3. Cunningham J, et al. Presented at the 52 nd ERA-EDTA Congress; May 2015; London, UK (Data on file, Amgen). 4. Chen P, et al. J Clin Pharmacol. 2015;55:620-628. 5. Goodman WG, et al. Kidney Int. 2008;74:276-288. 6. Moallem E, et al. J Biol Chem. 1998;273:5253-5259. 7. Brown EM. Rev Endocr Metab Disord. 2000;1:307-315. 8. Walter S, et al., J Pharmacol Exp Ther. 2013;346:229-240. Reactive Use Only. Do not copy or distribute.

Etelecalcetide (AMG416): pharmacokinetics Martin K et al. Kidney Int 2014

Cinacalcet and CKD-MBD Block et al. NEJM 2004 BONAFIDE Behets et al. Kidney Int 2015 EVOLVE Moe et al. Circulation Lab Abnormalities Bone Disease Secondary HPT FRACTURES ADVANCE Raggi et al. NDT 2011 Vascular Calcification EVOLVE Chertow et al. NEJM 2013 Moe et al. JASN 2015 MORTALITY

Etelcalcetide and CKD-MBD Block et al. JAMA 2017 Lab Abnormalities Bone Disease Secondary HPT FRACTURES Vascular Calcification MORTALITY

Head-to-Head Study: Etelcalcetide Vs Cinacalcet Study Design Screening (8 weeks) Randomization Etelcalcetide: Cinacalcet (N = 683) 1:1 TIW IV Etelcalcetide + Daily Oral Placebo (n = 340) Etelcalcetide starting dose was 5 mg and could be increased at Weeks 5, 9, 13, and 17 to maximum dose of 15 mg Daily Oral Cinacalcet + TIW IV Placebo (n = 343) Cinacalcet starting dose was 30 mg and could be increased at Weeks 5, 9, 13, and 17 to maximum dose of 180 mg Follow-up 30 days Day 1 (first dose) Dose titration 16 weeks Maintenance 10 weeks 26 weeks (last dose) Target PTH was 100 and 300 pg/ml. No dose increase for ongoing AEs, cca < 8.3, or PTH < 300 pg/ml was observed. IP could not be increased after week 17. AE = adverse event; cca = corrected calcium; IP = investigational product; PTH = parathyroid hormone; TIW = thrice weekly. Martin KJ, et al. Poster Presented at the 2015 ASN Annual Meeting; November 3-8, 2015;San Diego, CA (# SA-PO1115) Block et al., JAMA. 2017;317(2):156-164. doi:10.1001/jama.2016.19468 61

Head-to-Head Study: Etelcalcetide Vs Cinacalcet Etelcalcetide Was Superior to Cinacalcet in the Proportion of Patients With a > 30% Reduction From Baseline in Mean Serum PTH During the EAP P = 0.004 Proportion of Patients With > 30% Mean PTH Reduction From Baseline (%) P, etelecalcetide vs. cinacalcet EAP was defined as weeks 20 27. EAP = efficacy assessment phase; PTH = parathyroid hormone. (n = 198) (n = 232) 1. Martin KJ, et al. Abstract Presented at the 2015 ASN Annual Meeting; November 3-8, 2015;San Diego, CA. 2. Martin KJ, et al. Poster Presented at the 2015 ASN Annual Meeting; November 3-8, 2015;San Diego, CA (# SA-PO1115). Block et al., JAMA. 2017;317(2):156-164. doi:10.1001/jama.2016.19468 62

Mean cca (mg/dl) Head-to-Head Study: Etelcalcetide Vs Cinacalcet Mean cca Concentrations Over Time Treatment with etelcalcetide resulted in a greater reduction from baseline in mean cca compared to cinacalcet 10.0 Etelcalcetide Cinacalcet 9.5 9.0 8.5 8.0 Baseline 2 4 6 8 10 12 14 16 18 20 22 24 26 Study Week Etelcalcetide n = Cinacalcet n = 338 341 290 291 299 304 308 304 300 312 290 296 291 298 291 301 274 291 279 292 266 289 257 284 267 283 251 272 cca = corrected calcium; IP = investigational product; SE = standard error. On-treatment approach: data collected on or prior to the last on-missing dose of IP were summarized by visit. Vertical lines represent SE. Martin KJ, et al. Poster Presented at the 2015 ASN Annual Meeting; November 3-8, 2015;San Diego, CA (# SA-PO1115). Block et al., JAMA. 2017;317(2):156-164. doi:10.1001/jama.2016.19468 63

Percent Change Head-to-Head Study: Etelcalcetide Vs Cinacalcet Changes in Biomarkers: FGF-23, BSAP, and CTX (Median Percent Change From Baseline to Week 27) Etelcalcetide was associated with greater reductions in FGF-23, BSAP, and CTX from baseline to week 27 compared with cinacalcet ( 40, 20) ( 42, 13) ( 76, 25) ( 50, 2) ( 57, 6) ( 87, 26) BSAP = bone-specific alkaline phosphatase; CTX = type 1 collagen C-telopeptide; FGF = fibroblast growth factor; SE = standard error. Martin KJ, et al. Poster Presented at the 2015 ASN Annual Meeting; November 3-8, 2015;San Diego, CA (# SA-PO1115). Block et al., JAMA. 2017;317(2):156-164. doi:10.1001/jama.2016.19468 64

Head-to-Head Study: Etelcalcetide Vs Cinacalcet Summary of Safety and Efficacy Treatment with etelcalcetide achieved a > 50% and a > 30% reduction in PTH in more patients compared to cinacalcet, while nausea and vomiting did not differ There was a numerical imbalance in cardiac failure, for which a causal relationship to etelcalcetide could not be established Hypocalcemia was seen more tine.velghe@skynet.be often with etelcalcetide IV etelcalcetide is more efficacious than oral cinacalcet for the treatment of SHPT in patients on hemodialysis AE = adverse event Martin KJ, et al. Poster Presented at the 2015 ASN Annual Meeting; November 3-8, 2015;San Diego, CA (# SA-PO1115). Block et al., JAMA. 2017;317(2):156-164. doi:10.1001/jama.2016.19468 65

Targeting PTH Suppress PTH Calcimimetics Vitamin D(analogs) Parathyroidectomy PTH Systemic Toxicity Ca PTH Bone Disease Control Calcium Control intake Adjust dialysate calcium Use calcium supplements or vitamin D therapy Vit D P Increase Vitamin D Levels Nutritional/active VitD Lower Elevated Serum Phosphate Control dietary intake (additives!) Use phosphate binders a Treatment approach = vitamin D + phosphate binders used as first-line therapy; cinacalcet used later in the course of therapy. Tomasello S. Diabetes Spectrum. 2008;21:19-25

Parathyroidectomy (PTX) and fractures Rudser et al. JASN 2007

Parathyroidectomy (PTX) and morbidity Event rates in the 1 year before and 1 year after parathyroidectomy. Areef Ishani et al. CJASN 2015;10:90-97

Secondary hyperparathyroidism Pathogenesis Epidemiology Consequences Treatment options Challenges Limitations of PTH as outcome biomarker and target of therapy Uncontrolled secondary hyperparathyroidism

Outcome PTH as outcome biomarker in CKD Complex Imprecise PTH Palmer et al. JAMA 2011

How to explain imprecise association? Biological variability of PTH Gardham et al. CJASN 2010 Cavalier et al. AJKD Variable PTH resistance PTH1R desensitization PTH1R dysfunction Evenepoel, Bover, Urena KI 2016

PTH as target of therapy is imperfect Meta-Analysis: Drug effects on serum PTH are weakly and imprecisely correlated with all-cause and cardiovascular death in the setting of CKD.PTH is unsuitable as indicator of drug efficacy. Palmer et al. AJKD 2015

FGF23 Of note, patients with a > 30% decline of FGF23 were characterized by significantly higher BAP levels, indicating higher bone turnover. Thus cinacalcet may confer highest benefit in patients with high BAP Moe et al. Circulation 2015

Uncontrolled secondary hyperparathyroidism Therapeutic nihilism Non-adherence Low efficacy Side effects High cost

shpt 2017: trends and challenges Pathogenesis: remains incompletely understood; initial tigger? Epidemiology: PTH levels are on the rise Consequences: shpt in an integral component of CKD-MBD Treatment options: expanding armamentarium allows treatment choices Challenges: PTH as a biomarker is under siege; caution against therapeutic nihilism

shpt 2017: Opportunities Diagnosis-Monitoring Treatment PTH Cinacalcet? Biomarker (panel) Imaging Etelcalcetide Bone histomorphometry