Cinacalcet treatment in advanced CKD - is it justified?

Cinacalcet treatment in advanced CKD - is it justified? Goce Spasovski ERBP Advisory Board member University of Skopje, R. Macedonia TSN Congress October 21, 2017, Antalya

Session Objectives From ROD to CKD-MBD in CKD patients General issues Guidelines Controversies conference (updates) Bone quality / Clinical outcome data Cinacalcet treatment new evidence Efficacy - cost related evidence When to treat rationale Monitoring frequency Summary

From ROD to Mineral & Bone Disorder (MBD) - Systemic Complication in CKD From ROD to CKD-MBD: The first CKD-MBD Controversies Conference, Madrid 2005, definition of CKD-MBD. Mineral Hormonal Bone abnormalities, Vascular calcifications Soft tissue calcifications CVD, fractures, mortality

Bone, P & Ca Management guidelines K-DOQI Guidelines GB Renal Association Guidelines EDTA Guidelines KDIGO Guidelines

Publishing the CKD-MBD Guideline The first KDIGO clinical practice guideline on CKD-MBD was published in August 2009.

After the publication

Renal osteodystrophy The term traditionally used to describe the abnormalities in bone morphology that develop in patients with CKD 1 Bone abnormalities are common complications of CKD and are found in almost all patients with stage 5 CKD (glomerular filtration rate below 15 ml/1.73 m 2 /min) 2 2009 KDIGO Definition of Renal Osteodystrophy 3 Renal osteodystrophy is an alteration of bone morphology in patients with CKD It is one measure of the skeletal component of the systemic disorder of CKD-MBD that is quantifiable by histomorphometry of bone biopsy Evaluation and definitive diagnosis of renal osteodystrophy requires a bone biopsy 1 Histomorphometry is not essential for clinical diagnosis, but should be performed in research studies 1 1 Moe S, et al. KI, 2006;69:1945-53; 2 Malluche HH, et al. JBMR. 2011;26:1368-76; 3 KDIGO CKD-MBD WG. KI. 2009; 76 (Suppl 113):S1-130.

Bone Histology in ROD Osteitis Fibrosa Mixed lesion Adynamic bone disease Osteomalacia

Consequences of Elevated Serum Phosphorus Pi Ca ++ Calcitriol PTH resistance Calcitriol resistance PTH Secretion Parathyroid Cell Growth Increased CaxP & risk of metastatic calcifications HPTH Treatment ABD Morbidity & Mortality Spasovski G et al. Semin Dial 2009; 22(4): 357-362

Changing spectrum of renal osteodystrophy Spectrum of Renal Bone Disease in patients with end-stage renal bone disease not yet in dialysis Osteomalacia 12% Hyperpara 9% N = 84 Adynamic bone 23% Mixed lesion 18% Prospective, Non-randomized, Macedonian Population N = 84 patients Histomorphometric criteria according to: Salusky et al., Kidney Int.,33,1988 Parfitt et al., Calcif Tissue Int 42, 1988 Normal bone 38% GB Spasovski et al. Nephrol Dial Transpl 2003; 18: 1159-66

Physiopathology of Adynamic Bone Al + Fe Mg ++ Better Pi control Diabetes Vit.D VDR polymorphism cinacalcet Relative hypoparathyroidism VDR expression Down regulation of PTH receptor Insufficient PTH levels Osteoblastic dysfunction Diabetes Older age Older age Male gender Malnourishment Ca receptor expression Decreased BFR Uremic toxins Extracellular Ca ++ Growth factors Al + Fe Ca load: Ca based binders HD & CAPD dialysis fluid Ca conc. Vit.D treatment

Clinical Relevance and Consequences Association in CKD patients between: MBD (abnormal mineral metabolism & bone health) & Fractures decreased quality of life VC most important cause of morbidity CVD significant mortality Bone health and vascular calcification relationship in chronic kidney disease Spasovski G. Int Urol Nephrol 2007;39:1209 1216

CKD - MBD: Bone lose & fracture United States Renal Data System data (300,000 patients) - The relative risk for hip fracture in dialysed patients is 4.4 times (men and women) that of age-matched controls. Alem A et al. Kidney Int 2000, 58: 396-9

Disordered bone remodelling can induce vascular calcification High bone turnover Phosphate Calcium Precipitation in vessels and soft tissues Low bone turnover Calcification High bone turnover leads to release of Ca + P from bone. Low bone turnover hinders their emplacement in bone. Result is cardiovascular and soft tissue calcification. London et al. J Am Soc Nephrol 2004;15:1943 1951; Spasovski G. Int Urol Nephrol 2007;39:1209 1216

Arterial calcification increases mortality risk Probability of survival 1.00 0.75 0.50 0 arteries calcified 1 artery calcified 2 arteries calcified 3 arteries calcified 0.25 0 n=110 p<0.0001 0 20 40 60 80 Duration of follow-up (months) 4 arteries calcified Presence and extent of vascular calcifications predict cardiovascular and allcause mortality in dialysis patients. Prospective trial in 110 dialysis patients assessing cardiovascular (CV) calcifications, mean follow up 53 months. Endpoints: All cause and CV mortality using univariate and multivariate survival analysis. Blacher et al. Hypertension 2001;38:938 942

THERAPEUTIC APPROACH PREVENTION OF COMPLICATIONS OF THERAPY... OF HYPERPHOSPHATEMIA & MBD & ROD & VC IN CKD PATIENTS

New Strategies in Treatment of MBD and Associated Cardiovascular Disease in Patients with CKD - HPTH Spasovski G, Recent Patents on Cardiovascular Drug Discovery, 2008; 3(3):222-8 INDIVIDUALIZED COMBINATION Dose of Ca carbonate/acetate As much as needed (AMAN) Non Ca-based P binders in pts at risk for VC & CVD Vitamin D (AMAN) Use Low Calcium dialysate - always Use aluminum (small amount, shortly) Vit. D analogs upon indication Calcimimetics upon indication

Vitamin D therapy and cardiac structure and function in patients with CKD: the PRIMO RCT At 48 weeks, the change in left ventricular mass index did not differ between treatment groups. Doppler measures of diastolic function also did not differ. Episodes of hypercalcemia were more frequent in the paricalcitol group compared with the placebo group. Thadhani et al, JAMA 2012; 15;307(7):674-84

Effect of Cinacalcet on CVD in Pts Undergoing D The EVOLVE Trial Investigators* COST-EFFECTIVENESS OF THE TREATMENT WITH CINACALCET AND VITAMIN D ANALOGS? N Engl J Med. 2012; 367(26): 2482-94

Treatment of CKD-MBD after PRIMO & EVOLVE The treatment of CKD-MBD - improvement in biochemical parameters of the disease, hard clinical end points or surrogate end points studies are limited. PRIMO & EVOLVE study negative end points (change in left ventricular mass index and death, myocardial infarction, unstable angina, heart failure or peripheral vascular disease) The results of these two randomized controlled trials with negative primary end points require physicians to individualize therapies for the treatment of secondary hyperparathyroidism. Moe & Thadhiani, 2012

The Effects of Cinacalcet in Older and Younger Patients on HD: The Evaluation of Cinacalcet HCl Therapy to Lower Cardiovascular Events (EVOLVE) Trial Kaplan-Meier time-to-event curves for clinical end points. Time to the primary composite cardiovascular end point (A), to death (B), and to severe unremitting hyperparathyroidism (C) in the groups randomized to placebo (dotted line, <65 years; dashed line,>65 years) and to cinacalcet (solid line, <65 years; bold line, >65 years) by age group. Parfrey et al. CJASN 2015,10: 791 799

Cinacalcet, FGF-23, and CVD in HD (EVOLVE) Trial Reduction in FGF23 Is Associated With Reduced CVD Mortality and Morbidity Relative hazard (HR) of achieving a 30% reduction in FGF23 from baseline to week 20 vs not achieving such a reduction on clinical outcomes (patients randomized to cinacalcet from FGF23 cohort). Moe et al, Circululation 2015; 132:27-39

Cinacalcet, FGF-23, and CVD in HD (EVOLVE) Trial Reduction in FGF23 Is Associated With Reduced CVD Mortality and Morbidity Relative hazard (HR) of achieving a 50% reduction in FGF23 from baseline to week 20 vs not achieving such a reduction on clinical outcomes (patients randomized to cinacalcet from FGF23 cohort). Moe et al, Circululation 2015; 132:27-39

The ADVANCE and EVOLVE trial comparing cinacalcet vs standard treatment on shpth failed to demonstrate a significant effect on the primary end points but showed positive signals concerning some predefined secondary end points. Ketteler et al. KI 2015 Mar;87(3):502-28

Should patients with CKD stage 5D & biochemical evidence of shpth be prescribed calcimimetic therapy? An ERA-EDTA position statement What do the guidelines say? No guidelines on this subject (KDOQI, CARI, RA, NICE) have been produced on this topics since the release of the EVOLVE results. Recommendations ERBP 1. We do not recommend routine use of calcimimetic therapy to improve survival in patients with CKD stage 5D and biochemical evidence of secondary hyperparathyroidism (1A). 2. There is insufficient evidence whether parathyroidectomy or medical intervention with cinacalcet or standard care or a combination thereof should be preferred to control secondary hyperparathyroidism in patients with CKD stage 5D. Goldsmith et al. NDT; 2015; 30: 698 700

Topic #3: Bone Quality 3.2.1 In patients with CKD stages 3 5D, it is reasonable to perform a bone biopsy in various settings including, but not limited to: unexplained fractures, persistent bone pain, unexplained hypercalcemia, unexplained hypophosphatemia, possible aluminum toxicity, and prior to therapy with bisphosphonates in patients with CKD MBD (not graded) Argument: Secondary analyses in osteoporosis trials New therapies denosumab and teriparatide Revision Yes No

Bone histomorphometry before and after long-term treatment with cinacalcet in dialysis patients with shpt Cinacalcet is indicated for lowering parathyroid hormone (PTH) in dialysis patients with shpt, but its effects on bone remain unclear. The effect of cinacalcet on renal bone disease among patients undergoing dialysis has yet to be characterized adequately The multicenter, single-arm BONAFIDE study characterized the skeletal response to cinacalcet in adult dialysis patients with plasma PTH 300 pg/ml, serum calcium 8.4 mg/dl (2.1 mmol/l), bone-specific alkaline phosphatase (BALP) >20.9 ng/ml and biopsy-proven high-turnover bone disease. Behets, Spasovski et al. Kidney International; 2015;87(4):846-56

Study design and treatment schema 146 adult dialysis patients with plasma PTH (PTH) 300 pg/ml, serum calcium 8.4 mg/dl, and bone-specific alkaline phosphatase (BALP) >20.9 ng/ml underwent bone biopsy during screening. Behets, Spasovski et al. Kidney International; 2015;87(4):846-56

Comparison of PTH level at baseline and end of study (median-iqr-range) The median (interquartile range; IQR) PTH at baseline was 985 (674, 1621) pg/ml, and values decreased nominally to 480 (268, 798) pg/ml, or by a median (IQR) percent change of -48.3% (-68.8%, - 26.5%), after treatment with cinacalcet, p<0.001 BFR same pattern! Behets, Spasovski et al. Kidney International; 2015;87(4):846-56

Two Years of Cinacalcet Decreased PTgl. Vol. & Ser. PTH in HDP With Advanced shpth Yamada et al. TAD 2015; 19(4):367 77

Diameter of PT gl Measured by CT as an Indicator for Response to Cinacalcet in HDP with SHPTH Measurement of parathyroid gland (PTG) volume and diameter on high-resolution US and PTG diameter on CT before cinacalcet therapy. Study 1 - cutoff values of imaging parameters; study 2, we reevaluated the clinical and radiologic risk factors for response of cinacalcet treatment. A, B: Parathyroid gland volume and diameter measured by US. The PTG was diffusely hypoechoic and hypervascularized on color Doppler US. C: Measurement of parathyroid gland diameter by CT. Hong et al. Kidney Blood Press Res 2015;40:277-287

Diameter of PT gl Measured by CT as an Indicator for Response to Cinacalcet in HDP with SHPTH Comparison of clinical and biochemical parameters between responders and nonresponders to cinacalcet treatment in a single center (1) Hong et al. Kidney Blood Press Res 2015;40:277-287

Diameter of PT gl Meas. by CT - Indicator for Response to Cinacalcet in SHPTH Clinical factors influencing the response to cinacalcet treatment in SHPT in a multicenter study (2) Hong et al. Kidney Blood Press Res 2015;40:277-287

PTH-dependence of the effectiveness of cinacalcet in HDP with SHPTH Survival of people with CKD and SHPT remains controversial, in part because a recent randomized trial excluded patients with ipth <300 pg/ml. Prospective case-cohort and cohort study on 8229 pts with CKD stage 5D requiring maintenance hemodialysis who had SHPT on important clinical outcomes.by baseline ipth category Proportion of patients receiving cinacalcet continuously over the study period, stratified by baseline ipth category. Adjusted associations between cinacalcet use and clinical outcomes, computed using marginal structural models, stratified by baseline ipth category. Akizawa et al. Sci Rep. 2016 Apr 13;6:19612

PTH-dependence of the effectiveness of cinacalcet in HDP with SHPTH Survival of people with CKD and SHPT remains controversial, in part because a recent randomized trial excluded patients with ipth <300 pg/ml. Prospective case-cohort and cohort study on 8229 pts with CKD stage 5D requiring maintenance hemodialysis who had SHPT on important clinical outcomes.by baseline ipth category When analyses were restricted to patients with ipth levels 300 pg/ml (an inclusion criterion of the EVOLVE study), cinacalcet initiation was associated with a lower incidence of cardiovascular hospitalization or death due to any cause (adjusted RR 0.71, 95% CI 0.53 0.94). Adjusted associations between cinacalcet use and clinical outcomes, computed using marginal structural models, stratified by baseline ipth category. Akizawa et al. Sci Rep. 2016 Apr 13;6:19612

Etelcalcetide vs Cinacalcet on PTH in HDP With shpth A Randomized Clinical Trial Etelcalcetide IV & oral placebo (n = 340) or oral cinacalcet and IV placebo (n = 343) for 26 weeks. The IV study drug was administered 3 times weekly with hemodialysis the oral study drug was administered daily. Among patients receiving HD with moderate to severe shpth, the use o etelcalcetide was not inferior to cinacalcet in reducing serum PTH concentrations over 26 weeks. Block et al. JAMA. 2017;317(2):156-164

A Randomized Study Comparing PTx vs Cinacalcet for Hypercalcemia in KTx pts with shpth KTx pts. with hypercalcemia and elevated ipth concentration, transplanted >6months before the study and had an egfr 30 ml/min. The primary end point - proportion of patients with normocalcemia at 12 months. Secondary end points - serum ipth concentration, phosphate, BMD, vascular calcification, renal function, patient and graft survival, and economic cost. 30 pts cinacalcet (n=15) or subtotal PTx (n=15). At 12months, ten of 15 patients in the cinacalcet group and 15 of 15 patients in the PTx group (P=0.04) normocalcemic. Subtotal PTx had a higher proportion of patients achieving normocalcemia and ipth normaliz. (A) Serum calcium, (B) ipth, (C) Phosphate the reduction of ipth was greater in the PTx group than in the cinacalcet group. Cruzado et al. JASN 27: 2487 2494, 2016

Frequency of monitoring CKD-MBD in shpth pts: assoc. with achievements and adjusted therapy Japanese multicenter cohort study on 3276 HDP with shpth. Conclusion: increasing frequency of measurements is helpful when serum marker levels exceed the target range, partially via adjustment in the therapeutic regimen. No evidence that frequent measurements helps if mineral levels are already within target ranges. Yokoyama et al. NDT 2017: Epub ahead of print

Analyses such as the one presented cannot be the only criterion for setting a price, but such analyses are meant to inform the price that may be considered efficient by society at large. Models are never suitable to capture all aspects that should be considered for decision-making. JOURNAL OF MEDICAL ECONOMICS, 2017 VOL. 20, NO. 10, 1110 1115

Kidney Int. 2017 Jul;92(1):26-36

Summary - Research Recommandations - shpth Parathyroidectomy remains a valid treatment option especially in cases when PTH lowering therapies fail, Recom. 4.2.5 from 2009 KDIGO-CKD-MBD guideline Placebo controlled trials with calcimimetics versus standard therapy for the treatment of SHPT in patients with CKD stage 5D with emphasis on those at greatest risk (e.g. older, CVD) Prospective pts-centered RCTs with the new parenteral calcimimetics (etelcalcitide) surrogate outcomes (primary endpoints: mortality, cardiovascular events; secondary endpoints: FGF23, LVH progression, calcification) RCTs evaluating Calcimimetic vs vitamin D therapies on the specific reduction of FGF23 as a therapeutic endpoint Increasing freq. of CKD-MBD parameters measurements

Even the best treatment option are not perfect Do no harm and prevent complications