MODELLING ETELCALCETIDE EFFECTIVENESS ON HEALTH OUTCOMES: RELATING BIOCHEMICAL OUTCOMES TO MORTALITY, CARDIOVASCULAR EVENTS, FRACTURES AND PARATHYROIDECTOMY

Purpose: Etelcalcetide is a novel intravenous calcimimetic for the treatment of secondary hyperparathyroidism (SHPT) in hemodialysis patients. Clinical trials show that etelcalcetide reduces parathyroid hormone (PTH), but no efficacy estimates regarding health outcomes yet exist. Epidemiologic studies suggest an association of elevated PTH, calcium, and phosphate, and the risk of events, which may be attenuated by calcimimetic therapy. In the absence of a prospective clinical outcome trial, and to inform decision-modelling, the objective of this study was to model the effect of etelcalcetide on mortality, cardiovascular events, fractures and parathyroidectomy (PTx).

Method(s): The primary endpoint of the etelcalcetide trials was ‘PTH reduction >30%’. This outcome was linked to published [1] event-specific hazard ratios (HRs) based on the EVOLVE trial (baseline covariate-adjusted HRs). EVOLVE measured the health outcome of the first-in-class calcimimetic ‘cinacalcet’. As an alternative approach the patient-level bi-weekly biomarker measurements (PTH, calcium, phosphorus) of the etelcalcetide trial were applied to a published [2] risk-prediction scheme (RPS). The uncertainty of the estimated effects on hard endpoints was assessed via bootstrapping and Monte Carlo simulation.

Result(s):

HRs [95% CI]	EVOLVE		Risk-prediction scheme (RPS)
	ITT	Lag-censored (6 months)	ITT	Per protocol
Etelcalcetide vs. placebo
Mortality	0.84 [0.72,0.96]	0.75 [0.62,0.89]	0.78 [0.66,0.93]	0.78 [0.65,0.93]
Cardiovascular events	0.81 [0.68,0.96]	0.72 [0.59,0.88]	0.94 [0.77,1.14]	0.94 [0.77,1.15]
Fractures	0.82 [0.64,1.04]	0.67 [0.50,0.89]	0.86 [0.34,2.17]	0.86 [0.34,2.16]
PTx	0.33 [0.24,0.43]	0.17 [0.11,0.25]	0.38 [0.14,1.01]	0.37 [0.15,0.95]
Etelcalcetide vs. cinacalcet
Mortality	0.96 [0.91,0.99]	0.94 [0.88,0.98]	0.94 [0.88,1.01]	0.94 [0.88,1.01]
Cardiovascular events	0.95 [0.90,0.99]	0.93 [0.87,0.98]	0.99 [0.95,1.03]	0.99 [0.95,1.03]
Fractures	0.96 [0.89,1.01]	0.91 [0.83,0.98]	0.97 [0.74,1.28]	0.98 [0.76,1.26]
PTx	0.77 [0.65,0.88]	0.66 [0.51,0.81]	0.80 [0.62,1.02]	0.81 [0.63,1.04]

CI, confidence interval; ITT, intention to treat; HR, hazard ratio

The uncertainty of the RPS-HRs was mainly due to the RPS rather than the biomarker measurements.

Conclusion(s): We were able to extrapolate the efficacy of etelcalcetide on biomedical surrogates to hard clinical endpoints of mortality, cardiovascular events, fractures and PTx. These estimates will support decision-modelling. The results were broadly consistent among the different modelling approaches.

References:

[1] Belozeroff, V., et al., Economic evaluation of cinacalcet in the United States: the EVOLVE trial. Value Health, 2015. 18(8):1079-87.

[2] Eandi, M., et al., Economic evaluation of cinacalcet in the treatment of secondary hyperparathyroidism in Italy. Pharmacoeconomics, 2010. 28(11):1041-54.