The European Medicines Agency's (EMA) move to back approval for a new synthetic peptide drug with a D-amino acid backbone, which Amgen is developing for treating a common complication of kidney failure, makes its recent rejection by the US Food and Drug Administration (FDA) all the more mysterious. The EMA's Committee for Medicinal Human Products (CHMP) disclosed its positive recommendation for Parsabiv (etelcalcetide; AMG 416) in secondary hyperparathyroidism on September 16. The FDA issued a complete response letter to Amgen on August 24. The calcimimetic agent had hit the primary endpoint of two placebo-controlled Phase 3 trials in patients with secondary hyperparathyroidism, as well as a Phase 3 head-to-head study comparing it with the current standard of care, Amgen's soon-to-be generic blockbuster Sensipar (cinacalcet). In preclinical studies, Parsabiv—which comprises seven D-amino acids and one L-cysteine residue linked to a D-cysteine—demonstrated greater potency than an equivalent peptide based on L-amino acids. Its clinical profile also appeared promising. Ed Nemeth, an independent consultant based in Toronto, who is a co-discoverer of Sensipar, says, “When you look at the data that have been released, [they are] very good. I was surprised to hear it got a [complete response letter],” he says. Parsabiv was “a little more efficacious” and “a little less safe” than Sensipar, says Nemeth, previously CSO at NPS Pharmaceuticals (now part of Dublin-based Shire). It licensed Sensipar rights (excluding four Asian countries) to Thousand Oaks, California–based Amgen in 1996. Secondary hyperparathyroidism, a common complication of kidney failure, is characterized by increased secretion of parathyroid hormone in response to perturbations in mineral metabolism, including reduced serum levels of calcium. Etelcalcetide inhibits parathyroid hormone production by acting as an agonist of its negative regulator, 'calcium-sensing receptor', a G-protein-coupled receptor expressed by the cells of the parathyroid gland. Because it is dosed intravenously—Sensipar is an oral drug—it may lead to improved compliance, as patients would receive it at the conclusion of their dialysis sessions. In terms of safety, there was little to separate Parsabiv from Sensipar, apart from a fivefold increase in cardiac failure (3.0% vs. 0.6%). “That would be the only thing,” says Nemeth. But the events captured in that measure may not be highly significant from a clinical standpoint. “That could be simply be a change in left ventricular pressure.”