Secondary hyperparathyroidism (SHPT) is a common side-effect in patients with chronic kidney disease who are undergoing dialysis. It usually develops early on in the patient’s time on dialysis, and gets progressively worse. The condition usually presents with increased levels of parathyroid hormone (PTH), which results in an increased rate of production by the parathyroid glands in the neck. If a patient has reached end-stage disease and is on maintenance dialysis, the elevation in PTH can be substantial, and can lead to abnormal levels of both calcium and phosphorus, which can cause additional health issues.
Amgen’s drug cinacalcet is already available to treat SHPT in adult patients on dialysis. It binds to the calcium-sensing receptor leading to its allosteric activation, which in turn leads to a drop in PTH levels by inhibiting its synthesis and secretion. It also reduces serum calcium and phosphorus levels. The company is now working on an alternative, the peptidomimetic etelcalcetide. Instead of oral dosing, it would be given intravenously at the end of each dialysis session.
After safety was demonstrated in a Phase I study in healthy male subjects,1 its efficacy was studied in 28 patients undergoing dialysis who were suffering from SHPT.2 Subjects were enrolled across five cohorts, which were given single intravenous doses after dialysis of 5, 10, 20, 40 and 60mg respectively. The first three of these cohorts were treated in a two-period crossover design, and the remaining two cohorts, each of eight patients, randomised to receive the drug or placebo. All doses were well tolerated, and the drug was associated with significant and dose-dependent reductions in serum PTH. All except the lowest dose gave attenuation in the rise in serum phosphate between dialysis sessions.
A randomised, double blind, dose escalation, placebo controlled Phase II study has also been carried out.3 Subjects were given 5mg etelcalcetide or placebo for two weeks, or 5 or 10mg of the drug or placebo for four weeks after thrice-weekly dialysis sessions. The 10mg dose gave a mean reduction of 49% of PTH from baseline, and 5mg for four weeks a 33% reduction. Serum-corrected calcium decreases were well tolerated.
Its efficacy and safety have also been compared to oral cinecalcet in a randomised, active-controlled, double, blind, double dummy Phase III trial.4 A total of 683 subjects were given intravenous etelcalcetide plus oral placebo or oral cincalcet plus iv placebo for 26 weeks, with etelcalcetide doses starting at 5mg and titrating up by 2.5 or 5mg up to 15mg three times a week; cinecalcet was started at 30mg and titrated up to 180mg/day.
Etelcalcetide was superior to cinacalcet at reducing PTH levels from baseline, with 68% achieving at least a 30% reduction compared with 58% of the cinacalcet group, and 52% achieved at least a 50% reduction, compared with 40% with cinacalcet. The most common adverse event was, in both cases, a decrease in blood calcium.
References
1. K.J. Martin et al. Nephrol. Dial. Transplant 2014, 29, 385
2. K.J. Martin et al. Kidney Int. 2014, 85, 191
3. G. Bell et al. Curr. Med. Res. Opin. 2015, 31, 943
4. K.J. Martin et al. J. Am. Soc. Nephrol. 2015, 26, Abst. SA-PO1115