Etelcalcetide Lowers PTH in Patients on Dialysis

Jennifer Garcia

January 13, 2017

Etelcalcetide is more effective than placebo and noninferior to cinacalcet in lowering parathyroid hormone (PTH) levels in patients with end-stage renal disease and hyperparathyroidism according to two new studies published in the January 10 issue of JAMA.

However, editorialists note that the clinical benefit of the reduced PTH remains unclear, and randomized trials with hard clinical endpoints, such as mortality, are needed.

Both company funded-studies were conducted by the same group of researchers, led by Geoffrey A. Block, MD, from Denver Nephrology in Colorado and Glenn M. Chertow, MD, MPH, from Stanford University, Palo Alto, California.

Etelcalcetide vs Placebo

In the first study, researchers compared etelcalcetide with placebo in two separate 27-week placebo-controlled trials (trial A and trial B) in which they enrolled 1023 patients with moderate to severe hyperparathyroidism (parathyroid hormone [PTH] > 400 pg/mL) receiving hemodialysis three times a week. To be eligible, patients had to have an albumin-corrected calcium of 8.3 mg/dL or more and be taking stable doses of active vitamin D analogs or calcium supplements or phosphate binders.

Patients were not allowed to use cinacalcet during the study and could not have received the drug during the 4 weeks before the first screening laboratory test. The mean age of the patients was 58.2 years, and 60.4% were men.

Patients were randomly assigned in a 1:1 fashion to receive etelcalcetide or placebo by intravenous bolus once a week at the time of a hemodialysis session. The starting dose of etelcalcetide was 5 mg, which was increased in 2.5-mg increments as needed (15 mg maximum dose) at weeks 5, 9, 13, and 17, based on PTH and calcium levels.

The primary efficacy endpoint was a 30% reduction from baseline in the PTH concentration between week 20 and week 27. Calcium and phosphorous were checked weekly, and PTH was evaluated every 2 weeks. Investigators were blind to PTH and phosphate results.

Patients receiving etelcalcetide were significantly more likely to achieve the primary efficacy endpoint compared with those receiving placebo: in trial A, 188 (74.0%) of 254 vs 21 (8.3%) of 254 (P < .001), for a difference in proportions of 65.7% (95% confidence interval [CI], 59.4% - 72.1%); in trial B, 192 (75.3%) of 255 vs 25 (9.6%) of 260 (P < .001), for a difference in proportions of 65.7% (95% CI, 59.3% - 72.1%).

The most frequent adverse event was decreased calcium, with patients in the etelcalcetide groups more likely to receive calcium supplements, calcium-containing phosphate binders, or active vitamin D analogs.

Etelcalcetide vs Cinacalcet

The second study was a randomized, double-blind trial comparing etelcalcetide vs cinacalcet. The primary efficacy endpoint was noninferiority (noninferiority margin, 12%) of etelcalcetide to cinacalcet at achieving a more than 30% decrease in PTH levels at weeks 20 to 27 compared with baseline.

The authors enrolled patients with moderate to severe hyperparathyroidism (PTH ≥ 500 pg/mL) who were receiving hemodialysis 3 times a week. All patients had an albumin-corrected calcium of ≥8.3 mg/dL and were taking stable doses of active vitamin D analogs or calcium supplements or phosphate binders.

Patients were randomly assigned (1:1) to receive intravenous etelcalcetide and oral placebo (n = 340) or oral cinacalcet and intravenous placebo (n = 343) over the course of 26 weeks. The starting dose of etelcalcetide was 5 mg three times a week at the time of hemodialysis and could be titrated in 2.5- or 5-mg increments. The starting dose of cinacalcet was 30 mg daily. The mean age of participants was 54.7 years, and 56.2% were men.

The researchers found etelcalcetide to be noninferior to cinacalcet in the proportion of patients achieving a more than 30% reduction in PTH: 68.2% vs 57.7% (difference in proportions, −10.5%; 95% CI, −17.5% to −3.5%; P for noninferiority, <.001; P for superiority, .004).

In addition, 52.4% of etelcalcetide patients achieved a more than 50% reduction in serum PTH compared with 40.2% of cinacalcet patients, demonstrating superiority (P = .001; difference in proportions, 12.2%; 95% CI, 4.7% - 19.5%).

The authors note that the rate of adverse events such as nausea or vomiting was similar between the 2 groups, despite the fact that etelcalcetide was administered intravenously. Patients in both groups experienced decreases in calcium levels as an adverse event. This was more common among patients in the etelcalcetide group, "although there was similar use of interventions in both groups to counter this effect."

Promising Results but Clinical Endpoints Needed

"[T]he observation that many patients tolerated etelcalcetide and cinacalcet only if they were cotreated with therapies to increase serum calcium levels raises the question of whether the frequent requirement for calcium supplementation may undermine some of the potential benefits of etelcalcetide," write John P. Middleton, MD, and Myles Wolf, MD, MMSc, from the Duke University School of Medicine, Durham, North Carolina, in an accompanying editorial.

Although the study authors and editorialists agree that further studies are needed to assess clinical efficacy and safety, Dr Middleton and Dr Wolf note that use of a surrogate marker such as PTH establishes a "low bar" by which to assess the efficacy of this intervention.

"Although it may be tempting to assume that lowering individual patients' PTH levels by 30% to 50% or more...will result in commensurate reductions in risk, only randomized trials with hard clinical end points, including mortality, can provide clear answers," they write.

Further, they note that although etelcalcetide "offers the best opportunity yet for a future clinical trial to demonstrate that enhanced biochemical control of disordered mineral metabolism translates into improved clinical outcomes," it is incumbent upon regulatory authorities to "incentivize" the design of clinical trials that evaluate outcomes such as the effect on mortality and major cardiovascular events.

Funding for the study was provided by Amgen. Dr Block has reported receiving grants from Amgen and Kai Pharmaceutical, as well as medical director fees to his institution from Davita Inc. Celgene, and Janssen. Several coauthors reported various financial relationships with Amgen, Sanofi, Relypsa, Tricida, Medice, Pfizer, Shire, and Vifor Fresenius Medical Care Renal Pharma, Sanifit, Diasorin, UltraGenyx, Gilead Sciences, Trevi Therapeutics, Eli Lilly, Angion Biomedica Corp, CSL LTD, GlaxoSmithKline, and OPKO. Dr Middleton has served as a consultant or received honoraria from AstraZeneca, Relypsa, and ZS, and received grant support from Bristol-Myers Squibb and Keyx. Dr Wolf has served as a consultant or received honoraria from Amag, Amgen, Ardelyx, Diasorin, Incyte, Keryx, Lilly, Pfizer, Sanofi, Ultragenyx, and ZS, and received grant support from Shire.

JAMA. 2017;317:139-141, 146-164. Etelcalcetide vs placebo abstract, Etelcalcetide vs cinacalcet abstract, Editorial extract

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