A post-dialysis injection lowered parathyroid hormone, and calcium too

On 23 October 2026 the Journal of the American Society of Nephrology published PATH-1 and PATH-2, two identical phase 3 trials of upacicalcet, a drug injected into a vein after a haemodialysis session. The randomised analysis included 768 people on haemodialysis with secondary hyperparathyroidism and an intact parathyroid hormone (iPTH) level from 400 to 1,500 pg/mL. Participants were randomly assigned to upacicalcet (510 people) or placebo (258) in a double-blind design and treated for 27 weeks.

Failing kidneys push the parathyroid glands into overdrive

The parathyroid glands in the neck make parathyroid hormone. In people on haemodialysis, disturbed calcium and phosphate metabolism can drive the glands to overproduce it; this is secondary hyperparathyroidism, a common complication of kidney failure. The European Medicines Agency notes that high levels of the hormone can cause loss of calcium from the bones, bone pain and fractures.

Upacicalcet is a calcimimetic. According to the developer's documents filed with Japan's medicines regulator, it acts on the calcium-sensing receptor on parathyroid cells, the signal that tells the glands to release less hormone. In PATH it was injected after haemodialysis.

Four in ten reached the target, against fewer than one in five on placebo

The main measure was the share of participants whose average iPTH in weeks 22 to 27 fell by at least 30% from the start. In PATH-1 that happened in 42.1% on upacicalcet and 16.8% on placebo, a difference of 25.3 percentage points (95% CI 16.2 to 34.5). In PATH-2 the figures were 43.5% and 17.4%, a difference of 26.1 points (95% CI 17.4 to 34.8). Both differences were statistically significant.

The safety signal was in calcium. Corrected blood calcium fell below 7.5 mg/dL in 31% versus 12% of participants in PATH-1 and in 45% versus 19% in PATH-2, and treatment was interrupted in 44% versus 24% and 52% versus 27%, respectively. Investigators attributed symptomatic hypocalcaemia to 0.8% and 2% of people on upacicalcet and to no one on placebo. Under the protocol, calcium supplements and changes to active vitamin D were restricted when calcium was low without symptoms. Serious adverse events were similar in both groups (26% versus 24% and 23% versus 22%), and so were gastrointestinal symptoms.

The trials measured a hormone, not fractures or survival

The primary outcome in PATH was the change in iPTH, a laboratory measure; the trials did not report fractures, heart attacks or deaths as outcomes. That gap has a history. In the EVOLVE trial (New England Journal of Medicine, 2012), 3,883 people on haemodialysis with moderate-to-severe secondary hyperparathyroidism received the oral calcimimetic cinacalcet or placebo and were followed for up to 64 months. Death or a major cardiovascular event occurred in 48.2% on cinacalcet and 49.2% on placebo (hazard ratio 0.93; 95% CI 0.85 to 1.02), which was not a significant reduction in the main unadjusted analysis.

The PATH trials were funded by the developer, Pathalys Pharma, and two of the authors work for the company. Another intravenous calcimimetic, etelcalcetide, has been approved in the US since 2017 and is authorised in the EU. In its two placebo-controlled trials in 1,023 people (JAMA, 2017), 74.0% and 75.3% reached a reduction of more than 30%, against 8.3% and 9.6% on placebo. These numbers cannot be set against PATH: entry criteria and protocols differed, and the two drugs were not compared in the same trial.

Approval in Japan is not a result on clinical outcomes

Upacicalcet has been approved in Japan since June 2021 for secondary hyperparathyroidism in people on haemodialysis. PATH-1 and PATH-2 add placebo-controlled evidence in this population on how far it lowers the hormone, and on how often calcium has to be watched and treatment interrupted.

If you or someone close to you is on haemodialysis, iPTH and calcium are part of routine blood tests. How high the hormone is, which treatment is used and how calcium is monitored is worth discussing with your nephrologist.

This material is for information only and does not replace a consultation with a doctor. Nothing in it is a recommendation to start, stop or change treatment.

Sources

• Kendrick J, et al. Efficacy and Safety of Upacicalcet in Hemodialysis Patients with Secondary Hyperparathyroidism: Two Randomized Clinical Trials. J Am Soc Nephrol. 2026. PMID 42914959

• Parathyroid Hormone (PTH) Attenuation Trial in Hemodialysis-1. ClinicalTrials.gov. NCT05832931

• Parathyroid Hormone (PTH) Attenuation Trial in Hemodialysis-2. ClinicalTrials.gov. NCT05836220

• EVOLVE Trial Investigators. Effect of cinacalcet on cardiovascular disease in patients undergoing dialysis. N Engl J Med. 2012. PMID 23121374

• Block GA, et al. Effect of Etelcalcetide vs Placebo on Serum Parathyroid Hormone in Patients Receiving Hemodialysis With Secondary Hyperparathyroidism: Two Randomized Clinical Trials. JAMA. 2017. PMID 28097355

• Otsuki T. Pharmacological properties and clinical trial results of the novel calcium-sensing receptor agonist upacicalcet sodium hydrate. Nihon Yakurigaku Zasshi. 2025. PMID 40307051

• Sanwa Kagaku Kenkyusho. Upasita (upacicalcet sodium hydrate): CTD module 2.6, nonclinical overview, filed with the Pharmaceuticals and Medical Devices Agency, Japan (in Japanese). pmda.go.jp

• European Medicines Agency. Parsabiv (etelcalcetide): EPAR. ema.europa.eu

• US Food and Drug Administration. Drugs@FDA: Parsabiv (etelcalcetide), NDA 208325. accessdata.fda.gov