Upacicalcet Lowers PTH in Secondary Hyperparathyroidism on Hemodialysis

Upacicalcet, an investigational intravenous calcimimetic, significantly increased the proportion of patients receiving hemodialysis with secondary hyperparathyroidism (SHPT) who achieved at least a 30% reduction in intact parathyroid hormone (iPTH) versus placebo, according to results from the identical phase 3 PATH-1 and PATH-2 trials.¹

Jessica Kendrick, MD, MPH, of the University of Colorado Anschutz Medical Campus, discussed the findings with HCPLive at ASN Kidney Week 2026 in Denver, Colorado.

Existing calcimimetics are limited by hypocalcemia and gastrointestinal adverse effects, which reduce adherence, Kendrick explained. Upacicalcet is a positive allosteric modulator of the calcium-sensing receptor and is already approved for SHPT in Japan.² Pathalys Pharma is developing the agent for a potential US regulatory submission.

“It only works if the extracellular calcium levels are at a physiologic level,” Kendrick said. “So if they’re actually low, then it does not work, which is unlike other previous calcimimetics.”

How Effective Was Upacicalcet in the PATH-1 and PATH-2 Trials?

PATH-1 and PATH-2 were identical, double-blind, placebo-controlled trials conducted in parallel in 768 patients receiving hemodialysis with SHPT and baseline iPTH levels of 400 to 1500 pg/mL.¹ Participants were randomized 2:1 to intravenous upacicalcet (n = 510) or placebo (n = 258) after each hemodialysis session for 27 weeks, with dosing titrated based on iPTH and corrected serum calcium.

The primary end point was the proportion of participants achieving at least a 30% decrease from baseline in mean iPTH during the efficacy assessment period, weeks 22 to 27. Mean age was 58.6 years in PATH-1 and 59.2 years in PATH-2, and 66.3% and 59.7% of participants were male, respectively.¹

In PATH-1, 42.1% (101/239) of upacicalcet-treated participants met the primary end point vs 16.8% (20/120) receiving placebo, a difference of 25.3% (95% CI, 16.2%–34.5%; P < .0001). In PATH-2, the corresponding rates were 43.5% (118/271) vs 17.4% (24/138), a difference of 26.1% (95% CI, 17.4%–34.8%; P < .0001).¹

Upacicalcet was also superior to placebo for the key secondary end point of at least a 50% reduction in iPTH, according to Kendrick.

What Was the Safety Profile of Upacicalcet in Hemodialysis?

Adverse events occurred in 69.9% of upacicalcet-treated participants versus 60.8% receiving placebo in PATH-1, and in 71.6% versus 59.4% in PATH-2.¹ Serious adverse events were similar between groups, at 25.5% versus 24.2% in PATH-1 and 23.2% versus 21.7% in PATH-2. Gastrointestinal symptoms were low and similar between groups.

Asymptomatic decreased blood calcium was the most frequent adverse event, occurring in 23.4% compared with 8.3% of participants in PATH-1 and 19.2% vs 10.9% in PATH-2. Symptomatic hypocalcemia with upacicalcet occurred in 0.8% (2/239) of participants in PATH-1 and 2.2% (6/271) in PATH-2.¹

Kendrick noted upacicalcet is removed during the next dialysis session and does not accumulate. This allows clinicians to adjust the next dose in real time when calcium levels fall, rather than waiting a week or more for the drug to clear.¹

“So I think what this drug gives us is better clinical flexibility than the current options,” Kendrick said. She added lower rates of hypocalcemia and gastrointestinal effects may improve adherence and reduce treatment interruptions.

Longer-term questions remain. Kendrick said data on whether upacicalcet reduces cardiovascular events or fractures are not yet available, as the PATH trials assessed biochemical endpoints only.

References

1. Kendrick JB, Wolf M, Tirmenstajn Jankovic BH, et al. Efficacy and safety of upacicalcet in patients with secondary hyperparathyroidism (SHPT) on hemodialysis: two randomized controlled clinical trials (RCTs). Presented at: ASN Kidney Week 2026; October 21-25, 2026; Denver, CO. doi:10.1681/ASN.2026s02jzt6e

2. Waldron J. Pathalys raises $105M series B to prepare Japan-approved kidney disease drug for FDA. Fierce Biotech. Published August 20, 2024. Accessed October 24, 2026. https://www.fiercebiotech.com/biotech/pathalys-raises-105m-series-b-prepare-japan-approved-kidney-disease-drug-fda