AZP-3601 Results in Blood Calcium Increases in Healthy Volunteers

A single dose of AZP-3601 — Amolyt Pharma’s experimental therapy for hypoparathyroidism — resulted in a significant, sustained increase in blood calcium levels for at least 24 hours in healthy volunteers, according to interim data from a Phase 1 trial.

These early findings support the therapeutic potential of AZP-3601, as well as further dose escalation in the ongoing proof-of-concept trial. That trial also will now test the therapy in hypoparathyroidism patients.

The data were presented in a poster, “A Single Administration of AZP-3601, a Novel, Long-Acting PTH Analog, Induces a Significant and Sustained Calcemic Response: Preliminary Data From a Randomized, Double-Blind, Placebo-Controlled Phase 1 Study,” at the Endocrine Society’s Annual Meeting, held virtually March 20–23.

“We are delighted with this first set of clinical data highlighting AZP-3601’s unique mechanism of action,” Thierry Abribat, PhD, Amolyt’s founder and CEO, said in a press release.

“We are encouraged by these early results and look forward to reporting additional data from the multiple ascending dose portion of the study later this year,” he added.

Hypoparathyroidism is caused by abnormally low levels of the parathyroid hormone (PTH), which results in vitamin D deficiency, low levels of calcium, and high levels of phosphorus in the blood.

In many patients, current treatments fail to adequately or consistently control calcium blood levels and effectively prevent excessive calcium loss in the urine, which increases the risk of chronic kidney disease.

Originally developed by researchers at Massachusetts General Hospital and Harvard Medical School, AZP-3601 is a new PTH analog, or a compound with similar structure, but slight differences in composition relative to PTH.

The therapy was designed to bind to a specific configuration of the PTH receptor, which is thought to help promote sustained normal calcium levels in the blood and urine, thereby easing symptoms, while preventing chronic kidney disease.

In addition, its short half-life (the time it takes for its circulating levels to drop to half) is expected to prevent prolonged exposure and associated damaging effects on bone.

“We believe the short pharmacokinetic profile of AZP-3601 will maintain bone mass and integrity, a key benefit since the majority of patients with hypoparathyroidism are middle-aged women at risk of osteoporosis [a condition that causes brittle bones],” said Abribat. Pharmacokinetics refers to AZP-3601’s movement into, through, and out of the body.

Preclinical studies in a rat model of hypoparathyroidism and in healthy non-human primates showed that AZP-3601 outperformed PTH replacement therapy at increasing and maintaining calcium levels, without promoting calcium loss in the urine.

Early this year, the therapy received orphan drug designation from the U.S. Food and Drug Administration for the treatment of hypoparathyroidism. The designation is meant to accelerate clinical development by providing regulatory support and financial benefits, as well as a seven-year marketing exclusivity period in the U.S. upon regulatory approval.

The ongoing placebo-controlled, Phase 1 trial is evaluating the safety, tolerability, pharmacological properties, and preliminary effectiveness of single and multiple increasing doses of AZP-3601 in up to 130 people, including healthy men and hypoparathyroidism patients.

The therapy’s pharmacological properties include pharmacokinetics and pharmacodynamics (effects on the body).

Participants with hypoparathyroidism are treated at several specialized centers across Europe, while healthy participants receive the therapy at a single site.

In the first four groups of the study’s single-dose portion, healthy adults (18–60 years) were assigned to receive a morning, under-the-skin injection of either 5, 10, 20 or 40 micrograms (mcg) of AZP-3601 or a placebo. The first participant was dosed in October.

Analyzed data included seven participants on a placebo, three on 5 mcg of AZP-3601, and six each on the other doses.

Compared with the placebo group, AZP-3601 resulted in a clear, dose-dependent increase in blood calcium levels relative to placebo.

Notably, a single injection of AZP-3601 at 40 mcg led to a clinically significant increase in calcium levels in the blood, which remained within the normal range and elevated for at least 24 hours.

In addition, participants given AZP-3601 showed a dose-dependent reduction in blood PTH levels, consistent with the observed increases in calcium levels. At 40 mcg, this drop appeared to be sustained for up to 48 hours (two days) post-injection.

“These data provide initial evidence of the pharmacodynamic effect of AZP-3601 in healthy humans with a sustained calcemic response over 24 hours following a single administration and support further dose escalation,” the researchers wrote.

“By targeting a specific conformation of the PTH1 receptor, these data demonstrate a prolonged serum calcium response, despite AZP-3601 having a very short half-life,” Abribat said.

“We believe that this pharmacological profile is ideally suited to fulfill the clinical needs of patients with hypoparathyroidism, including symptom management and prevention of kidney disease,” he added.