AZP-3601 Treatment Still Showing Positive Results in Phase 2 Trial

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by Patricia Inácio, PhD |

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Daily treatment with AZP-3601, Amolyt Pharma’s investigational therapy for hypoparathyroidism, was well tolerated and allowed patients to discontinue standard supplement treatment, early data from a Phase 2a trial show.

The treatment also rapidly normalized 24-hour urine calcium levels and improved bone health.

The findings, from a first group of 12 patients with hypoparathyroidism enrolled in a proof-of-concept Phase 2 trial, follow promising top-line data from a Phase 1 study.

“In addition to its efficacy on serum [blood] calcium, data from these first patients with hypoparathyroidism demonstrate that AZP-3601 was able to rapidly normalize 24-hour urinary calcium in all patients, and, in particular, in patients with elevated urinary calcium at baseline [study start],” Soraya Allas, MD, PhD, Amolyt’s senior vice president of clinical development and regulatory affairs, said in a press release.

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Hypoparathyroidism is marked by low levels of parathyroid hormone (PTH), which leads to a depletion of calcium and vitamin D deficiency, as well as elevated phosphorus in the blood.

AZP-3601 works as a PTH analog, a compound designed to mimic the activity of PTH. It activates a specific configuration of the PTH receptor, helping to maintain normal blood and urine calcium levels.

Excessive PTH, however, can have a negative effect on bone health. AZP-3601 was designed to be eliminated from the body quickly, a mechanism of action that’s believed to help preserve bone health.

While calcium and vitamin D supplements are the current standard treatment, several patients still have problems in stabilizing their blood calcium levels. They often excrete excessive calcium in their urine, which increases the risk of chronic kidney infections.

“Patients with hypoparathyroidism have a ~5- fold increased risk of kidney stones and chronic kidney disease,” Allas said.

In the Phase 2a study, the 12 participants received AZP-3601 at a fixed dose for four weeks. During this period, both oral calcium and vitamin D supplementation — standard of care therapy — could be progressively removed, while the mean calcium levels in the blood were maintained within the target limits. In a two-month extension period, patients were allowed to adjust their supplement therapy.

Results showed AZP-3601 induced a rapid and sustained normalization of 24-hour urinary calcium in all patients, according to Amolyt.

Moreover, it led to a mild increase in bone turnover — the process of bone resorption followed by replacement with new bone — as assessed by bone biomarkers. No safety concerns were reported, and neither severe nor serious side effects were identified.

“We are very pleased with the promising results from cohort [group] 1 of this important study. Not only does AZP- 3601 appear to fulfill the primary therapeutic objective in terms of serum calcium control and elimination of supplementation, but also its effects on urinary calcium and bone biomarkers support a potential long-term protective effect on both kidney and bone health,” Thierry Abribat, PhD, founder and CEO of Amolyt, said. “This is exactly the target product profile we are seeking, based on a novel mechanism of action that appears to result in a more selective effect on reabsorption of calcium by the kidney and no deleterious impact on bone metabolism.”

Allas called the bone biomarker data encouraging as they point to “resumption of a more physiologic bone turnover without excess bone resorption, which is critical, as 17% of patients with hypoparathyroidism have osteopenia or osteoporosis [bone diseases] and 53% are peri- and post-menopausal women at an increased risk of osteoporosis.”

The trial’s second group of patients will help assess effectiveness and safety across a dose range. These findings will aid the design of a next pivotal trial, Allas said.

The results of the first patient group will be presented this year at a medical conference. Full data is expected in the fall.

In March, the European Commission granted orphan drug designation to AZP-3601 for the treatment of hypoparathyroidism.

Orphan designation is given to candidate therapies for life-threatening and debilitating rare diseases, those affecting up to five in every 10,000 people in the European Union. Financial incentives and regulatory support are included in its benefits.