AZP-3601 Safely Raises Blood Calcium Levels in Trial in Healthy Adults
“We are pleased with these clinical trial results for AZP-3601 … as they support a potential therapeutic profile that we believe can address the multiple clinical needs of patients with hypoparathyroidism, including a significant number who suffer from or who are at risk of kidney disease, osteopenia or osteoporosis [bone diseases],” Thierry Abribat, PhD, said in a press release. Abribat is the founder and CEO of Amolyt Pharma, the company developing AZP-3601.
Hypoparathyroidism is characterized by abnormally low levels of the parathyroid hormone (PTH), resulting in overly low levels of vitamin D and calcium in the blood, as well as excess phosphorus levels.
AZP-3601 is an analog of PTH — a molecule designed to mimic the activity of the naturally occurring hormone. AZP-3601 is designed to activate a specific configuration of the PTH receptor, thereby raising blood calcium levels. Notably, the therapy does not last long in the body, which may reduce the risk of bone disease due to prolonged exposure to PTH.
The investigational therapy has shown efficacy at treating hypoparathyroidism in preclinical models, and the U.S. Food and Drug Administration (FDA) has named AZP-3601 an orphan drug, which aids work on potential rare disease therapies by offering regulatory support and financial benefits.
Amolyt launched a Phase 1 clinical trial into the safety, tolerability, and pharmacological properties of AZP-3601 late last year in healthy volunteers before moving to hypoparathyroidism patients. It opened with two parts, testing single-ascending doses (SAD) and multiple-ascending doses (MAD) in volunteers.
In the SAD portion, 52 healthy adults were given a single injection of AZP-3601, ranging from 5 to 120 micrograms (mcg), or a placebo. During MAD, 50 healthy adults were given multiple injections of the therapy — at doses ranging from 10 to 80 mcg a day — or a placebo over the course of two weeks.
In all participants, the medication was administered via a subcutaneous (under-the-skin) injection done in the morning.
Results from the SAD portion were presented earlier this year. They showed that a single injection of the experimental treatment was generally well-tolerated, with no serious or severe adverse events (side effects) or noteworthy safety findings. Findings also indicated that the treatment could increase blood calcium levels for at least 24 hours, and pharmacological data were in line with expectations from preclinical studies.
New data from the MAD portion, which ended last month, generally did not show any new safety concerns. Most reported adverse events — such as headache, nausea, and sleepiness — were deemed likely related to hypercalcemia, when blood calcium levels are higher than normal, and in a dose-dependent manner, starting at the 40 mcg dose.
Notably, treatment with AZP-3601 in this MAD part did not affect any measured markers of bone health.
In agreement with the earlier SAD data, MAD findings also showed that treatment raised blood calcium levels. Higher doses of AZP-3601 led to higher blood calcium levels.
“There is a dose-related increase in [blood] calcium that is quite rapid, [occurring] very quickly after the start of the treatment. This increase is sustained for the duration of the treatment period, which is 14 days,” Soraya Allas, MD, PhD, vice president of clinical development and regulatory affairs at Amolyt, said in a webinar.
At study day 15 — the day following the last dose of AZP-3601 — blood calcium levels were maintained. This confirms the long-lasting effect of the medication, according to Allas.
Results also showed a dose-dependent decrease in blood phosphorus and a reduction in PTH levels, which is consistent with the elevation of calcium with AZ-3601, Allas added.
Notably, in both parts of the study, treatment with AZP-3601 did not increase the amount of calcium excreted in the urine. This suggests that the calcium is being properly absorbed in the body, which is also important from a safety perspective because excessive calcium in the urine can strain the kidneys, and lead to kidney disease.
Overall, data from this portion of the Phase 1 study “further support the development of AZP-3601 as a potential treatment for chronic hypoparathyroidism,” Allas said.
Amolyt is now moving into a three-month study of multiple ascending doses of AZP-3601 in people with chronic hypoparathyroidism at sites in Europe.
“Based on [the Phase 1 healthy volunteer] positive results, we have initiated our next trial in patients. This is an important step forward in our quest to bring patients with hypoparathyroidism a potential new treatment option, and we look forward to reporting data from this new trial in the first half of 2022,” Abribat added.