Amolyt Pharma has announced positive results from the second patient cohort in its phase 2a clinical proof of concept trial of AZP-3601, a PTH1 receptor agonist, which the company is developing as a potential treatment for hypoparathyroidism.
Consistent with the findings from cohort 1, in the full data set from the phase 2a study, AZP-3601 was well-tolerated, and daily administration enabled 93% of patients to discontinue standard of care therapy (calcium and vitamin D supplementation) while mean serum calcium was maintained within the target range.
Mean urinary calcium excretion was rapidly normalized and bone biomarkers increased in line with a resumption of a normalized physiological level of bone turnover.
Key findings from cohort 2
At the end of the 3-month treatment period, 93% (13 of 14 patients) had discontinued both active vitamin D and oral calcium supplementation. Consistent with cohort 1, mean albumin-adjusted serum calcium (AdsCa) remained within the target range.
The 24-hour urinary excretion of calcium was rapidly normalized in all but one patient, including those with hypercalciuria at baseline.
Also consistent with cohort 1, bone turnover biomarkers, P1NP and CTX, increased after two weeks of treatment and remained within their mid-normal range through the end of the study, consistent with a balanced increase in bone turnover. Consistent with the findings in bone biomarkers, bone mineral density (BMD) was stable, including in patients with osteopenia.
AZP-3601 was well tolerated with no serious adverse events. There were only mild to moderate adverse events, consistent with prior studies.
The lower starting dose (10 mg) used in this cohort required an early up-titration to 20 mg in most patients after two weeks to allow discontinuation of oral vitamin D and calcium supplementation, supporting the selection of 20µg as the starting dose for the phase 3 trial.
Data from both cohorts provide further support for the target profile of AZP-3601 and for the planned initiation of the phase 3 trial next year.
Trial in 2023
“We are very pleased to see that the safety and efficacy data from Cohort 2 validate the findings from the first cohort of patients in this study,” said Mark Sumeray, chief medical officer at Amolyt Pharma.
“We observed success in the control of serum calcium and elimination of active vitamin D and oral calcium at levels that were even better than those achieved in Cohort 1. Mean urinary calcium excretion also rapidly normalized, particularly in patients with elevated urinary calcium at baseline, an important finding since more than 50% of patients with hypoparathyroidism have hypercalciuria.
“Bone biomarkers again provided evidence of a balanced and physiologic restoration of bone turnover without excess bone resorption, as also suggested by the BMD data. We now have the clinical data needed to finalize our plans for a phase 3 trial of AZP-3601 and look forward to end-of-phase 2 discussions with health authorities with the goal of initiating the trial as soon as possible next year.”
Thierry Abribat, founder and chief executive officer of Amolyt Pharma, said: “The data are very encouraging for the future development of AZP-3601. Over recent weeks, as we have discussed the emerging efficacy and safety profile of this novel PTH1 receptor agonist with experts in the management of hypoparathyroidism, it has become increasingly clear that the observed rapid normalization of mean urinary calcium excretion combined with balanced resumption of bone turnover supports the potential of AZP-3601 to uniquely address the key treatment goals for these patients. We are excited to move forward to our Phase 3 study.”
Hypoparathyroidism is defined by a deficiency of parathyroid hormone (PTH) that results in decreased calcium and elevated phosphorus levels in the blood. Approximately 80% of the estimated 80,000 people in the U.S. and 110,000 in the European Union with hypoparathyroidism are women.
Despite available treatments, patients experience persistent, life-altering symptoms and often develop complications and comorbidities that diminish quality of life and create segments of the patient population with specific clinical needs. Clinical manifestations of hypoparathyroidism impact many tissues and organ systems, in particular, the kidneys and bone. Also, 17% of patients with hypoparathyroidism have osteopenia or osteoporosis and 53% are peri- or postmenopausal women with an increased risk of developing osteoporosis.
Approximately 26% of patients with hypoparathyroidism have chronic kidney disease or failure, highlighting the importance of reducing urinary calcium excretion as a key treatment goal.
AZP-3601 is an investigational therapeutic peptide designed to target a specific conformation of the parathyroid hormone (PTH) receptor to safely produce sustained and stable levels of calcium in the blood and thereby manage the symptoms of hypoparathyroidism, and to limit urine calcium excretion by restoring calcium reabsorption by the kidney, with the goal of consequently preventing chronic kidney disease. In addition to its unique receptor profile, AZP-3601 is also designed to have a short half-life to potentially preserve bone integrity, an important benefit, since the majority of patients are peri- and postmenopausal women with an increased risk of developing osteoporosis.