Ascendis Pharma Reports Positive Phase 3 Results for Hypoparathyroidism Therapy

Ascendis Pharma reported that top-line data from its phase 3 PaTHway Trial of TransCon PTH in adults with hypoparathyroidism met its primary and all secondary endpoints.

The primary endpoint—defined as serum calcium levels in the normal range and independence from conventional therapy with no increase in prescribed study drug within the four weeks prior to the Week 26 visit—was achieved by 78.7 percent of TransCon PTH-treated patients, compared to 4.8 percent for patients in the control group.

Hypoparathyroidism (also called “hypopara” or HP) is a rare endocrine disorder characterized by insufficient levels of parathyroid hormone (PTH), resulting in low calcium and elevated phosphate levels in the blood. HP affects approximately 200,000 patients in the United States, Europe, and Japan, most of whom develop the condition following damage to or accidental removal of the parathyroid glands during thyroid surgery. Conventional treatment with calcium supplements and active vitamin D (also called calcitriol) does not effectively address the short-term symptoms, long-term complications, or quality-of-life impacts of hypoparathyroidism.

Short-term symptoms include weakness, severe muscle cramps, abnormal sensations such as tingling, burning and numbness, memory loss, impaired judgment, and headache. Patients often experience decreased quality of life, and, over the long term, this complex disorder can increase risk of major complications, such as calcium deposits in the brain, blood vessels, eye, and other soft tissues—including the kidneys, which can lead to impaired renal function.

Current standard of care with active vitamin D and calcium supplements does not fully control the disease and may contribute to risk of renal disease. Patients with HP have an estimated 4-fold to 8-fold greater risk of renal disease compared to healthy populations. The disease is also associated with a 2-fold increased risk of depression or bipolar disorder compared to healthy populations. HP remains among the few hormonal insufficiency states without a replacement therapy that restores the missing hormone at physiologic levels.

TransCon PTH is an experimental once-daily long-acting prodrug of parathyroid hormone (PTH) in development as a treatment for adult hypoparathyroidism. TransCon PTH is designed to restore PTH at physiologic levels for 24 hours each day to address both the short-term symptoms and long-term complications of the disease. TransCon PTH has been granted orphan drug designation in the United States and European Union for the treatment of HP.

“Conventional therapy with calcium supplements and active vitamin D is aimed at maintaining serum calcium in the normal range, with the hope of reducing short-term symptoms, and is not able to address the underlying disease,” said Jan Mikkelsen, president and CEO of Ascendis Pharma. “In addition, conventional therapy can lead to long-term complications that include severe diseases such as chronic kidney diseases, liver and basal ganglia calcifications, cardiovascular complications, and bone damage. This is the first phase 3 trial where more than three quarters of patients achieved control of their hypoparathyroidism, defined as normalization of serum calcium and independence from conventional therapy.”

The PaTHway Trial is a phase 3 double-blind, placebo-controlled trial of 82 dosed adults with chronic hypoparathyroidism. A statistically significant decrease in patient-reported, disease-specific physical and cognitive symptoms compared to patients in control group was seen, as shown on Hypoparathyroidism Patient Experience Scales (HPES) Symptom-Physical domain scores and HPES Symptom-Cognitive domain scores.

There was also a statistically significant reduction in patient-reported disease impact compared to patients in control group, as shown on HPES Impact-Physical Functioning domain scores and HPES Impact-Daily Life domain scores, and statistically significant improvements in patient-reported physical functioning compared to patients in control group, as shown on the SF-36v2 survey Physical Functioning subscale.

At Week 26, 95 percent of TransCon PTH-treated patients were able to discontinue conventional treatments with therapeutic levels of calcium supplements and active vitamin D. PaTHway patients had low levels of bone turnover at baseline. TransCon PTH-treated patients demonstrated increased levels of bone turnover markers at Week 26.

TransCon PTH was generally well tolerated, with no discontinuations related to study drug. Three patients discontinued during the treatment period—2 from the placebo arm and 1 from the TransCon PTH arm. Some 82 percent of TransCon PTH patients and 100 percent of patients in control group reported treatment-emergent adverse events, the majority of which were Grade 1, 2 in severity. One serious related treatment-emergent adverse event in the TransCon PTH arm was reported due to a dosing error.

Ascendis plans to submit a New Drug application to the U.S. Food and Drug Administration for TransCon PTH for adults with hypoparathyroidism during the third quarter of 2022 and a Marketing Authorisation Application to the European Medicines Agency during the fourth quarter of 2022.

Ascendis plans to initiate a clinical trial of TransCon PTH in pediatric hypoparathyroidism during the fourth quarter of 2022.

Photo: Jan Mikkelsen, president and CEO of Ascendis Pharma.

Author: Rare Daily Staff