Patients with hypoparathyroidism have been clamoring for an alternative to a Takeda Pharmaceutical therapy set to cease production by the end of the year, leaving them with no drug treatments. FDA approval of an Ascendis Pharma drug finally gives them another one, albeit much later than expected.
Ascendis Pharma announced Monday that the FDA approved its hypoparathyroidism therapy, a peptide drug intended to bring deficient levels of parathyroid hormone to within the normal range in adults. The regulatory decision keeps Copenhagen, Denmark-based Ascendis at the front of a group of companies developing novel treatments for the rare hormone deficiency. Ascendis will market its once-daily injection as Yorvipath.
Hypoparathyroidism develops when the parathyroid glands do not produce enough parathyroid hormone, which is needed to regulate levels of calcium and phosphate in the body. This chronic condition can lead to heart and muscle problems as well as brain fog. Calcium and vitamin supplements are the standard of care for this rare disease affecting between 70,000 to 90,000 patients in the U.S., according to Ascendis estimates. For those who cannot manage hypoparathyroidism with supplements alone, the only therapy is Natpara, an engineered version of parathyroid hormone from Takeda Pharmaceutical.
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Though Natpara won FDA approval in 2015, Takeda has been unable to resolve FDA concerns about particles from cartridges housing the once-daily injectable drug. In late 2022, Takeda said it planned to discontinue manufacturing of Natpara (Natpar outside the U.S.) by the end of 2024. Its availability has been limited anyway, offered only through a Takeda special use program. Forteo, an old Eli Lilly osteoporosis drug whose main ingredient, teriparipeptide, is an engineered version of parathyroid hormone, has been used for hypoparathyroidism. But this off-label use requires multiple daily injections.
Ascendis takes a different approach to boosting parathyroid hormone levels with a therapy that’s prodrug, an inactive molecule that converts to an active drug inside the body. The main ingredient in Yorvipath is palopegteriparatide, a peptide that’s a prodrug of teriparipeptide. Dosed once daily, Yorvipath is intended to bring parathyroid hormone levels within the normal range and keep them there. Yorvipath utilizes Ascendis’s TransCon technology, which extends the duration of a drug’s action in the body and permits less frequent dosing. The drug was known in development as TransCon PTH.
In the placebo-controlled Phase 3 clinical trial that supported Yorvipath’s regulatory submission, results showed 68.9% of participants (42 of 61) who received the study drug achieved an overall response to the therapy at week 26 compared to 4.8% (one participant) in the placebo group. The therapy also led to statistically significant changes in calcium levels in the blood and independence from calcium and vitamin supplements. Adverse reactions reported in the study included injection site reactions, signs and symptoms of low blood pressure, headache, and diarrhea.
“The consequences of hypoparathyroidism on the health and quality of life of our patients can be extraordinarily debilitating,” Dr. Lynn Kohlmeier, an endocrinologist at Spokane Osteoporosis & Endocrinology, chair of the Medical Advisory Board of the HypoPARAthyroidism Association, and an investigator in Yorvipath’s pivotal study, said in a prepared statement. “The ability to address the underlying cause of this disease is crucial and will be an important advancement for our patients with hypoparathyroidism.”
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Yorvipath was initially set to receive an FDA decision in April 2023, but the FDA turned down Ascendis’s submission, citing in part concerns about dosing variability from the drug/device combination product. Ascendis resubmitted its application last November, but the FDA needed more time to review the additional information. In May, the agency extended the review period to August 14.
The European Commission approved Yorvipath for chronic hypoparathyroidism last November. Marketing authorizations have since followed in Norway, Iceland, and the United Kingdom. Ascendis has not yet settled on the U.S. price for Yorvipath, which carries a list price of €105,000 (about $114,700) annually in Europe. Ascendis expects to launch Yorvipath in the U.S. in the first quarter of 2025, which leaves many American hypoparathyroidism patients waiting as availability of the Takeda drug ends. But Ascendis said it will ask the FDA to approve for commercial use doses of the therapy that are already manufactured. If those European doses are approved for use in the U.S., they could become available in the fourth quarter of this year.
In a note sent to investors Monday, Leerink Partners analyst Joseph Schwartz said clinicians have told the firm that reimbursement for Yorvipath could be a challenge, but patients who have had acute episodes of excessively low calcium levels requiring hospitalization could make for more compelling cases to payers. Schwartz added that regardless of what payers decide, Leerink’s survey of clinicians “suggests that specialists will push for Yorvipath and it could ultimately gain meaningful traction despite standard of care (calcium and vitamin D) continuing to have a place in the treatment landscape.”
Other companies are developing hypoparathyroidism drugs. Ascendis’s closest competitor might be Amolyt Pharma, which is in Phase 3 testing with a peptide designed to bind to the parathyroid hormone receptor. Preliminary data are expected in 2025. Earlier this year, AstraZeneca acquired Amolyt for $800 million up front. Meanwhile, Extend Biosciences is in early clinical development with a drug derived from parathyroid hormone while MBX Biosciences is in Phase 2 testing with a peptide drug. South San Francisco-based startup Septerna Therapeutics takes a different approach with an oral small molecule designed to target and activate the parathyroid hormone 1 receptor. A little more than a year ago, Septerna raised a $150 million Series B round to support plans that include advancing its hypoparathyroidism pill to the clinic.
Ascendis’s TransCon technology is the basis for its drug pipeline, which spans endocrinology, oncology, and ophthalmology. The platform has already yielded one commercialized product, the pediatric growth hormone deficiency drug Skytrofa. Approved by the FDA in 2021, this once-weekly injectable drug offers an alternative to daily growth hormone injections. In its report of first quarter 2024 financial results, Ascendis projected Skytrofa revenue for the year will be between €3220 million and €340 million. The company’s cash position at the end of the quarter was €320 million.
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