Yorvipath for hypoparathyroidism

Last updated Aug. 19, 2024, by Lindsey Shapiro, PhD
Fact-checked by José Lopes, PhD

What is Yorvipath for hypoparathyroidism?

Yorvipath (palopegteriparatide) is a daily treatment used to manage blood calcium levels in adults with hypoparathyroidism.

Developed by Ascendis Pharma, it’s given as a once daily under-the-skin (subcutaneous) injection, and is intended to minimize the need for therapeutic calcium and vitamin D supplements in hypoparathyroidism patients.

The therapy (formerly known as TransCon PTH) also is approved in the European Union and the U.K. for adults with chronic hypoparathyroidism.

Therapy snapshot

How does Yorvipath work?

Hypoparathyroidism results from a lack of the parathyroid hormone (PTH), an important regulator of blood calcium levels. When PTH levels get too low, blood calcium levels drop (hypocalcemia), driving the symptoms of hypoparathyroidism. Standard-of-care treatment includes supplements of calcium and vitamin D, which helps the body absorb calcium.

Yorvipath is a long-acting PTH replacement therapy that intends to supply the body with the deficient hormone. Its active ingredient is palopegteriparatide, an inactive precursor molecule, or prodrug, of PTH. Once ingested, palopegteriparatide is converted into teriparatide, a shorter-than-normal version of PTH that works similarly to the naturally occurring hormone. The prodrug also is bound to an inert carrier molecule to ensure the medication is slowly released and not prematurely degraded, making it last longer in the bloodstream.

By providing a round-the-clock supply of PTH, Yorvipath aims to increase blood calcium levels and ease hypoparathyroidism symptoms without the need for vitamin D supplements or therapeutic calcium (i.e., doses higher than recommended for the general population), in addition to preventing the long-term consequences of the disease.

Who can take Yorvipath?

The U.S. Food and Drug Administration approved Yorvipath in August 2024 for the treatment of adults with hypoparathyroidism.

The therapy also is approved in the European Union and U.K. for adults with hypoparathyroidism that’s chronic, or lasting for more than six months.

Who should not take Yorvipath?

According to its U.S. label, Yorvipath should not be used by people with a history of severe hypersensitivity (allergic) reactions to any of its ingredients. Such reactions may include anaphylaxis (a life-threatening reaction that can cause shock, a sudden drop in blood pressure, and trouble breathing), angioedema (swelling in deeper layers of skin, often around the face and lips), and urticaria (hives).

Patients at an elevated risk of osteosarcoma, a type of bone cancer, are recommended to avoid treatment with Yorvipath. This group includes people with metabolic bone diseases such as Paget’s disease, or with inherited disorders predisposing them to osteosarcoma.

How is Yorvipath administered?

Yorvipath is administered as a once daily subcutaneous injection into the abdomen or front of the thigh. The treatment comes as a clear solution in a pre-filled injection pen.

The recommended starting dose of Yorvipath is 18 micrograms (mcg) once daily. The dose then can be adjusted up in 3 mcg increments (no more often than once a week) or adjusted down in 3 mg increments (no more often than every three days) to stay within a range of 6 to 30 mcg daily.

A person’s blood calcium levels will be monitored throughout treatment. The goal is to achieve normal blood calcium levels without the need for vitamin D supplements or therapeutic calcium supplements, although this may not be possible for every patient. A doctor may recommend changes to each patient’s vitamin D and calcium supplements before starting Yorvipath, and again with each dose change to keep blood calcium levels optimal.

Depending on the selected dosage, three different injector pens may be used:

• 168 mcg/0.56 mL: delivers a dose of 6, 9, or 12 mcg PTH (blue push button on pen)
• 294 mcg/0.98 mL: delivers a dose of 15, 18, or 21 mcg PTH (orange push button)
• 420 mcg/ 1.4 mL : delivers a dose of 24, 27, or 30 mcg PTH (burgundy push button)

The maximum recommended dose is 30 mcg daily. If treatment is not effective at this dosage, adding or restarting calcium and/or active vitamin D supplements should be considered. Other treatment options also may be available.

If a dose of Yorvipath is missed by less than 12 hours, it should be administered as soon as possible. If more than 12 hours have passed since the last dose, the missed dose should be skipped and the next dose administered as scheduled.

Yorvipath in clinical trials

Yorvipath’s approval largely was supported by findings in two Ascendis-sponsored global clinical studies — the Phase 2 PaTH Forward trial (NCT04009291) and the PaTHway Phase 3 trial (NCT04701203).

PaTH Forward trial

In PaTH Forward, 59 adults with hypoparathyroidism were randomly assigned to a fixed-dose of Yorvipath (15, 18, or 21 mcg) or a placebo once daily for four weeks. This monthlong period was followed by an ongoing long-term extension where all are being treated with Yorvipath, with the dose titrated between 6-60 mcg daily based on individual needs.

The study employed a composite primary endpoint aimed at assessing the proportion of treated patients who achieved normalized blood calcium levels, normal urine calcium levels or at least a 50% drop in those levels, stopped taking vitamin D supplements, and reduced their calcium supplements to no more than 1,000 mg/day.

This combined endpoint was achieved by 50% of patients given Yorvipath compared with 15% of those on the placebo, meeting the study’s goal. Moreover, 82% of patients on the therapy achieved independence from conventional therapy altogether (no need for vitamin D and calcium supplements of not more than 500 mg/day), meeting a key secondary goal.

After six months in the trial’s extension, when all were on the active therapy, 71% of patients had met the combined endpoint and 76% were completely free from conventional therapy. Yorvipath also was associated with improvements in health-related life quality and other patient-reported outcome measures related to symptom severity and daily life.

Additional extension period analyses showed that benefits of Yorvipath were generally sustained over time, with continued normalizations in calcium levels and reduced dependence on calcium and vitamin D supplements.

PaTHway trial

The Phase 3 PaTHway trial further evaluated Yorvipath’s efficacy and safety in 82 adults with hypoparathyroidism. All were randomly assigned to Yorvipath or a placebo for about six months, along with conventional therapy. The dose was optimized after a starting dose of 18 mcg given over the first 2.5 months. In both groups, active vitamin D, followed by calcium supplements, gradually were reduced once normal calcium levels were achieved.

The study had a composite primary endpoint, looking for the proportion of patients who achieved normal blood calcium levels, independence from conventional therapy (no vitamin D and no more than 600 mg calcium), and who did not require an increase in a Yorvipath dose in the last month of treatment.

Reasonable safety and tolerability also were seen, with no one discontinuing the therapy due to a side effect.

After the six months, 79% of treated patients achieved this composite endpoint compared with 5% of those on the placebo, again meeting the trial’s main goal. The vast majority (93%) of treated patients achieved independence from conventional therapy, allowing for a significant drop in daily pill burden. Mean blood calcium levels remained in the normal range for the treatment group throughout the study, but they declined in the placebo group on conventional therapy.

The treatment also was seen to be superior to a placebo across several secondary endpoints, including patient-reported reductions in physical and cognitive hypoparathyroidism symptoms, as well as improvements in health-related life quality.

In the long-term extension study following this six-month trial, all are being given an individualized therapy dose for up to 156 weeks (about three years). Results at one year of treatment showed that Yorvipath’s benefits generally were sustained, with the majority of patients retaining normal calcium levels and not requiring conventional therapy. Kidney function also significantly improved, with more recent analyses showing these benefits were sustained for two years.

Common side effects of Yorvipath

The most common side effects of Yorvipath reported in clinical trials include:

• Injection site reactions
• Vasodilatory (blood vessel widening) signs and symptoms, such as a blood pressure drop when standing up, dizziness, and palpitations
• Headache
• Diarrhea
• Back pain
• Hypercalcemia, or high blood calcium levels
• Oropharyngeal (throat) pain.

Unintended changes in blood calcium levels with number of daily injections

Taking two Yorvipath injections to reach the recommended daily dose may affect the total delivered dose, raising the risk of abnormal calcium levels. As such, patients are advised to use only one injection to achieve their intended dose.

Serious elevations or decreases in blood calcium levels

It is possible that blood calcium levels will drop too low (hypocalcemia) or rise too high (hypercalcemia) in people using Yorvipath, which is why blood calcium levels should be monitored throughout treatment. Patients also should be watched for signs of either condition.

Hypercalcemia is most likely when starting the medication or adjusting its dose. If hypercalcemia occurs, patients may need to have their Yorvipath dose and their vitamin D and/or calcium supplements dose adjusted, or they may need to temporarily stop treatment for a few days.

Hypocalcemia is most likely when the treatment is abruptly discontinued, but it may occur at any time. If severe hypocalcemia occurs, dose adjustments of Yorvipath, and vitamin D and/or calcium supplements may be needed.

Potential risk of osteosarcoma

As male and female rats treated with molecules similar to PTH have shown higher rates of osteosarcoma, use of Yorvipath, whose teriparatide is one such type of molecule, may raise a risk of this bone cancer. Long-term data exploring the risk of osteosarcoma with Yorvipath use, however, are lacking.

Patients deemed at higher risk of osteosarcoma, such as those with metabolic bone diseases like Paget’s disease, unexplained elevations of alkaline phosphatase (a marker of liver and bone damage), and inherited disorders predisposing to osteosarcoma, should not be treated with Yorvipath.

Symptoms (such as persistent, localized pain) and signs (including a soft tissue mass tender to palpation) that are consistent with osteosarcoma should be promptly reported.

Orthostatic hypotension

Orthostatic hypotension, a sudden drop in blood pressure when standing up, has been reported with Yorvipath. Signs and symptoms may include dizziness, palpitations, and a fast heart rate. Dosing at bedtime while reclining may help to manage these symptoms. With the risk of orthostatic hypotension in mind, Yorvipath initially should be given when the patient can sit or lie down.

Digoxin toxicity

If Yorvipath leads to high blood calcium levels, simultaneous use of digoxin (a medicine for some heart problems, such as irregular heartbeats) may predispose patients to digitalis toxicity. Conversely, the efficacy of digoxin may be reduced if low calcium occurs. Patients taking both Yorvipath and digoxin should have their digoxin levels measured frequently, and be checked for signs and symptoms of digoxin toxicity.

Pregnancy or breastfeeding

Data are insufficient on the use of Yorvipath during pregnancy and breastfeeding. The decision to use the treatment during these times should be made with consideration of all possible risks and benefits to the mother and child. Women who take Yorvipath while pregnant should be informed of a pregnancy safety study monitoring pregnancy outcomes. Ascendis asks that these patients be encouraged to report their pregnancy to the company and consider enrolling in the study.

Hypoparathyroidism News is strictly a news and information website about the disease. It does not provide medical advice, diagnosis, or treatment. This content is not intended to be a substitute for professional medical advice, diagnosis, or treatment. Always seek the advice of your physician or other qualified health provider with any questions you may have regarding a medical condition. Never disregard professional medical advice or delay in seeking it because of something you have read on this website.