Yorvipath (palopegteriparatide) for hypoparathyroidism

What is Yorvipath for hypoparathyroidism?

Yorvipath (palopegteriparatide) is an approved daily hormone replacement therapy used to help manage blood calcium levels in adults with hypoparathyroidism.

In hypoparathyroidism, levels of the parathyroid hormone (PTH) become too low. Because PTH helps regulate calcium, its loss leads to hypocalcemia, or abnormally low blood calcium levels, which can result in a wide range of symptoms and complications.

Yorvipath, formerly known as TransCon PTH, is designed to provide the body with a steady supply of the deficient hormone in order to boost calcium levels and ease symptoms, while reducing reliance on standard-of-care calcium and vitamin D supplements.

Its main ingredient is an inactive PTH precursor, which is converted in the body to an active form of the hormone that should mimic naturally occurring PTH. The medication is attached to a carrier molecule that helps it last longer in the bloodstream.

Developed by Ascendis Pharma, Yorvipath is administered as a daily under-the-skin (subcutaneous) injection.

Therapy snapshot

Who can take Yorvipath?

In the U.S., Yorvipath is approved for adults with hypoparathyroidism. Regulators haven’t assessed Yorvipath for hypoparathyroidism that occurs after surgery.

The therapy is also approved in other regions, including the European Union, the U.K., Australia, and Canada, for adults with chronic hypoparathyroidism.

Yorvipath is contraindicated, or should not be used, by people who have previously had severe immune reactions (hypersensitivity) to Yorvipath or any of its ingredients. These reactions can include swelling, hives, or a potentially life-threatening systemic reaction called anaphylaxis.

It is also not recommended for people at a high risk of osteosarcoma, a type of bone cancer.

How is Yorvipath administered?

Yorvipath is administered as a once-daily subcutaneous injection. The treatment comes as a clear solution in a pre-filled injection pen. After training from a healthcare professional, patients can administer the injection at home into their abdomen or the front of their thigh, rotating the injection site each day.

The recommended starting dose of Yorvipath is 18 micrograms (mcg) once daily. Doctors will monitor blood calcium levels and side effects, and may gradually adjust the dose, typically staying within a range of 6 mcg to 30 mcg daily. The goal is to achieve normal blood calcium levels without the need for active vitamin D supplements or therapeutic calcium supplements, although this may not be possible for every patient.

Yorvipath in clinical trials

Yorvipath’s approval was largely supported by findings from the PaTHway Phase 3 trial (NCT04701203), which enrolled 82 adults with hypoparathyroidism who received either daily Yorvipath or a placebo for about six months. Participants also started off on conventional calcium and active vitamin D supplements, which could be reduced if normal calcium levels were achieved. The study demonstrated:

• significantly more participants on Yorvipath than in the placebo group achieved the combined primary outcome of normal blood calcium levels, independence from conventional supplements (no active vitamin D and no more than 600 mg calcium), and no need for Yorvipath dose increases in the last month of treatment (79% vs. 5%)
• the majority (93%) of the Yorvipath group achieved independence from conventional therapy
• Yorvipath was associated with improvements in patient-reported quality of life and well-being
• mean blood calcium levels remained within the normal range for people on Yorvipath, but declined in the placebo group

Further analyses showed that these benefits were sustained for up to one year.

Similar benefits were observed in an earlier Phase 2 study called PaTH Forward (NCT04009291), which also involved adults with hypoparathyroidism.

Yorvipath side effects

The most common side effects of Yorvipath include:

• injection site reactions
• signs and symptoms related to blood vessel widening and increased blood flow, such as a blood pressure drop when standing up, dizziness, and palpitations
• headache
• diarrhea
• back pain
• hypercalcemia, or high blood calcium levels
• throat pain

Yorvipath’s prescribing label also mentions potentially serious side effects for which patients will be carefully monitored, including:

• severe hypercalcemia or hypocalcemia
• orthostatic hypotension, or a sudden drop in blood pressure when standing up

Only one Yorvipath injection should be administered daily. Using multiple injections to achieve the desired dose increases the risk of abnormal calcium levels.

Careful monitoring of blood calcium levels is particularly important for people taking the heart medication digoxin, as hypercalcemia can increase the risk of digoxin-related toxicity, while hypocalcemia can reduce digoxin’s effectiveness.

Abnormal calcium levels may require dose adjustments of Yorvipath, and calcium and active vitamin D supplements.

Orthostatic hypertension can cause dizziness, fainting, palpitations, or a fast heart rate. Delivering the injections while sitting or lying down may help.

Medications similar to Yorvipath have been associated with an increased risk of osteosarcoma in animal studies, so it isn’t recommended for people already at elevated risk, including individuals with certain metabolic bone diseases and other inherited disorders.