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After rejecting it a year ago, the FDA approved once-daily palopegteriparatide (Yorvipath) for adults with hypoparathyroidism, drugmaker on Monday.

Injectable palopegteriparatide is a prodrug of parathyroid hormone (PTH[1-34]) that is designed to provide sustained exposure to the hormone over 24 hours. Parathyroid hormone is the primary regulator of calcium and phosphate balance and acts directly on the bone and kidneys and indirectly on the intestines.

As Takeda announced plans to stop manufacturing its by year's end due to unresolved supply issues, palopegteriparatide will become the only approved drug on the market targeting the underlying cause of hypoparathyroidism.

Approval of palopegteriparatide, developed under the moniker TransCon PTH, was supported in large part by the .

In an efficacy analysis of 82 patients in the phase III study, a significantly higher proportion of those assigned to palopegteriparatide achieved the primary endpoint compared with placebo recipients (69% vs 5% at week 26). That endpoint was defined as normocalcemia and independence from conventional therapy (active vitamin D and a therapeutic dose of calcium), with no increase in the assigned study drug in the 4 weeks prior to week 26.

Hypoparathyroidism is caused by insufficient parathyroid hormone levels, and the rare endocrine condition affects an estimated 70,000 to 90,000 people in the U.S. Most commonly triggered by surgery, complications of the condition extend to neuromuscular irritability, renal complications, extra-skeletal calcifications, and cognitive impairment.

"The consequences of hypoparathyroidism on the health and quality of life of our patients can be extraordinarily debilitating," said PaTHway investigator Lynn Kohlmeier, MD, of Spokane Osteoporosis & Endocrinology, in a statement. "The ability to address the underlying cause of this disease is crucial and will be an important advancement for our patients with hypoparathyroidism."

Conventional therapy (i.e., active vitamin D and >600 mg doses of calcium supplements) aims to only reduce the short-term symptoms of hypoparathyroidism by maintaining serum calcium in the normal range.

During an open-label extension period of PaTHway, the percentage of patients on palopegteriparatide meeting the primary efficacy endpoint decreased to 39% at weeks 52 and 78. But with up-titration, 66% of the patients were able to maintain normocalcemia and independence from conventional therapy at week 78.

Of note, the titration scheme was only evaluated in participants who first achieved an albumin-corrected serum calcium of at least 7.8 mg/dL with calcium supplementation and active vitamin D, and the injection was not tested in patients with acute post-surgical hypoparathyroidism.

The most common adverse events with palopegteriparatide in the phase III trial were injection site reactions (39% vs 5% with placebo), vasodilatory signs and symptoms (28% vs none), headache (21% vs 10%), diarrhea (10% vs 5%), back pain (8% vs none), hypercalcemia (8% vs none), and oropharyngeal pain (7% vs none).

Palopegteriparatide will come in three strengths of single-use, prefilled pens. It should be injected into the abdomen or front of thigh each day, with the site rotated daily.

Dosage should be individualized based on serum calcium. The recommended starting dosage is 18 mcg once daily and is titrated in 3 mcg increments or decrements with the goal of maintaining normocalcemia without the need for conventional therapy. Calcium supplementation sufficient to meet daily dietary requirements may be continued. The maximum recommended daily dose of palopegteriparatide is 30 mcg.

Palopegteriparatide is contraindicated in people with a severe hypersensitivity to palopegteriparatide. The label also warns of unintended serum calcium level changes, serious hypercalcemia and hypocalcemia events, osteosarcoma risk, orthostatic hypotension, and digoxin toxicity.

The path to palopegteriparatide's approval wasn't completely smooth, as the FDA initially the drug in 2023 over manufacturing concerns.

Ascendis Pharma said it expects the initial commercial supply of palopegteriparatide to be available in the U.S. early next year, but plans to ask the FDA to grant it permission to use an existing manufactured product, in which case it "could be introduced in the U.S. in the fourth quarter" of this year.

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