FDA Approves Palopegteriparatide for Hypoparathyroidism

On August 12, 2024, Ascendis Pharma announced that the U.S. Food and Drug Administration (FDA) has approved Yorvipath (palopegteriparatide, TransCon PTH,) injection as the First and Only treatment for adults with hypoparathyroidism.

Hypoparathyroidism is a rare endocrine disorder characterized by insufficient parathyroid hormone (PTH) levels, leading hypocalcemia (blood calcium levels that are too low). The most common cause of hypoparathyroidism is damage to the glands during thyroid surgery. Conventional therapy for hypoparathyroidism consisting of active vitamin D and calcium aims to alleviate hypocalcemia but fails to restore normal parathyroid hormone (PTH) physiology. PTH replacement therapy is the ideal physiologic treatment for hypoparathyroidism.

Palopegteriparatide is a prodrug consisting of a parent drug, PTH(1‐34), transiently conjugated to a branched methoxypolyethylene glycol (mPEG) carrier through a proprietary TransCon linker. This conjugate mimics or manipulates the effects of naturally occurring PTH, regulating calcium and phosphate and acting on the bone, kidney, and intestine.

Palopegteriparatide

Figure 1. Structure of Palopegteriparatide

PEG addition can prolong the pharmacokinetic and pharmacodynamic actions of a bioactive peptide in vivo, in part by impeding rates of glomerular filtration. For palopegteriparatide, pegylation could help in exploring the actions of the hormone in the kidney. Biopharma PEG provides high-quality PEG derivatives for your PEGylation needs. These reagents are water soluble, biocompatible, and almost aggregation-free, making them ideal for bioconjugation or crosslinking of proteins, antibodies, peptides, oligonucleotides, or solid surfaces to other macromolecules, therapeutic compounds or other small molecules, and dyes.

The approval was based on data from two global clinical trials: the Phase 2 PaTH Forward trial and the Phase 3 PaTHway trial. The Phase 3 trial enrolled 82 adult patients with chronic hypoparathyroidism.

Results showed that 78.7% of patients treated with Yorvipath maintained normal blood calcium levels (8.3–10.6 mg/dL) without conventional treatments, compared to just 4.8% in the placebo group (p<0.0001). Additionally, patients experienced a statistically significant reduction in both physical and cognitive symptoms, as measured by the Hypoparathyroidism Patient Experience Scale (HPES).

PaTHway

Figure 2. Primary composite endpoint of Phase 3 PaTHway

In terms of safety, Yorvipath was generally well tolerated, with no discontinuations due to treatment-related issues. Three patients discontinued treatment during the study — two from the placebo group and one from the Yorvipath group. Treatment-emergent adverse events (TEAEs) were reported in 82% of the Yorvipath group and 100% of the placebo group, with most being mild to moderate (grades 1 or 2).

Before this approval, the FDA had rejected Yorvipath in May 2023 due to concerns about the consistency of dosage delivery from the TransCon PTH drug-device system. After further discussions with the FDA, Ascendis Pharma resubmitted the application in November with a new manufacturing control strategy for TransCon PTH.

References:
[1] FDA Approves YORVIPATH® (Palopegteriparatide) as the First and Only Treatment for Hypoparathyroidism in Adults. Retrieved August 12, 2024 from https://investors.ascendispharma.com/news-releases/news-release-details/fda-approves-yorvipathr-palopegteriparatide-first-and-only
[2] YORVIPATH® FDA Approval. Retrieved August 12, 2024 from https://investors.ascendispharma.com/static-files/32590c52-6842-4250-956c-0e8a05b43894