Palopegteriparatide

Long-acting prodrug of PTH(1-34) built on a transient PEG carrier (TransCon PTH), approved as Yorvipath (EU 2023, FDA 2024) as once-daily parathyroid hormone replacement therapy for adults with hypoparathyroidism.

Also referenced as: Yorvipath, TransCon PTH, TransCon-PTH, palopegteriparatide, PEGylated PTH(1-34) prodrug

Also appears in: Longevity

COA Public product evidence No certificate records are bound to a tracked Palopegteriparatide product page A record counts here only when a vendor publishes a certificate against one of its own tracked Palopegteriparatide product pages. Other certificates naming this compound may still exist — search the wider certificate database. →

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What is Palopegteriparatide?

Palopegteriparatide (development name TransCon PTH, brand name Yorvipath) is a prodrug of teriparatide, the 34-amino-acid N-terminal fragment of human parathyroid hormone, PTH(1-34). The peptide is attached through a self-cleaving TransCon linker to a branched 40 kDa (2 x 20 kDa) methoxypolyethylene glycol carrier, giving a conjugate of roughly 47.4 kDa that is essentially inactive until the linker hydrolyzes under physiologic pH and temperature and releases free PTH(1-34) at a controlled rate. The design goal was an infusion-like, around-the-clock PTH exposure from a single daily subcutaneous injection, which is what hypoparathyroidism replacement requires and what short-acting daily PTH injections cannot provide. It is approved as parathyroid hormone replacement therapy for adults with hypoparathyroidism, a rare condition in which the parathyroid glands make too little hormone, most often after neck surgery; it is not an osteoporosis drug, and it does not meaningfully circulate as a research-market compound, where the unconjugated “PTH 1-34” sequence appears instead.

How it works

Released PTH(1-34) binds the PTH/PTHrP type 1 receptor (PTH1R) in kidney and bone and reproduces the actions of endogenous PTH: it raises serum calcium, lowers serum phosphate, increases renal calcium reabsorption, and stimulates renal 1-alpha-hydroxylase to make active vitamin D. The pharmacology that distinguishes it from teriparatide is the exposure pattern rather than the receptor.

• Sustained release converts a pulse into a plateau — in rats and monkeys the conjugate showed a half-life of 28 and 34 hours and, after repeated dosing, a low peak-to-trough “infusion-like” profile of released PTH; in a rat model of hypoparathyroidism it normalized serum calcium and phosphate for the full 24 hours, which an up-to-6-fold higher molar dose of PTH(1-84) achieved only transiently (Holten-Andersen et al., Journal of Bone and Mineral Research, 2019;34(11):2075–2086)
• An effective half-life of about 60 hours in humans — the first-in-human single- and multiple-ascending-dose trial in healthy adults measured dose-dependent, sustained free PTH within the calculated physiologic range at steady state, a dose-dependent rise in albumin-adjusted serum calcium with controlled fractional calcium excretion, and a fall in renal phosphate reabsorption (TmP/GFR) and serum phosphate (Karpf et al., Journal of Bone and Mineral Research, 2020;35(8):1430–1440). The US label reports a median Tmax of about 4 hours for released PTH, an apparent half-life of about 60 hours, steady state within 7 days, and continuous PTH exposure across the 24-hour dosing interval.
• Restoring renal calcium handling instead of forcing calcium through the gut — conventional therapy (calcium plus active vitamin D) corrects hypocalcemia at the cost of hypercalciuria; continuous PTH replacement lowers urinary calcium while keeping serum calcium normal. Mean 24-hour urine calcium fell from 415 to 178 mg/24 h by week 26 in the Phase 2 trial (Khan et al., Journal of Clinical Endocrinology and Metabolism, 2022;107(1):e372–e385), and the Phase 3 trial normalized mean 24-hour urine calcium while participants came off active vitamin D (Khan et al., Journal of Bone and Mineral Research, 2023;38(1):14–25)
• Bone turnover is restored, not driven — in healthy adults 10 days of dosing did not raise bone-formation markers (BSAP, P1NP) and only modestly and transiently raised serum CTx (Karpf et al., 2020); in hypoparathyroidism, where turnover is abnormally low, bone turnover markers rose from baseline and stabilized, and BMD Z-scores trended toward age- and sex-matched norms rather than climbing (Khan et al., Journal of Clinical Endocrinology and Metabolism, 2026, online ahead of print; the 3-year Phase 2 skeletal analysis is Rubin et al., Journal of Bone and Mineral Research, 2026;41(10):1069–1079). This is replacement physiology, not the intermittent-pulse anabolic effect that teriparatide relies on in osteoporosis.

Research status

The evidence base is a single sponsor-run program, but it runs from first-in-human through 3.5 years of controlled follow-up and has been published in peer-reviewed journals at each stage.

• Phase 1 (healthy adults) — Karpf et al., J Bone Miner Res, 2020;35(8):1430-1440. Randomized, double-blind, placebo-controlled SAD/MAD trial; 10 subjects per cohort (8 active, 2 placebo); single doses 3.5 to 124 mcg PTH(1-34) and daily doses 3.5 to 24 mcg for 10 days. No drug-related serious adverse events; all adverse events transient; modest hypercalcemia at the higher doses.
• Phase 2, PaTH Forward — Khan et al., J Clin Endocrinol Metab, 2022;107(1):e372-e385 (NCT04009291; 59 adults). Four-week randomized comparison of 15, 18, or 21 mcg/day against placebo, followed by an open-label extension with titration from 6 to 60 mcg/day. By week 26, 91% of participants had stopped active vitamin D and were taking 500 mg/day or less of calcium; SF-36 scores moved from below normal into the normal range. The trial ran from August 2019 to April 2025, nearly six years of follow-up.
• Phase 3, PaTHway — the pivotal trial (NCT04701203; 84 randomized 3:1, 82 dosed, 21 sites in North America and Europe; February 2021 to January 2025).
  • 26 weeks — Khan et al., J Bone Miner Res, 2023;38(1):14-25. Primary composite endpoint (normal albumin-adjusted serum calcium 8.3-10.6 mg/dL, no active vitamin D, 600 mg/day or less of calcium, and no study-drug increase in the prior 4 weeks) was met by 79% (48/61) on palopegteriparatide versus 5% (1/21) on placebo (p < 0.0001); 93% achieved independence from conventional therapy; all Hypoparathyroidism Patient Experience Scale domains improved versus placebo. Adverse events occurred in 82% of treated and 100% of placebo participants, mostly mild or moderate, with no drug-related withdrawals. The FDA’s own analysis in the label applies a stricter composite (adding no missing data and a dose of 30 mcg/day or less throughout) and reports 68.9% (42/61) versus 4.8% (1/21), a 64-point difference; the two numbers describe the same trial. This trial, with PaTH Forward, was the basis of the US and EU approvals.
  • 52 weeks — Clarke et al., J Clin Endocrinol Metab, 2025;110(4):951-960 (erratum e1292-e1293). Of 78 completers, 81% met the multicomponent endpoint and 95% were independent of conventional therapy; none required active vitamin D.
  • Renal function — Rejnmark et al., Advances in Therapy, 2024;41(6):2500-2518: post hoc analysis showing a mean eGFR increase of 9.3 mL/min/1.73 m² at 52 weeks, with 43% gaining 10 or more; the 2-year follow-up (Rejnmark et al., J Bone Miner Res, 2026;41(9):922-933) reported a sustained mean gain of 9.0 mL/min/1.73 m² at week 104.
  • 182 weeks (3.5 years) — Khan et al., J Clin Endocrinol Metab, 2026 (online ahead of print, October 27, 2026). Of 73 completers, 96% were independent of therapeutic calcium, 100% were off active vitamin D, and 89% were normocalcemic; urine calcium normalization, eGFR gains, and patient-reported outcomes were preserved; most adverse events were mild to moderate.
• Regional Phase 3 trials — PaTHway Japan (jRCT2051210058; single-arm, 13 participants): 92% met the primary multicomponent endpoint at week 26 and 92% of extension participants (11/12) at week 52, with no discontinuations for adverse events (Ashida et al., Endocrine Journal, 2026;73(2):275-289). PaTHway China (NCT05387070; 81 participants, run by the regional licensee) is listed as completed in January 2026; a peer-reviewed publication was not identified.
• Ongoing — a Phase 3 trial of doses above 30 mcg/day in adults (NCT07081997, recruiting from May 2026), a Phase 3 trial in adolescents aged 12 to 17 with chronic hypoparathyroidism (NCT07706764, recruiting from April 2026), a global pregnancy registry (NCT07345494), and a lactation study (NCT07264634). No pediatric indication exists as of October 2026.

There are no failed or discontinued efficacy trials in the program. The one regulatory setback was a May 1, 2023 FDA Complete Response Letter that concerned the manufacturing control strategy for delivered-dose variability of the pen (a drug/device combination issue), not the clinical data; the resubmission was approved in 2024.

Common dosage forms

Prescription palopegteriparatide is supplied as a single-patient-use, multi-dose prefilled pen for once-daily subcutaneous injection. Three pen strengths are approved in the US, each holding 14 daily doses: 168 mcg/0.56 mL (delivering 6, 9, or 12 mcg), 294 mcg/0.98 mL (15, 18, or 21 mcg), and 420 mcg/1.4 mL (24, 27, or 30 mcg); strengths are expressed as teriparatide equivalents (300 mcg teriparatide per mL, equal to 3,456 mcg palopegteriparatide per mL). Pens are dispensed in packs of two and are stored refrigerated before first use. The same pen presentations are marketed in the EU, UK, Japan, Switzerland, and Canada. Because the molecule is a PEG conjugate with a proprietary linker rather than a plain peptide, it is not something research vendors synthesize; “PTH 1-34” vials on the research market are unconjugated teriparatide, a different product with different pharmacokinetics.

Key considerations

• Regulatory status — FDA approved on August 9, 2024 (NDA 216490; new molecular entity, priority review, orphan drug) for the treatment of hypoparathyroidism in adults; the FDA Approved status reflects that an approved drug product containing the molecule exists. The European Commission granted marketing authorization on November 17, 2023, the UK MHRA in April 2024, Japan in 2025 (launched November 2025 by licensee Teijin Pharma), Swissmedic on December 9, 2025, and Health Canada in January 2026. The current US label is revised August 2026 (supplement S-011, approved August 3, 2026), which added hypersensitivity reactions (anaphylaxis, angioedema, urticaria) as the first Warnings and Precautions item and a contraindication for prior severe hypersensitivity, under a class-wide FDA safety labeling change for parathyroid hormone products that also reached teriparatide labels. The label notes the drug was not studied in acute post-surgical hypoparathyroidism and that the titration scheme was evaluated only in adults who first reached a corrected calcium of at least 7.8 mg/dL on conventional therapy. Safety and effectiveness in patients under 18 have not been established.
• Naming confusions — palopegteriparatide releases teriparatide, but it is not teriparatide. Teriparatide (Forteo and generics) is a daily short-acting PTH(1-34) pulse approved for osteoporosis; palopegteriparatide is a sustained-release PTH(1-34) prodrug approved for hypoparathyroidism, and the two are not interchangeable in either direction. It is also distinct from full-length recombinant PTH(1-84) (Natpara/Natpar), the previous hypoparathyroidism replacement product, which Takeda stopped manufacturing worldwide at the end of 2024 after unresolved manufacturing and particle-formation problems (the EU authorization was withdrawn on July 1, 2026), and from abaloparatide (Tymlos), a PTHrP(1-34) analog for osteoporosis. The “teriparatide equivalent” strengths on the US label are a further source of confusion when reading pen labels side by side with teriparatide pens.
• Safety signals in the literature and label — serious hypercalcemia (highest risk at initiation and dose increases; the label says to withhold if corrected calcium exceeds 12 mg/dL) and serious hypocalcemia (highest risk after abrupt discontinuation) are the principal risks; a published case describes symptomatic hypocalcemia a month after stopping three years of therapy despite resumed calcium and calcitriol (Naciu et al., Calcified Tissue International, 2025;116(1):121). Orthostatic hypotension with early doses, digoxin toxicity through calcium, and increased dose variability when two injections are used to reach a single daily dose are labeled warnings. The osteosarcoma warning is a class warning inherited from rat studies of PTH analogs; the label advises against use in patients at increased baseline risk (open epiphyses, Paget disease or other metabolic bone disease, prior skeletal radiation, hereditary predisposition). Observational studies of teriparatide have not shown an increased human risk, but the label is explicit that data for palopegteriparatide itself are limited and its exposure history is far shorter than teriparatide’s 15-year surveillance.
• Evidence gaps — the controlled comparison is 26 weeks in 84 people; everything beyond that is open-label extension data from the same cohort, published by the sponsor’s investigators. There is no head-to-head trial against PTH(1-84) or against daily teriparatide in hypoparathyroidism, no fracture or hard renal-outcome data, and the eGFR improvement is a post hoc finding whose durability past 3.5 years and clinical meaning remain to be shown. Participants were adults with chronic disease on stable conventional therapy (85% post-surgical, 93% white in the pivotal trial); acute post-surgical disease, adolescents, pregnancy, and doses above 30 mcg/day are only now being studied.
• Continuous versus intermittent exposure — the compound is the clearest clinical demonstration that continuous versus intermittent PTH exposure produces opposite skeletal programs with the same peptide, and untreated hypoparathyroidism carries long-term renal and quality-of-life burdens that replacement therapy appears to reverse. None of this supports use outside hypoparathyroidism, and no such use has been studied.