| Size | Price | |
|---|---|---|
| 500mg | ||
| 1g | ||
| Other Sizes |
| Targets |
Palopegteriparatide itself is inactive at the PTH receptor in its prodrug state. Following cleavage of the linker under physiological conditions, the released active PTH(1-34) targets and activates the parathyroid hormone 1 receptor (PTH1R, Gene ID: 5745). PTH1R is a G protein-coupled receptor expressed on target organs including bone, kidney, and nerve tissue. Activation stimulates bone turnover, increases renal calcium reabsorption, promotes phosphate excretion, and facilitates active vitamin D synthesis. The compound is also reported to have calcium-sensing receptor (CaSR) antagonist activity.
Palopegteriparatide acts as a prodrug that releases active PTH(1-34), which targets the Parathyroid Hormone 1 Receptor (PTH1R). PTH1R is a G protein-coupled receptor highly expressed in osteoblasts, osteocytes, and renal tubular cells. Activation of PTH1R increases serum calcium and decreases serum phosphate by mobilizing calcium from bone, promoting renal calcium reabsorption and phosphate excretion, and facilitating the synthesis of active vitamin D (calcitriol) . |
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| ln Vitro |
Palopegteriparatide itself is inactive at the PTH receptor in its prodrug state, with its activity dependent on linker cleavage. The released active component, PTH(1-34), is equivalent to endogenous PTH and the approved drug teriparatide, demonstrating similar affinity for and activation of PTH1R. Under physiological pH and temperature conditions, the prodrug undergoes controlled, continuous cleavage to release active PTH, providing平稳 drug exposure.
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| ln Vivo |
Palopegteriparatide is administered as a once-daily subcutaneous injection, providing sustained PTH exposure of approximately 60 hours with an infusion-like release profile. In the Phase 3 PaTHway trial, 93% of patients receiving palopegteriparatide were able to discontinue conventional therapy (calcium and active vitamin D) while maintaining normocalcemia, with normalization of urinary calcium levels. Normal 24-hour urinary calcium excretion (≤250 mg/24 h) was achieved in 60.7% of treated patients compared to 28.6% in the placebo group. Long-term data (162 weeks) showed that 91% of participants achieved the composite endpoint of normocalcemia, independence from active vitamin D, oral calcium ≤1000 mg/day, and normal urinary calcium. Treatment also significantly improved quality of life scores.
In the pivotal 26-week, double-blind, Phase 3 PaTHway trial, Palopegteriparatide demonstrated significant efficacy. At week 26, 79% (48/61) of patients receiving the drug vs. 5% (1/21) on placebo met the primary composite endpoint of normal serum calcium (8.3-10.6 mg/dL) and independence from conventional therapy (no active vitamin D and ≤600 mg/day calcium supplementation) (p 请 。 After 52 weeks in an open-label extension, 81% (63/78) of patients continued to meet this composite endpoint, and 95% (74/78) achieved independence from conventional therapy. Mean (SD) 24-hour urinary calcium excretion, a key marker of treatment-related complications, decreased from 376 (168) mg/day at baseline to 195 (114) mg/day at week 52 。 Furthermore, Palopegteriparatide significantly improved health-related quality of life, including physical functioning, well-being, and disease-specific symptoms as measured by the SF-36 and HPES questionnaires 。 |
| Enzyme Assay |
As palopegteriparatide is a prodrug, cell-free binding studies typically examine the interaction of released PTH(1-34) with PTH1R. Radioligand binding assays can be performed using membrane preparations expressing PTH1R incubated with ¹²⁵I-labeled PTH(1-34) tracer and varying concentrations of the sample (palopegteriparatide pre-cleaved to release active PTH). Bound and free radioligands are separated by filtration, and radioactivity is measured to calculate IC₅₀ or Kd values. The binding affinity of this compound is similar to that of teriparatide.
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| Cell Assay |
To evaluate palopegteriparatide activity, cAMP assays are typically performed using PTH1R-expressing cell lines such as UMR-106 rat osteosarcoma cells. Cells are incubated with pre-cleaved or directly cleaving palopegteriparatide (starting concentration approximately 4000 ng/mL, serially diluted) for 30 minutes at 25°C in the dark. After adding cAMP detection reagents and incubating for an additional 60 minutes, intracellular cAMP levels are measured using time-resolved fluorescence resonance energy transfer, and relative potency is calculated using four-parameter fitting analysis.
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| Animal Protocol |
Pharmacodynamic and pharmacokinetic studies of palopegteriparatide in animals typically use hypoparathyroidism models such as parathyroidectomized rats or dogs. Animals receive daily subcutaneous injections of varying palopegteriparatide doses (e.g., equivalent to PTH(1-34) 0.5-2 μg/kg) for 4-8 weeks. Serum calcium, phosphate, urinary calcium, and bone turnover markers (P1NP, CTX) are monitored periodically. At study termination, bone tissue is collected for micro-CT analysis and histological examination to assess bone microarchitecture and bone mineral density changes. In rat studies, long-term high-dose administration of PTH analogs has been associated with an increased incidence of osteosarcoma.
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| ADME/Pharmacokinetics |
Absorption: Following once-daily subcutaneous administration, Palopegteriparatide releases PTH with first-order kinetics, providing continuous exposure over 24 hours within the estimated normal range (approx. 4-26 pg/mL for PTH(1-34) equivalent). The prodrug reaches steady state in ~10 days, while released PTH reaches steady state in ~7 days. The peak-to-trough ratio is low, approximately 1.5 for released PTH over 24 hours .
Distribution: The apparent volume of distribution (CV%) is 4.8 L (50%) for palopegteriparatide and 8.7 L (18%) for released PTH . Metabolism and Elimination: Active PTH released from the prodrug consists of PTH(1-34) and the active metabolite PTH(1-33). PTH is renally metabolized and cleared; most is cleared by cathepsins in the liver, and a small portion is filtered and excreted by the kidneys . Half-life: The apparent half-life of PTH released from palopegteriparatide is approximately 60 hours . Palopegteriparatide achieves a significantly prolonged half-life of approximately 60 hours through TransCon technology, compared to approximately 1 hour for unmodified PTH(1-34). Following subcutaneous administration, the drug undergoes controlled, continuous cleavage under physiological conditions to release active PTH(1-34), providing a平稳 plasma concentration profile. The major metabolite PTH(1-33) exhibits similar PTH1R affinity and activation capability as endogenous PTH. The polyethylene glycol carrier is cleared renally. Once-daily dosing maintains sustained PTH exposure. |
| Toxicity/Toxicokinetics |
Clinical trial safety data show that Palopegteriparatide is generally well-tolerated. In the Phase 3 trials, most treatment-emergent adverse events were mild or moderate in severity. The most common adverse reactions included injection site reactions (31.1%), headache (21.3%), fatigue (14.8%), and paresthesia (18%) . Overdosage can lead to hypercalcemia, which was manageable with treatment interruption and supportive care .
Palopegteriparatide is generally well tolerated but has adverse reactions that require monitoring. Adverse reactions occurring in ≥5% of patients in Phase 3 trials include injection site reactions (31.1%), vasodilatory signs and symptoms, headache (9.8%), diarrhea, back pain, hypercalcemia (9.8%), and oropharyngeal pain. Serious hypercalcemia and hypocalcemia have been reported, with the highest risk during treatment initiation or dose adjustment. As with other PTH analogs, there is a potential risk of osteosarcoma based on rat studies; therefore, it is not recommended for patients at increased risk of osteosarcoma (e.g., those with open epiphyses, Paget‘s disease of bone, or history of skeletal malignancies). Orthostatic hypotension has also been reported, and administration in a sitting or lying position is recommended for the first dose. |
| References |
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| Additional Infomation |
Approval: Palopegteriparatide is marketed under the brand name YORVIPATH. It received its first approval in the European Union in November 2023 and was approved by the U.S. FDA in August 2024 for the treatment of adults with chronic hypoparathyroidism .
Mechanism of Action: The product is a prodrug that provides sustained release of active PTH(1-34). This is designed to mimic the physiological secretion pattern of endogenous PTH more closely than other available therapies, leading to better control of calcium and phosphorus levels and reduced urinary calcium excretion . Dosing: The recommended starting dose is 18 mcg of PTH(1-34) once daily, which can be individually titrated based on serum calcium levels. Doses up to 60 mcg/day can be administered as two sequential subcutaneous injections . |
| CAS # |
2222514-07-8
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|---|---|
| Sequence |
{X}-Ser-Val-Ser-Glu-Ile-Gln-Leu-Met-His-Asn-Leu-Gly-Lys-His-Leu-Asn-Ser-Met-Glu-Arg-Val-Glu-Trp-Leu-Arg-Lys-Lys-Leu-Gln-Asp-Val-His-Asn-Phe (X= O-methylpolyethylene glycol (2 x 20 kDa mPEG)-Aib){X}-SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNF (X= O-methylpolyethylene glycol (2 x 20 kDa mPEG)-Aib)
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| SequenceShortening |
{X}-SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNF (X= O-methylpolyethylene glycol (2 x 20 kDa mPEG)-Aib)
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| Appearance |
Typically exists as solids at room temperature
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| Synonyms |
Transcon PTH; ACP-014; ACP014;
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| HS Tariff Code |
2934.99.9001
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| Storage |
Powder -20°C 3 years 4°C 2 years In solvent -80°C 6 months -20°C 1 month |
| Shipping Condition |
Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)
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| Solubility (In Vitro) |
May dissolve in DMSO (in most cases), if not, try other solvents such as H2O, Ethanol, or DMF with a minute amount of products to avoid loss of samples
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| Solubility (In Vivo) |
Note: Listed below are some common formulations that may be used to formulate products with low water solubility (e.g. < 1 mg/mL), you may test these formulations using a minute amount of products to avoid loss of samples.
Injection Formulations
Injection Formulation 1: DMSO : Tween 80： Saline = 10 : 5 : 85 (i.e. 100 μL DMSO stock solution → 50 μL Tween 80 → 850 μL Saline)(e.g. IP/IV/IM/SC) *Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH ₂ O to obtain a clear solution. Injection Formulation 2: DMSO : PEG300 ：Tween 80 : Saline = 10 : 40 : 5 : 45 (i.e. 100 μL DMSO → 400 μLPEG300 → 50 μL Tween 80 → 450 μL Saline) Injection Formulation 3: DMSO : Corn oil = 10 : 90 (i.e. 100 μL DMSO → 900 μL Corn oil) Example: Take the Injection Formulation 3 (DMSO : Corn oil = 10 : 90) as an example, if 1 mL of 2.5 mg/mL working solution is to be prepared, you can take 100 μL 25 mg/mL DMSO stock solution and add to 900 μL corn oil, mix well to obtain a clear or suspension solution (2.5 mg/mL, ready for use in animals). View More
Injection Formulation 4: DMSO : 20% SBE-β-CD in saline = 10 : 90 [i.e. 100 μL DMSO → 900 μL (20% SBE-β-CD in saline)] Oral Formulations
Oral Formulation 1: Suspend in 0.5% CMC Na (carboxymethylcellulose sodium) Oral Formulation 2: Suspend in 0.5% Carboxymethyl cellulose Example: Take the Oral Formulation 1 (Suspend in 0.5% CMC Na) as an example, if 100 mL of 2.5 mg/mL working solution is to be prepared, you can first prepare 0.5% CMC Na solution by measuring 0.5 g CMC Na and dissolve it in 100 mL ddH2O to obtain a clear solution; then add 250 mg of the product to 100 mL 0.5% CMC Na solution, to make the suspension solution (2.5 mg/mL, ready for use in animals). View More
Oral Formulation 3: Dissolved in PEG400 (Please use freshly prepared in vivo formulations for optimal results.) |
Calculation results
Working concentration： mg/mL；
Method for preparing DMSO stock solution： mg drug pre-dissolved in μL DMSO (stock solution concentration mg/mL). Please contact us first if the concentration exceeds the DMSO solubility of the batch of drug.
Method for preparing in vivo formulation:：Take μL DMSO stock solution, next add μL PEG300, mix and clarify, next addμL Tween 80, mix and clarify, next add μL ddH2O，mix and clarify.
(1) Please be sure that the solution is clear before the addition of next solvent. Dissolution methods like vortex, ultrasound or warming and heat may be used to aid dissolving.
(2) Be sure to add the solvent(s) in order.
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