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YORVIPATH (palopegteriparatide injection) is a parathyroid hormone analog (PTH(1-34)). Palopegteriparatide is a prodrug of teriparatide (PTH(1-34)) consisting of PTH(1-34) transiently conjugated to an inert carrier via a proprietary TransCon Linker. PTH(1-34) is identical to the 34 N-terminal amino acids (the biologically active region) of the 84-amino acid human parathyroid hormone. The carrier is a branched 40 kDa (2×20 kDa) methoxypolyethylene glycol (mPEG) moiety. The average molecular weight of palopegteriparatide is approximately 47.4 kDa.
The structure of palopegteriparatide drug substance is shown in Figure 2. The theoretical molecular formula is C209H340N60O59S3 + 2 × (C2H4O)n, where n is between approximately 450 and 500.
Figure 2: Structure of Palopegteriparatide
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YORVIPATH is a sterile, clear, and colorless solution in a glass cartridge which is preÂassembled in a single-patient-use prefilled pen for subcutaneous administration. The prefilled pen is co-packaged with safety pen needles to administer 14 doses of YORVIPATH. YORVIPATH is available in three presentations containing 0.56 mL, 0.98 mL, or 1.4 mL of YORVIPATH solution, and each pen presentation can deliver one of three distinct doses for 14 days of therapy.
Each mL of YORVIPATH solution contains 3456 mcg of palopegteriparatide, equivalent to 300 mcg of teriparatide (PTH(1-34)), and the following inactive ingredients: 41.7 mg mannitol, 2.5 mg metacresol, 0.13 mg sodium hydroxide, 1.18 mg succinic acid, and water for injection. YORVIPATH has a pH of 3.7 to 4.3.
Each pen of 0.56 mL contains 168 mcg teriparatide equivalent to 1935 mcg palopegteriparatide.
Each pen of 0.98 mL contains 294 mcg teriparatide equivalent to 3387 mcg palopegteriparatide.
Each pen of 1.4 mL contains 420 mcg teriparatide equivalent to 4838 mcg palopegteriparatide.
YORVIPATH is indicated for the treatment of hypoparathyroidism in adults.
Table 1: Dosage Adjustments to Active Vitamin D (calcitriol) and Calcium Supplements upon Initiation or Up-titration of YORVIPATH Treatment
| Albumin-Corrected Serum Calcium | Current Active Vitamin D (calcitriol) Intake | Adjust Active Vitamin D (calcitriol) Intake | Adjust Calcium Supplements |
| ≥8.3 mg/dL | >1 mcg/day | Reduce calcitriol dosage by ≥50% | Maintain current calcium dosage |
| ≥8.3 mg/dL | ≤1 mcg/day | Discontinue calcitriol | Maintain current calcium dosage |
| ≥7.8 to <8.3 mg/dL | Any amount | Reduce calcitriol dosage by ≥50% | Maintain current calcium dosage |
| ≥7.8 mg/dL | Not currently on active vitamin D | Not applicable | Reduce calcium daily dosage by at least 1500 mg or discontinuea if current calcium daily dosage is ≤1500 mg/day |
| a If calcium supplements are needed to meet dietary requirements, continuing dietary calcium supplements at elemental dosages ≤600 mg/day may be considered instead of discontinuing the calcium entirely. | |||
Figure 1 shows dosage titration recommendations for YORVIPATH, active vitamin D, and calcium in adults with specific albumin-corrected serum calcium ranges that are less than or equal to 12 mg/dL. The maximum recommended dosage of YORVIPATH is 30 mcg once daily [see DOSAGE AND ADMINISTRATION].
Figure 1: Titration of YORVIPATH, Active Vitamin D, and Calcium Supplements
 |
Withhold YORVIPATH for 2 to 3 days and then recheck serum calcium. If albumin-corrected serum calcium remains ≥12 mg/dL, withhold YORVIPATH for an additional 2 to 3 days and then recheck serum calcium. Once the albumin-corrected serum calcium is <12 mg/dL, resume titration of YORVIPATH, active vitamin D, and calcium supplements per the applicable section of Figure 1 using the most recent serum calcium value.
Take YORVIPATH as soon as possible if a dose is missed by less than 12 hours. Skip the missed dose if the dose has been missed by more than 12 hours. Take the next dose as scheduled.
If YORVIPATH treatment is delayed or interrupted for 3 days or more, evaluate patients for signs and symptoms of hypocalcemia and consider measuring serum calcium. If indicated, resume treatment with, or increase the dose of, calcium supplements and active vitamin D. Resume YORVIPATH at the previously prescribed dose as soon as possible after an interruption then measure serum calcium within 7 to 10 days and adjust doses of YORVIPATH, active vitamin D, and/or calcium supplements per Figure 1 [see DOSAGE AND ADMINISTRATION].
Patients and caregivers who will administer YORVIPATH should receive appropriate training by a healthcare professional prior to first use.
Follow the Instructions For Use to administer YORVIPATH using pen and needle:
Injection: Clear, colorless solution in single-patient-use prefilled pens in three presentations
Table 2 displays the YORVIPATH prefilled pen presentations, strengths, labeled doses, and deliverable dose ranges.
Table 2: YORVIPATH Prefilled Pen Presentations, Strengths, Labeled Doses, and Deliverable Dose Ranges
| Pen Type and Strength | Labeled Dose (mcg) | Range of Deliverable Dose* (Minimum - Maximum) (mcg) |
| Prefilled pen with blue push button (168 mcg/0.56 mL) | 6 | 4.5 -7.5 |
| 9 | 7.5 -10.5 | |
| 12 | 10.5 -13.5 | |
| Prefilled pen with orange push button (294 mcg/0.98 mL) | 15 | 13.1 - 16.5 |
| 18 | 16.1 - 19.5 | |
| 21 | 19.1 -22.5 | |
| Prefilled pen with burgundy push button (420 mcg/1.4 mL) | 24 | 21.6 -25.5 |
| 27 | 24.6 -28.5 | |
| 30 | 27.6 -31.5 | |
| * Deliverable dose range at each labeled dose setting based on prefilled pen performance. Use only labeled dose for titration (refer to Figure 1). | ||
YORVIPATH is available in a prefilled, disposable, 14-dose pen-injector (Table 6). Each pen contains a clear and colorless solution of 3456 mcg/mL of palopegteriparatide equivalent to 300 mcg/mL of teriparatide. Each pack contains 2 prefilled pens and 28 needles for 28 injections (plus two spare needles).
Table 6: YORVIPATH Prefilled Pen Presentations
| Prefilled Pen Presentation | Labeled Doses | Content of Pack | NDC |
| YORVIPATH (168 mcg/0.56 mL) identified by blue push button | 6, 9, and 12 mcg | 2 prefilled pens 30 needles | 73362-100-01 |
| YORVIPATH (294 mcg/0.98 mL) identified by orange push button | 15, 18, and 21 mcg | 2 prefilled pens 30 needles | 73362-101-01 |
| YORVIPATH (420 mcg/1.4 mL) identified by burgundy push button | 24, 27, and 30 mcg | 2 prefilled pens 30 needles | 73362-102-01 |
Do not freeze. Store away from heat. Keep YORVIPATH in the packaging to protect from light.
Until first use, store YORVIPATH in the refrigerator between 2°C to 8°C (36°F to 46°F).
After first use, store YORVIPATH for 14 days at room temperature below 30°C (86°F). After each use, remove the needle and put the pen cap on to protect from light. Discard the prefilled pen 14 days after first use.
Manufactured by: Ascendis Pharma Bone Diseases A/S Tuborg Boulevard 12, DK-2900 Hellerup, Denmark. Revised: Aug 2024
The following clinically significant adverse reactions are described elsewhere in the labeling:
Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.
The phase 3 trial included 82 subjects with hypoparathyroidism with a median YORVIPATH treatment duration of 182 days (Study 1) [see Clinical Studies].
Adverse reactions associated with YORVIPATH in Study 1 during the 26-week blinded period (incidence ≥5% and occurring ≥2% more frequently than placebo) are shown in Table 3.
Table 3: Adverse Reactions in ≥5% of Subjects with Hypoparathyroidism Treated with YORVIPATH and with ≥2% Higher Frequency Compared to Placebo in Study 1
| Adverse Reaction | YORVIPATH N=61 n (%) |
Placebo N=21 n (%) |
| Injection site reactionsa | 24 (39) | 1 (5) |
| Vasodilatory signs and symptomsb | 17 (28) | 0 |
| Headache | 13 (21) | 2 (10) |
| Diarrhea | 6 (10) | 1 (5) |
| Back painc | 5 (8) | 0 |
| Hypercalcemia | 5 (8) | 0 |
| Oropharyngeal pain | 4 (7) | 0 |
| a Injection site reactions includes the preferred terms injection site bruising, injection site erythema, injection site rash, and injection site reaction. b Vasodilatory signs and symptoms includes the preferred terms blood pressure orthostatic decreased, dizziness, dizziness postural, orthostatic hypotension, palpitations, postural orthostatic tachycardia syndrome, presyncope, syncope, and vertigo. c Back pain includes the preferred terms back pain, flank pain, and spinal pain. Abbreviations: N, total number of subjects in the treatment arm; n, number of subjects with the adverse reaction; %, percent of subjects with the adverse reaction. |
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Table 4 summarizes the number of subjects who had at least one serum calcium measurement greater than the upper limit of the reference range at a post-baseline visit in Study 1. The incidence of hypercalcemia was greater in subjects treated with YORVIPATH.
Symptomatic hypercalcemia was reported in 8% of subjects treated with YORVIPATH, and all occurred within the first 3 months after initiation of YORVIPATH.
Table 4: Incidence of Elevated Albumin-Corrected Serum Calcium (>10.6 mg/dL or >12 mg/dL) Post-Baseline in Subjects with Hypoparathyroidism Treated with YORVIPATH or Placebo in Study 1
| YORVIPATH N=61 |
Placebo N=21 |
|
| Albumin-Corrected Serum Calcium >10.6 mg/dL, n (%)a | 33 (54.1) | 2 (9.5) |
| Albumin-Corrected Serum Calcium >12 mg/dL, n (%) | 8 (13.1) | 0 (0) |
| a Subjects meeting albumin-corrected serum calcium >10.6 mg/dL criterion includes subjects meeting albumin-corrected serum calcium >12 mg/dL criterion. Abbreviations: N, total number of subjects in the treatment arm; n, number of subjects meeting criteria. |
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YORVIPATH increases serum calcium, therefore, concomitant use with digoxin (which has a narrow therapeutic index) may predispose patients to digitalis toxicity if hypercalcemia develops. Digoxin efficacy may be reduced if hypocalcemia is present. When YORVIPATH is used concomitantly with digoxin, measure serum calcium and digoxin levels, and monitor for signs and symptoms of digoxin toxicity. Adjustment of the digoxin and/or YORVIPATH dose may be needed.
Drugs that affect serum calcium may alter the therapeutic response to YORVIPATH. Measure serum calcium more frequently when YORVIPATH is used concomitantly with these drugs, particularly after these drugs are initiated, discontinued, or dose-adjusted.
Included as part of the PRECAUTIONS section.
Use only one YORVIPATH injection to achieve the recommended once daily dosage. Using two YORVIPATH injections to achieve the recommended once daily dosage increases the variability of the total delivered dose, which can cause unintended changes in serum calcium levels, including hypercalcemia and hypocalcemia [see DOSAGE AND ADMINISTRATION and WARNINGS AND PRECAUTIONS].
Serious events of hypercalcemia requiring hospitalization have been reported with YORVIPATH. The risk is highest when starting or increasing the dose of YORVIPATH but may occur at any time. Measure serum calcium 7 to 10 days after any dose change or if there are signs or symptoms of hypercalcemia, and at a minimum of every 4 to 6 weeks once the maintenance dose is achieved. Treat hypercalcemia if needed. If albumin-corrected serum calcium is greater than 12 mg/dL, withhold YORVIPATH for at least 2-3 days [see DOSAGE AND ADMINISTRATION]. For less serious hypercalcemia, adjust the dose of YORVIPATH, active vitamin D, and/or calcium supplements [see DOSAGE AND ADMINISTRATION, ADVERSE REACTIONS].
Serious events of hypocalcemia have been observed with PTH products, including YORVIPATH. The risk is highest when YORVIPATH is abruptly discontinued, but may occur at any time, even in patients who have been on stable doses of YORVIPATH. Measure serum calcium 7 to 10 days after any dose change or if there are signs or symptoms of hypocalcemia, and at a minimum of every 4 to 6 weeks once the maintenance dosage is achieved. Treat hypocalcemia if needed, and adjust the dose of YORVIPATH, active vitamin D, and/or calcium supplements if hypocalcemia occurs [see DOSAGE AND ADMINISTRATION].
YORVIPATH is a PTH analog. An increased incidence of osteosarcoma (a malignant bone tumor) has been reported in male and female rats treated with PTH analogs, including teriparatide. Osteosarcoma occurrence in rats is dependent on teriparatide or PTH dose and treatment duration. Osteosarcoma has been reported in patients treated with teriparatide in the postmarketing setting; however, an increased risk of osteosarcoma has not been observed in observational studies in humans. There are limited data assessing the risk of osteosarcoma beyond 2 years of teriparatide use.
YORVIPATH is not recommended in patients who are at increased risk of osteosarcoma, such as patients with:
Instruct patients to promptly report clinical symptoms (e.g., persistent localized pain) and signs (e.g., soft tissue mass tender to palpation) that could be consistent with osteosarcoma.
Orthostatic hypotension has been reported with YORVIPATH. Associated signs and symptoms may include decreased blood pressure, dizziness (including postural dizziness), palpitations, tachycardia, presyncope, or syncope. Such symptoms can be managed by dosing at bedtime, while reclining. YORVIPATH should be administered initially when the patient can sit or lie down due to the potential of orthostatic hypotension.
YORVIPATH increases serum calcium, and therefore, concomitant use with digoxin (which has a narrow therapeutic index) may predispose patients to digitalis toxicity if hypercalcemia develops. Digoxin efficacy may be reduced if hypocalcemia is present. When YORVIPATH is used concomitantly with digoxin, measure serum calcium and digoxin levels routinely, and monitor for signs and symptoms of digoxin toxicity. Refer to the digoxin prescribing information for dose adjustments, if needed [see DRUG INTERACTIONS].
Advise the patient to read the FDA-approved patient labeling (Medication Guide and Instructions for Use).
Advise patients to use only one injection to achieve the once daily recommended dosage [see DOSAGE AND ADMINISTRATION and WARNINGS AND PRECAUTIONS].
Advise patients that the healthcare provider may change the dose of YORVIPATH, calcium, or active vitamin D supplements based on serum calcium levels.
Advise patients to administer YORVIPATH subcutaneously to the abdomen or front of the thigh. Advise patients to rotate the injection site daily [see DOSAGE AND ADMINISTRATION].
Risk of YORVIPATH Adverse Reactions with Use of Two Injections to Achieve the Recommended Once Daily Dosage
Advise patients that using two YORVIPATH injections to achieve the recommended once daily dosage increases the variability of the total delivered dose, which can cause unintended changes in serum calcium levels, including hypercalcemia and hypocalcemia. Advise patients to use only one YORVIPATH injection to achieve the recommended once daily dosage [see WARNINGS AND PRECAUTIONS].
Advise patients taking YORVIPATH to contact their healthcare provider promptly if they develop symptoms of hypercalcemia (e.g., nausea, vomiting, constipation, lethargy, muscle weakness) or hypocalcemia, to report abrupt discontinuations in YORVIPATH dosing, and to follow recommended serum calcium monitoring [see WARNINGS AND PRECAUTIONS].
Advise patients that administration of other PTH products causes an increase in the incidence of osteosarcoma in rats. No increased risk of osteosarcoma was observed with teriparatide compared to a general population. Advise patients to promptly report clinical symptoms (e.g., persistent localized pain) and signs (e.g., soft tissue mass tender to palpation) that could be consistent with osteosarcoma [see WARNINGS AND PRECAUTIONS].
When initiating YORVIPATH treatment, advise patients to be prepared to immediately sit or lie down during or after administration if they feel lightheaded or have palpitations after the injection until their symptoms resolve. If these symptoms persist or worsen, advise patients to consult their healthcare provider [see WARNINGS AND PRECAUTIONS].
Advise patients to report use of a digoxin-containing medication and to follow recommended serum calcium and digoxin monitoring [see WARNINGS AND PRECAUTIONS].
Advise patients that serious hypersensitivity reactions (including anaphylaxis and angioedema) are possible with PTH products. Advise patients to discontinue YORVIPATH and promptly seek medical attention if signs or symptoms of hypersensitivity reaction occur [see CONTRAINDICATIONS].
Advise females who are exposed to YORVIPATH during pregnancy that there is a pregnancy safety study that monitors pregnancy outcomes. Encourage these patients to report their pregnancy to Ascendis Pharma (1-844-442-7236) [see Use In Specific Populations].
Long-term animal studies to address the carcinogenic potential of palopegteriparatide have not been conducted.
Palopegteriparatide was not genotoxic in an in vitro bacterial reverse-mutation assay (Ames test), an in vitro human lymphocyte chromosome-aberration assay, and an in vivo rat bone-marrow micronucleus assay.
In fertility studies, palopegteriparatide was administered by subcutaneous injection at 2, 6, and 20 mcg/kg/day. Palopegteriparatide did not impair fertility in male and female rats up to the highest tested dose, which is 7-fold and 11-fold the MRHD, respectively, based on PTH(1-34) and active metabolite PTH(1-33) exposure by AUC.
Available data from reports of pregnancies in the clinical trials from drug development are insufficient to identify a drug-associated risk of major birth defects, miscarriage, or other adverse maternal or fetal outcomes. There are disease-associated risks to the mother and fetus related to hypocalcemia in pregnancy (see Clinical Considerations). In animal reproduction studies, administration of palopegteriparatide to pregnant rats and rabbits during the period of organogenesis resulted in no significant adverse effects up to doses 16-and 13-fold, respectively, the maximum recommended human dose (MRHD), based on PTH(1-34) and active metabolite PTH(1-33) exposure by area under the curve (AUC) (see Data).
The background risk of birth defects and miscarriages for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriages in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.
If YORVIPATH is administered during pregnancy, or if a patient becomes pregnant while receiving YORVIPATH, healthcare providers should report YORVIPATH exposure by calling 1-844-442-7236.
Disease-Associated Maternal And Embryo/Fetal Risk
Maternal hypocalcemia can result in an increased rate of spontaneous abortion, premature and dysfunctional labor, and possibly preeclampsia. Infants born to mothers with hypocalcemia can have associated fetal and neonatal hyperparathyroidism, which may cause fetal and neonatal skeletal demineralization, subperiosteal bone resorption, osteitis fibrosa cystica, and neonatal seizures. Infants born to mothers with hypocalcemia should be monitored for signs of hypocalcemia or hypercalcemia, including neuromuscular irritability (e.g., myotonic jerks, seizures), apnea, cyanosis, and cardiac arrhythmias.
Animal Data
In an embryo-fetal developmental toxicity study in rats, palopegteriparatide was administered subcutaneously during the period of organogenesis (gestation days (GD) 6 to 17) at doses of 2, 8, and 30 mcg/kg/day. In pregnant rats, there was no evidence of embryo-lethality, fetotoxicity, or fetal malformations up to the highest dose tested corresponding to 16-fold the MRHD, based on PTH(1-34) and active metabolite PTH(1-33) exposure by AUC.
In an embryo-fetal developmental toxicity study in rabbits, palopegteriparatide was administered subcutaneously to pregnant female rabbits during the period of organogenesis (GD 7 to 19) at doses of 1, 3, and 6 mcg/kg/day. There was no evidence of any palopegteriparatide-related embryo-lethality, fetotoxicity, or fetal malformations at any dose level up to 13-fold the MRHD, based on PTH(1-34) exposure by AUC.
There are no data available on the presence of palopegteriparatide or its metabolite in either human or animal milk, the effects on the breastfed infant, or the effects on milk production. Infants breastfed by females treated with YORVIPATH should be monitored for signs and symptoms of hypercalcemia or hypocalcemia. Monitoring of serum calcium in the infant should be considered.
The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for YORVIPATH and any potential adverse effects on the breastfed child from YORVIPATH or from the underlying sub-optimally treated maternal condition.
The safety and effectiveness of YORVIPATH have not been established in pediatric patients.
In Study 1, 8 of 61 (13%) YORVIPATH-treated subjects were 65 years of age or over compared to 2 of 21 (10%) subjects in the placebo group. Clinical studies of YORVIPATH did not include a sufficient number of subjects 65 years of age and older to determine whether they respond differently from younger adult subjects.
No dose adjustment is required in patients with mild, moderate, or severe renal impairment (estimated glomerular filtration rate ≥ 15 mL/min/1.73 m²).
In a dedicated renal impairment study, patients with severe renal impairment (estimated glomerular filtration rate 15 to 30 mL/min/1.73 m²) had no clinically significant difference in total PTH compared to subjects with normal renal function upon treatment with YORVIPATH [see CLINICAL PHARMACOLOGY].
Accidental overdose of YORVIPATH may cause hypercalcemia that can be severe and require medical intervention. One subject in Study 1 accidentally received approximately 3-fold the prescribed dose of YORVIPATH for more than 7 consecutive days and developed albumin-corrected serum calcium as high as 16.1 mg/dL, requiring hospitalization.
YORVIPATH is contraindicated in patients with severe hypersensitivity to palopegteriparatide or to any of its excipients. Hypersensitivity reactions, including anaphylaxis, angioedema, and urticaria, have been observed with parathyroid hormone (PTH) analogs.
At physiological conditions, palopegteriparatide releases PTH(1-34) to maintain a continuous systemic exposure. Endogenous PTH maintains extracellular calcium and phosphate homeostasis by increasing serum calcium and decreasing serum phosphate. These effects are mediated by stimulating bone turnover to mobilize calcium and phosphate from bone, promoting renal calcium reabsorption and phosphate excretion, and facilitating active vitamin D synthesis, in turn increasing intestinal absorption of calcium and phosphate. Similar to endogenous PTH, PTH(1-34) released from palopegteriparatide exerts these effects through its main receptor, parathyroid hormone 1 receptor (PTH1R), which is highly expressed on osteoblasts, osteocytes, renal tubular cells, and in several other tissues.
Serum PTH(1-34) and serum calcium concentrations increased in a dose-related manner when YORVIPATH was administered to healthy volunteers. Exposure-response is not established in subjects with hypoparathyroidism.
Mean steady state concentration-time profile of albumin-corrected serum calcium concentrations over 24 hours following administration of YORVIPATH is presented in Figure 3.
Figure 3: Mean Steady-State Albumin-Corrected Serum Calcium Concentrations Following Subcutaneous Administration of YORVIPATH* in Subjects with Hypoparathyroidism
 |
The normal range for albumin-corrected serum calcium is 8.3 to 10.6 mg/dL.
* Mean dose (range): 22.3 (12-33) mcg/day, n=7.
YORVIPATH is a prodrug that releases PTH(1-34) via autocleavage of the TransCon linker.
PTH Cmax and AUC increased proportionally over a YORVIPATH dosage range of 12 to 24 mcg/day. PTH steady state is achieved after administration of YORVIPATH for 7 days.
Mean steady state concentration-time profile of PTH(1-34) over 24 hours following administration of YORVIPATH is presented in Figure 4. At steady state, administration of YORVIPATH resulted in continuous exposure to released PTH throughout the 24Âhour dosing period.
Figure 4: Mean Steady State PTH(1-34) Following SubcutaneousAdministration of YORVIPATH* in Subjects with Hypoparathyroidism
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* Mean dose (range): 22.3 (12-33) mcg/day, n=7.
a PTH(1-34) concentrations includes PTH(1-34) and active metabolite PTH(1-33).
The median (range) time to reach maximum concentrations (Tmax) of PTH is 4 (4 to 8) hours.
The estimated apparent volume of distribution (CV%) of palopegteriparatide is 4.8 (50) L. A similar distribution pattern as observed for endogenous PTH is expected for PTH released from palopegteriparatide.
The apparent half-life of PTH released from palopegteriparatide is approximately 60 hours. The estimated clearance (CV%) of palopegteriparatide at steady state is 0.58 (52) L/day.
Metabolism
Released PTH includes PTH(1-34) and the active metabolite PTH(1-33). PTH(1-33) and PTH(1-34) have comparable affinity to and activation of PTH1R.
There are no clinically significant differences in the pharmacokinetics of palopegteriparatide based on age, sex, or body weight. The data for race and ethnicity did not show any trends indicating differences, but the available data are too limited to make definitive conclusions.
A dedicated renal impairment study showed that mild, moderate, and severe renal impairment did not have a clinically significant impact on systemic exposure of total PTH following a single 50 mcg subcutaneous dose of palopegteriparatide. No studies were conducted in subjects with hypoparathyroidism who have severe renal impairment.
No dedicated hepatic impairment study was conducted. Mild and moderate hepatic impairment is not expected to have a clinically significant impact on the pharmacokinetics of palopegteriparatide.
The observed incidence of anti-drug antibodies is highly dependent on the sensitivity and specificity of the assay. Differences in assay methods preclude meaningful comparisons of the incidence of anti-drug antibodies in the studies described below with the incidence of anti-drug antibodies in other studies, including those of YORVIPATH or other teriparatide products.
Mean duration of exposure to YORVIPATH in clinical studies was 850 days. Of patients with post-baseline assessments, 0.7% (1 of 139 YORVIPATH-treated patients) had low titer, non-neutralizing antibodies towards PTH and 5% (7 of 139 YORVIPATH-treated patients) had low titer treatment-emergent antibodies against PEG. Three of 139 YORVIPATH-treated patients (2.2%) had pre-existing PEG antibodies that had a transient impact on the pharmacokinetics of palopegteriparatide and serum calcium, however, therapeutic effectiveness was maintained by dose adjustment of YORVIPATH using the trial titration algorithm.
In a 26-week rat study, daily subcutaneous administration of palopegteriparatide resulted in bone turnover imbalances in healthy euparathyroid rats. The bone effects tended towards a net catabolic effect (bone resorption) as evidenced by a decrease in proximal tibial trabecular bone volume and bone mineral content (BMC) in both sexes treated at the low dose of 5 mcg/kg/day (5-fold the MRHD, based on PTH(1-34) and active metabolite PTH(1-33) exposure by AUC) and in females treated at 10 mcg/kg/day (9-fold the MRHD, based on PTH(1-34) and PTH(1-33) exposure by AUC). A net anabolic bone effect (bone formation) including histologic increases in bone at several skeletal sites accompanied by increased osteoblast cellularity and increases in proximal tibia trabecular bone volume and BMC were observed in males at 10 mcg/kg/day (10-fold the MRHD, based on PTH(1-34) and PTH(1-33) exposure by AUC) and in both sexes treated at the high dose of 20 mcg/kg/day (19-fold the MRHD, based on PTH(1-34) and PTH(1-33) exposure by AUC). In a 4-week study in hypoparathyroid female rats, daily subcutaneous administration of palopegteriparatide at 5 and 10 mcg/kg/day (5-to 9-fold the MRHD, based on PTH(1-34) and PTH(1-33) exposure by AUC) resulted in a net catabolic bone effect as bone resorption (e.g., high urinary C-telopeptide of type 1 collagen, decreased tibial trabecular bone volume, increase in osteoclast surface, and endocortical eroded surface) appeared to exceed bone formation.
The effectiveness and safety of YORVIPATH in adults with hypoparathyroidism were evaluated in a 26-week, randomized, double-blind, placebo-controlled, phase 3 study (Study 1 [NCT04701203]).
Study 1 was conducted in 82 subjects with hypoparathyroidism. Prior to randomization, all subjects underwent an approximate 4-week screening period in which calcium and active vitamin D supplements were adjusted to achieve an albumin-corrected serum calcium concentration between 7.8 and 10.6 mg/dL, a magnesium concentration ≥1.3 mg/dL and below the upper limit of the reference range, and a 25(OH) vitamin D concentration between 20 to 80 ng/mL. During the double-blind period, subjects were randomized to either YORVIPATH (N = 61) or placebo (N= 21), at a starting dose of 18 mcg/day, co-administered with conventional therapy (calcium and active vitamin D). Randomization was stratified by etiology of hypoparathyroidism (postsurgical vs. all other causes). Study drug and conventional therapy were subsequently titrated according to the albumin-corrected serum calcium levels [see DOSAGE AND ADMINISTRATION].
The mean age at enrollment was 49 years (range: 19 to 78 years), 78% were female, and 93% were Caucasian. Eighty-five percent (85%) of subjects had hypoparathyroidism acquired from neck surgery. Of the subjects with other etiologies of hypoparathyroidism, 7 (8.5%) subjects had idiopathic disease, 2 had autoimmune polyglandular syndrome type 1 (APS-1), 1 had autosomal dominant hypocalcemia type 1 (ADH1, CaSR mutation), 1 had DiGeorge Syndrome, and 1 had hypoparathyroidism, sensorineural deafness and renal dysplasia (HDR) syndrome (GATA3 mutation). At baseline, the median duration of hypoparathyroidism was 8.5 years (range 1 to 56 years). Baseline mean albumin-corrected serum calcium was 8.8 mg/dL and 8.6 mg/dL and mean 24-hour urine calcium was 392 mg/day and 329 mg/day for YORVIPATH and placebo, respectively. The mean baseline dose of elemental calcium was 1839 mg/day, and the mean baseline doses of active vitamin D were 0.75 mcg/day in calcitriol-treated subjects (n=70), and 2.3 mcg/day in alfacalcidol-treated subjects (n=12).
Efficacy was assessed based on the proportion of subjects who achieved all of the following at Week 26:
In the YORVIPATH group, 68.9% (42/61) of subjects met the efficacy endpoint at Week 26 compared with 4.8% (1/21) of subjects in the placebo group. The treatment difference was 64.2% (95% confidence interval: 49.5%, 78.8%) (Table 5).
Table 5: Efficacy at Week 26 in Adults with Hypoparathyroidism in Study 1
| YORVIPATH (N=61) |
Placebo (N=21) |
Response Rate Difference (95% CI) | |
| Overall Response at Week 26 | 42 (68.9%) | 1 (4.8%) | 64.2% (49.5%, 78.8%) |
| Response for each component | |||
| Normal albumin-corrected serum calciuma | 49 (80.3%) | 10 (47.6%) | 32.7% (9.2%, 56.3%) |
| Independence from active vitamin Db | 58 (95.1%) | 5 (23.8%) | 71.3% (52.5%, 90.2%) |
| Independence from therapeutic dose of calciumc | 53 (86.9%) | 1 (4.8%) | 82.2% (70.0%, 94.4%) |
| No increase in study drug dose since Week 22d | 57 (93.4%) | 12 (57.1%) | 36.4% (14.2%, 58.5%) |
| Study drug dose ≤30 mcg/day up to Week 26e | 56 (91.8%) | NA | NA |
| a Normal range for albumin-corrected serum calcium was 8.3 to 10.6 mg/dL. b No daily standing doses of active vitamin D, no PRN doses, and no missing active vitamin D data within 4 weeks prior to Week 26 visit. c Average daily standing dose of elemental calcium ≤600 mg, no PRN doses, and no missing calcium data within 4 weeks prior to Week 26 visit. d No increase in study drug dose within 4 weeks prior to Week 26 visit. e Subjects who received more than 30 mcg/day at any timepoint during the 26-week treatment period were considered as non-responders for the efficacy endpoint. Abbreviations: CI: confidence interval; NA: not applicable; PRN: pro re nata. |
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The proportion of subjects randomized to YORVIPATH who met the efficacy endpoint decreased over time as follows: 68.9% (42/61) at Week 26 and 39.3% (24/61) at both Week 52 and Week 78 during the open-label extension period. Allowing for dose up-titration, the proportion of subjects who were able to maintain normocalcemia and independence from active vitamin D and therapeutic dose of calcium was 64% (39/61) at Week 52 and 66% (40/61) at Week 78.
YORVIPATH®
(YOR-vih-path)
(palopegteriparatide) injection, for subcutaneous use
What is the most important information I should know about YORVIPATH?
YORVIPATH may cause serious side effects, including:
Tell your health care provider right away if you have any of these signs and symptoms of osteosarcoma, or high or low blood calcium levels.
See “What are the possible side effects of YORVIPATH?” for information about side effects.
What is YORVIPATH?
It is not known if YORVIPATH is safe and effective in people who have been recently diagnosed with hypoparathyroidism after surgery.
It is not known if YORVIPATH is safe and effective if it is started in people with low levels of calcium in the blood.
It is not known if YORVIPATH is safe and effective in children. YORVIPATH should not be used in children and young adults whose bones are still growing.
Who should not take YORVIPATH?
Do not use YORVIPATH if you:
Before using YORVIPATH, tell your health care provider about all of your medical conditions, including if you:
Tell your health care provider about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements. YORVIPATH and other medicines may affect each other causing side effects. Know the medicines you take. Keep a list of them to show your health care provider and pharmacist when you get a new medicine.
How should I use YORVIPATH?
What are the possible side effects of YORVIPATH?
YORVIPATH may cause serious side effects:
The most common side effects of YORVIPATH include injection site reactions, vasodilatory signs or symptoms such as a drop in blood pressure or lightheadedness when standing up, headache, diarrhea, back pain, high calcium levels, and sore throat.
These are not all of the possible side effects of YORVIPATH. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.
How should I store YORVIPATH?
Keep YORVIPATH and all medicines out of the reach of children.
General information about the safe and effective use of YORVIPATH.
Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use YORVIPATH for a condition for which it was not prescribed. Do not give YORVIPATH to other people, even if they have the same symptoms that you have. It may harm them. You can ask your pharmacist or health care provider for information about YORVIPATH that is written for health professionals.
What are the ingredients in YORVIPATH?
Active ingredient: palopegteriparatide
Inactive ingredients: mannitol, metacresol, sodium hydroxide, succinic acid, and water for injection.
This Medication Guide has been approved by the U.S. Food and Drug Administration
