Palopegteriparatide Prescribing Information

Limitations of Use

• YORVIPATH was not studied for acute post-surgical hypoparathyroidism.
• YORVIPATH's titration scheme was only evaluated in adults who first achieved an albumin-corrected serum calcium of at least 7.8 mg/dL using calcium and active vitamin D treatment [see Dosage and Administration (2.3, 2.4) and Clinical Studies (14)].

2.1 Overview of Dosage and Monitoring

• Use only one injection to achieve the once daily recommended dosage. Using two injections to achieve the recommended once daily dosage increases the risk of unintended changes in serum calcium levels, including hypocalcemia and hypercalcemia. [see Dosage and Administration (2.4, 2.6) and Warnings and Precautions (5.1)].
• The maximum recommended dosage is 30 mcg subcutaneously once daily. If an adequate response is not achieved with a maximum YORVIPATH dosage of 30 mcg, consider adding or restarting calcium and/or active vitamin D therapy and/or seek other treatment options [see Warnings and Precautions (5.1)].
• YORVIPATH's once daily subcutaneous dosage is individualized. The recommended starting dosage is 18 mcg once daily and is titrated in 3 mcg increments or decrements with the goal of maintaining serum calcium within the normal range without the need for active vitamin D (e.g., calcitriol) or therapeutic calcium doses (elemental calcium >600 mg/day). Calcium supplementation sufficient to meet daily dietary requirements may be continued.
• Advise patients to monitor daily for clinical signs and symptoms of hypocalcemia or hypercalcemia.
• Measure serum calcium 7 to 10 days after the first YORVIPATH dose and after any dose change in YORVIPATH, active vitamin D, or calcium supplements, and monitor for clinical signs and symptoms of hypocalcemia or hypercalcemia. Once the YORVIPATH maintenance dosage is achieved, measure serum calcium levels at a minimum every 4 to 6 weeks or as indicated for symptoms of hypocalcemia or hypercalcemia.
• Adjust YORVIPATH, active vitamin D, and/or calcium supplements per Figure 1. Some patients may require an increase in the YORVIPATH dose over time to maintain the same therapeutic effect [see Clinical Studies (14)].
• Refer to the Instructions for Use (IFU) for detailed instructions on the proper preparation and administration of YORVIPATH [see Dosage and Administration (2.6)].

2.2 Laboratory Testing Prior to Initiation of YORVIPATH

• Within two weeks before the first dose of YORVIPATH, confirm serum 25(OH) vitamin D is within the normal range and albumin-corrected serum calcium is ≥7.8 mg/dL.

2.3 Modification of Active Vitamin D and Calcium Supplements on Day of YORVIPATH Initiation or Up-titration

• On the day of initiation or up-titration of YORVIPATH, adjust the dose of active vitamin D and calcium supplements based on albumin-corrected serum calcium and current active vitamin D intake (Table 1).

2.4 Recommended Dosage, Titration Scheme, and Monitoring

• The recommended starting dosage of YORVIPATH is 18 mcg once daily. Dosage adjustments should be made in 3 mcg increments or decrements. Do not increase the YORVIPATH dosage more often than every 7 days. Do not decrease the YORVIPATH dosage more often than every 3 days.
• The recommended dosage range of YORVIPATH is 6 to 30 mcg once daily.
• Measure serum calcium within 7 to 10 days after the first dose and any dose change in YORVIPATH, active vitamin D, or calcium supplements, and monitor for clinical symptoms of hypocalcemia or hypercalcemia. Adjust YORVIPATH, active vitamin D, and/or calcium supplements per Figure 1.
• The maintenance dosage is individualized and should be the YORVIPATH dose that achieves serum calcium within the normal range, without the need for active vitamin D or therapeutic doses of calcium. Calcium supplementation sufficient to meet daily dietary requirements may be continued. Once the maintenance dosage is achieved, monitor for clinical signs and symptoms of hypocalcemia or hypercalcemia and measure serum calcium levels as indicated, and at a minimum every 4 to 6 weeks, as some patients may require further dose titration. If calcium levels remain low with the maximum recommended dosage of 30 mcg once daily, consider adding or restarting calcium and/or active vitamin D therapy and/or seek other treatment.

Titration Recommendations for Albumin-Corrected Serum Calcium Less Than 12 mg/dL

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 (2.1)].

Figure 1: Titration of YORVIPATH, Active Vitamin D, and Calcium Supplements

Albumin-Corrected Serum Calcium <8.3 mg/dL:

Albumin-Corrected Serum Calcium 8.3 to 10.6 mg/dL:

Albumin-Corrected Serum Calcium 10.7 to 11.9 mg/dL:

2.5 Dose Delay, Interruption, or Discontinuation of YORVIPATH

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 (2.4)].

2.6 Preparation of Pen and Administration Instructions

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:

• YORVIPATH must be refrigerated at 2°C to 8°C (36°F to 46°F) until first use.
• YORVIPATH should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. YORVIPATH is a clear, colorless solution. Do not use if solid particles appear or if the solution is cloudy or colored.
• When a pen is used for the first time, test pen flow.
• Click the needle straight onto the pen, then screw the needle onto the pen until secure.
• Administer YORVIPATH subcutaneously to the abdomen or front of the thigh. Rotate the injection site daily.
• YORVIPATH should be administered initially when the patient can sit or lie down because of the potential of orthostatic hypotension [see Warnings and Precautions (5.5)].

5.1 Risk of Unintended Changes in Serum Calcium Levels Related to Number of Daily Injections

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 (2.1) and Warning and Precautions (5.2, 5.3)].

5.2 Serious Hypercalcemia

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 (2.4)]. For less serious hypercalcemia, adjust the dose of YORVIPATH, active vitamin D, and/or calcium supplements [see Dosage and Administration (2), Adverse Reactions (6.1)].

5.3 Serious Hypocalcemia

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 (2.4)].

5.4 Potential Risk of Osteosarcoma

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:

• Open epiphyses. YORVIPATH is not approved in pediatric patients [see Use in Specific Populations (8.4)].
• Metabolic bone diseases other than hypoparathyroidism, including Paget's disease of bone.
• Unexplained elevations of alkaline phosphatase.
• Bone metastases or a history of skeletal malignancies.
• History of external beam or implant radiation therapy involving the skeleton.
• Hereditary disorders predisposing to osteosarcoma.

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.

5.5 Orthostatic Hypotension

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.

5.6 Risk of Digoxin Toxicity with Concomitant Use of Digitalis Compounds

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 (7.1)].

6.1 Clinical Trials Experience

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 (14)].

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.

7.1 Drugs Affected by Serum Calcium

7.2 Drugs Known to Affect Serum Calcium

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.

8.1 Pregnancy

8.2 Lactation

8.4 Pediatric Use

The safety and effectiveness of YORVIPATH have not been established in pediatric patients.

8.5 Geriatric Use

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.

8.6 Renal Impairment

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 (12.3)].

12.1 Mechanism of Action

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.

12.2 Pharmacodynamics

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.

12.3 Pharmacokinetics

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 24-hour dosing period.

12.6 Immunogenicity

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.

13.1 Carcinogenesis, Mutagenesis, and Impairment of Fertility

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.

13.2 Animal Pharmacology and Toxicology

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.

14.1 Treatment of Adults with Hypoparathyroidism

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 (2.3, 2.4)].

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).

16.1 How Supplied

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).

16.2 Storage and Handling

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.

Dosage and Administration

Advise patients to use only one injection to achieve the once daily recommended dosage [see Dosage and Administration (2.1) and Warnings and Precautions (5.1)].

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 (2.6)].

Adverse Reactions