Palopegteriparatide

YORVIPATH is indicated for the treatment of hypoparathyroidism in adults. YORVIPATH is a parathyroid hormone analog (PTH(1-34)) indicated for the treatment of hypoparathyroidism in adults. ( 1 ) Limitations of Use : Not studied for acute post-surgical hypoparathyroidism. ( 1 ) Titration scheme 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. ( 1 ) 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) ] .

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 Deliverable dose range at each labeled dose setting based on prefilled pen performance. Use only labeled dose for titration (refer to Figure 1). (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 Injection: single-patient-use prefilled pen ( 3 ) 168 mcg/0.56 mL pen, labeled doses of 6, 9, or 12 mcg 294 mcg/0.98 mL pen, labeled doses of 15, 18, or 21 mcg 420 mcg/1.4 mL pen, labeled doses of 24, 27, or 30 mcg

YORVIPATH is contraindicated in patients with a history of severe hypersensitivity to palopegteriparatide or any of the inactive ingredients of YORVIPATH. Reactions have included anaphylaxis, angioedema, and urticaria. Severe hypersensitivity to palopegteriparatide or any of the inactive ingredients of YORVIPATH. ( 4 )

Hypersensitivity Reactions : Anaphylaxis, angioedema, and urticaria have been reported in patients treated with parathyroid hormone analogs, including YORVIPATH. If signs or symptoms of a hypersensitivity reaction occur, discontinue treatment with YORVIPATH, initiate supportive care, and monitor until signs and symptoms resolve. Discontinue YORVIPATH permanently in patients with a severe hypersensitivity reaction to YORVIPATH. ( 5.1 ) Unintended Changes in Serum Calcium Levels Related to Number of Daily Injections : Use only one daily YORVIPATH injection. Using two YORVIPATH injections to achieve the recommended once daily dosage increases the variability of the total delivered dose. ( 5.2 ) Serious Hypercalcemia and Hypocalcemia : Have occurred with YORVIPATH. Periodically measure serum calcium and monitor for signs and symptoms of hypercalcemia and hypocalcemia. ( 5.3 , 5.4 ) Potential Risk of Osteosarcoma : YORVIPATH is not recommended in patients at increased risk of osteosarcoma. ( 5.5 ) Orthostatic Hypotension : Has been reported with YORVIPATH. Monitor for signs and symptoms of orthostatic hypotension. ( 5.6 ) Digoxin Toxicity : Concomitant use with digoxin may predispose to digitalis toxicity if hypercalcemia develops. With concomitant use, frequently measure serum calcium and digoxin levels, and monitor for signs and symptoms of digoxin toxicity. ( 5.7 , 7.1 )

5.1 Hypersensitivity Reactions Hypersensitivity reactions, including anaphylaxis, angioedema, and urticaria have been reported in patients treated with parathyroid hormone (PTH) analogs, including YORVIPATH [see Adverse Reactions (6.2) ] . If signs or symptoms of a hypersensitivity reaction occur, discontinue treatment with YORVIPATH, initiate appropriate supportive care, and monitor until signs and symptoms resolve. Discontinue YORVIPATH permanently in patients with a severe hypersensitivity reaction to YORVIPATH . YORVIPATH is contraindicated in patients with a history of severe hypersensitivity to palopegteriparatide or any of the inactive ingredients of YORVIPATH [see Contraindications (4) ] .

5.2 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 (5.3 , 5.4) ] .

5.3 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) and Adverse Reactions (6.1) ] .

5.4 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) ] .

5.5 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.

5.6 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.

5.7 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) ] .

The following clinically significant adverse reactions are described elsewhere in the labeling: Hypersensitivity Reactions [see Warnings and Precautions (5.1) ] Risk of Unintended Changes in Serum Calcium Levels Related to Number of Daily Injections [see Warnings and Precautions (5.2) ] Serious Hypercalcemia [see Warnings and Precautions (5.3) ] Serious Hypocalcemia [see Warnings and Precautions (5.4) ] Potential Risk of Osteosarcoma [see Warnings and Precautions (5.5) ] Orthostatic Hypotension [see Warnings and Precautions (5.6) ] Risk of Digoxin Toxicity with Concomitant Use of Digitalis Compounds [see Warnings and Precautions (5.7) ] Adverse reactions occurring in ≥ 5% of patients: injection site reactions, vasodilatory signs and symptoms, headache, diarrhea, back pain, hypercalcemia, and oropharyngeal pain. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Ascendis Pharma at 1-844-442-7236 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

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. 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 (%) 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. Injection site reactions Injection site reactions includes the preferred terms injection site bruising, injection site erythema, injection site rash, and injection site reaction. 24 (39) 1 (5) Vasodilatory signs and symptoms 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. 17 (28) 0 Headache 13 (21) 2 (10) Diarrhea 6 (10) 1 (5) Back pain Back pain includes the preferred terms back pain, flank pain, and spinal pain. 5 (8) 0 Hypercalcemia 5 (8) 0 Oropharyngeal pain 4 (7) 0 Description of Selected Adverse Reactions Hypercalcemia 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 Abbreviations: N, total number of subjects in the treatment arm; n, number of subjects meeting criteria. Albumin-Corrected Serum Calcium >10.6 mg/dL, n (%) Subjects meeting albumin-corrected serum calcium > 10.6 mg/dL criterion includes subjects meeting albumin-corrected serum calcium > 12 mg/dL criterion. 33 (54.1) 2 (9.5) Albumin-Corrected Serum Calcium >12 mg/dL, n (%) 8 (13.1) 0 (0)

6.2 Postmarketing Experience The following adverse reactions have been identified during post-approval use of YORVIPATH. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Allergic reactions: Anaphylaxis, angioedema, drug hypersensitivity, urticaria

Drugs Known to Affect Calcium : When used concomitantly with YORVIPATH, measure serum calcium levels more frequently. ( 7.2 )

7.1 Drugs Affected by Serum Calcium Digoxin 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.

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.

Lactation : Monitor breastfed infants for symptoms of hypercalcemia or hypocalcemia. Consider monitoring serum calcium in the breastfed infant ( 8.2 ).

8.1 Pregnancy Risk Summary 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 1-877-229-2184. Clinical Considerations 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. Data 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.

8.2 Lactation Risk Summary 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.

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 m 2 ). In a dedicated renal impairment study, patients with severe renal impairment (estimated glomerular filtration rate 15 to 30 mL/min/1.73 m 2 ) had no clinically significant difference in total PTH compared to subjects with normal renal function upon treatment with YORVIPATH [see Clinical Pharmacology (12.3) ] .

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.