Palopegteriparatide

1 INDICATIONS AND USAGE 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) ] .

2 DOSAGE AND ADMINISTRATION Use only one injection to achieve the once daily recommended dosage. ( 2.1 ) Maximum recommended YORVIPATH dosage is 30 mcg subcutaneously once daily. ( 2.1 ) Individualize YORVIPATH dosage based on serum calcium. ( 2.1 ) Refer to the Full Prescribing Information for complete dosage and administration information. ( 2 ) 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). 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 discontinue 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. if current calcium daily dosage is ≤1500 mg/day 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: Figure 1 Figure 1 Figure 1 Titration Recommendations for Albumin-Corrected Serum Calcium 12 mg/dL or Greater 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. 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) ].

6 ADVERSE REACTIONS The following clinically significant adverse reactions are described elsewhere in the labeling: Risk of Unintended Changes in Serum Calcium Levels Related to Number of Daily Injections [see Warnings and Precautions (5.1) ] Serious Hypercalcemia [see Warnings and Precautions (5.2) ] Serious Hypocalcemia [see Warnings and Precautions (5.3) ] Potential Risk of Osteosarcoma [see Warnings and Precautions (5.4) ] Orthostatic Hypotension [see Warnings and Precautions (5.5) ] Risk of Digoxin Toxicity with Concomitant Use of Digitalis Compounds [see Warnings and Precautions (5.6) ] 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)

12.3 Pharmacokinetics YORVIPATH is a prodrug that releases PTH(1-34) via autocleavage of the TransCon linker. PTH C max 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. Figure 4: Mean Steady State PTH(1-34) Following Subcutaneous Administration of YORVIPATH Mean dose (range): 22.3 (12-33) mcg/day, n=7. in Subjects with Hypoparathyroidism a PTH(1-34) concentrations includes PTH(1-34) and active metabolite PTH(1-33). Figure 4 Absorption The median (range) time to reach maximum concentrations (T max ) of PTH is 4 (4 to 8) hours. Distribution 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. Elimination 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. Specific Populations 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. Patients with Renal Impairment 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. Patients with Hepatic 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.