YORVIPATH 168mcg / 0.56ml injection for pre-filled pen medication leaflet

Yorvipath 168 micrograms/0.56 mL solution for injection in pre-filled pen

Yorvipath 294 micrograms/0.98 mL solution for injection in pre-filled pen

Yorvipath 420 micrograms/1.4 mL solution for injection in pre-filled pen

Yorvipath consists of PTH(1-34) conjugated to a methoxypolyethylene glycol carrier (mPEG) via a

Linker.

Yorvipath 168 micrograms/0.56 mL solution for injection in pre-filled pen

Each pre-filled pen contains palopegteriparatide equivalent to 168 micrograms of PTH(1-34) in0.56 mL of solvent*. The concentration based on PTH(1-34) is 0.3 mg/mL.

Each pre-filled pen delivers doses of 6, 9, or 12 micrograms of PTH(1-34).

Yorvipath 294 micrograms/0.98 mL solution for injection in pre-filled pen

Each pre-filled pen contains palopegteriparatide equivalent to 294 micrograms of PTH(1-34) in0.98 mL of solvent*. The concentration based on PTH(1-34) is 0.3 mg/mL.

Each pre-filled pen delivers doses of 15, 18, or 21 micrograms of PTH(1-34).

Yorvipath 420 micrograms/1.4 mL solution for injection in pre-filled pen

Each pre-filled pen contains palopegteriparatide equivalent to 420 micrograms of PTH(1-34) in1.4 mL of solvent*. The concentration based on PTH(1-34) is 0.3 mg/mL.

Each pre-filled pen delivers doses of 24, 27, or 30 micrograms of PTH(1-34).

*The strength indicates the quantity of the PTH(1-34) moiety without consideration of themPEG-linker.

For the full list of excipients, see section 6.1.

Solution for injection (injection)

Clear and colourless with a pH of 3.7 - 4.3.

Yorvipath is a parathyroid hormone (PTH) replacement therapy indicated for the treatment of adultswith chronic hypoparathyroidism.

Treatment should be initiated and monitored by physicians or qualified healthcare professionalsexperienced in the diagnosis and management of patients with hypoparathyroidism.

Dose recommendations of Yorvipath refer to micrograms of PTH(1-34). The dose should beindividualised based on serum calcium. The optimal dose after titration is the minimum dose requiredto prevent hypocalcaemia. This is the dose that maintains serum calcium within the normal rangewithout the need for active forms of vitamin D or calcium supplementation beyond recommendednutritional supplementation for the general population (generally less than 600 mg per day). Doses ofactive forms of vitamin D and calcium supplements will need to be adjusted prior to initiating andduring treatment with Yorvipath based on serum calcium value (see section 4.4).

Patients receiving the maximum Yorvipath dose of 60 mcg per day who experience ongoinghypocalcaemia may require co-administration of therapeutic calcium and/or active forms of vitamin D.

Before initiation of Yorvipath

Serum 25(OH) vitamin D should be within the normal range and serum calcium should be stablewithin or slightly below the normal range (1.95 - 2.64 mmol/L [7.8 - 10.6 mg/dL]) on at least1 laboratory value within two weeks prior to first dose of treatment.

Initiation of Yorvipath

The recommended starting dose is 18 mcg once daily with dose adjustments in 3 mcg incrementsthereafter every 7 days (see figure 1). The dose range is 6 to 60 mcg per day.

When initiating treatment with Yorvipath, the dose of active vitamin D or calcium supplements shouldbe adjusted:

* If taking active vitamin D:

o If serum calcium is ≥ 2.07 mmol/L [≥ 8.3 mg/dL], active vitamin D (calcitriol oralfacalcidol) should be discontinued on the same day as the first dose of Yorvipath. Dosesof calcium supplements should be maintained.

o If serum calcium is < 2.07 mmol/L [< 8.3 mg/dL], active vitamin D should be reduced by≥ 50% on the same day as the first dose of Yorvipath. Doses of calcium supplementsshould be maintained.

* If not taking active vitamin D:o Calcium supplements should be decreased by at least 1 500 mg on the same day as thefirst dose of Yorvipath. If taking elemental calcium doses ≤ 1 500 mg per day, calciumsupplements should be discontinued entirely.

* If calcium supplements are indicated to meet dietary requirements, continuing dietary calciumsupplements at doses ≤ 600 mg per day may be considered instead of discontinuing entirely.

Dose adjustment and maintenance of Yorvipath

Serum calcium concentration must be monitored during titration (see section 4.4).

Yorvipath dose may be increased in increments of 3 mcg if at least 7 days have elapsed since a priordose change (see figure 1). The dose must not be increased more often than every 7 days. Yorvipathmay be reduced in increments of 3 mcg no more often than every 3 days in response tohypercalcaemia (see figure 1).

Serum calcium should be measured 7 days after the first dose and figure 1 should be followed forappropriate Yorvipath, active vitamin D, and calcium supplement dosing. After any subsequent dosechange in Yorvipath, active vitamin D, or calcium supplements, serum calcium should be measuredwithin 7 to 14 days and patients should be monitored for clinical symptoms of hypocalcaemia orhypercalcaemia. Yorvipath, active vitamin D, and/or calcium supplements should be adjusted as perfigure 1. Dose adjustments of Yorvipath, active vitamin D, and calcium supplements should be madeon the same day.

The maintenance dose should be the dose that achieves serum calcium within the normal range,without the need for active vitamin D or therapeutic doses of calcium. Optionally, calciumsupplementation sufficient to meet dietary requirements (≤ 600 mg per day) may be continued. Serumcalcium and 25(OH) vitamin D should be measured as per standard of care when a maintenance doseis achieved. 25(OH) vitamin D (non-active vitamin D) supplementation may be needed to reachnormal serum levels.

Figure 1: Titration of Yorvipath, active vitamin D, and calcium supplements

Serum calcium low (< 2.07 mmol/L [< 8.3 mg/dL]):

Increase calcium supplements and/or active

No vitamin D toward prior doses based on≥ 7 days since prescriber’s clinical judgment and continuestarted same Yorvipath dose

Yorvipath,or changed

Yorvipathdose? Yes Continue same calcium supplement andactive vitamin D doses and increase

Yorvipath dose by 3 mcg

Serum calcium normal (≥ 2.07 to ≤ 2.64 mmol/L [≥ 8.3 to ≤ 10.6 mg/dL]):

Continue same

Yorvipathdose, Discontinue

No calcium No Continue same calcium≥ 7 days since supplement, Yorvipath supplementsstarted and active dose and increase

Yorvipath, vitamin D No Still taking No Yorvipathor changed doses calcium by 3 mcg

Yorvipath supplements?

Yes Is calciumdose? Still taking supplement

Yesactive Decrease or ≥ 1 500 mg/day? Yes Decreasevitamin D? discontinue calcium

Yes active supplements byvitamin D and ≥ 1 500 mgincrease and increase

Yorvipath Yorvipathby 3 mcg by 3 mcg

Serum calcium high (≥ 2.65 to < 3.00 mmol/L [≥ 10.7 to < 12.0 mg/dL]):

No Decrease Discontinue

Yorvipath calciumby 3 mcg supplements and

No Still taking No continue samecalcium supplements?

Still taking Yorvipath doseactive Yes Is calciumvitamin D? supplement

Decrease or discontinue ≥ 1 500 mg/day? Decrease calcium

Yes active vitamin D Yessupplements byand continue ≥ 1 500 mg andsame Yorvipath and continue samecalcium supplement Yorvipath dosedoses

Serum calcium very high (≥ 3.00 mmol/L [≥ 12 mg/dL]):

Treatment should be withheld for 2 to 3 days and then serum calcium should be rechecked. Ifsubsequent serum calcium is < 3.00 mmol/L [< 12 mg/dL], titration of Yorvipath, active vitamin D,and calcium supplements should be resumed as per the applicable section of figure 1 using the mostrecent serum calcium value obtained. If serum calcium remains ≥ 3.00 mmol/L [≥ 12 mg/dL],

Yorvipath should be withheld for an additional 2 to 3 days and then serum calcium should berechecked. See section 4.4 for more information on hypercalcaemia.

If a dose is missed by less than 12 hours, it should be administered as soon as possible. If a dose ismissed by more than 12 hours, it should be skipped and the next dose should be administered asscheduled.

Interruption or discontinuation of Yorvipath

Interruption of daily administration should be avoided to minimise serum PTH fluctuations.

Interruption or discontinuation of treatment can result in hypocalcaemia. When interrupting ordiscontinuing treatment for 3 or more consecutive doses, patients should be monitored for signs andsymptoms of hypocalcaemia and consider to measure serum calcium. If indicated, treatment withcalcium supplements and active vitamin D should be resumed. Treatment at the prescribed doseshould be resumed as soon as possible after an interruption. When resuming treatment after aninterruption, serum calcium should be measured and doses of Yorvipath, active vitamin D, andcalcium supplements should be adjusted as per figure 1.

Dose adjustment is not required based on age (see section 5.2).

Yorvipath has not been studied in patients with severe hepatic impairment and should be used withcaution in these patients (see section 4.4).

Dose adjustment is not required in patients with an estimated glomerular filtration rate (eGFR)≥ 30 mL/min. Serum calcium levels should be measured more frequently when used in patients witheGFR < 45 mL/min (see section 4.4). Yorvipath has not been studied in patients withhypoparathyroidism and severe renal impairment (eGFR < 30 mL/min) (see section 5.2).

The safety and efficacy of Yorvipath in children less than 18 years of age have not yet beenestablished. No data are available.

Yorvipath must be administered as a subcutaneous injection to the abdomen or front of the thigh. Theinjection site should be rotated daily between four possible sites; abdomen (left or right) and front ofthe thigh (left or right).

Doses > 30 mcg per day (sequential injections)

All doses > 30 mcg per day should be administered as two single doses injected sequentially atdifferent injection sites (table 1). It is recommended to use a different Yorvipath pen for the seconddaily injection, even if the two pens have the same-coloured push button (same strength).

Table 1: Recommended scheme for Yorvipath dosing > 30 mcg/day

Dose Dosing scheme Pen combination33 mcg/day 15 mcg/day + 18 mcg/day36 mcg/day 18 mcg/day + 18 mcg/day Two pre-filled pens of Yorvipath 294 mcg/0.98 mL39 mcg/day 18 mcg/day + 21 mcg/day (orange push button)*42 mcg/day 21 mcg/day + 21 mcg/day

One pre-filled pen of Yorvipath 294 mcg/0.98 mL(orange push button)45 mcg/day 21 mcg/day + 24 mcg/day +

One pre-filled pen of Yorvipath 420 mcg/1.4 mL(burgundy push button)**48 mcg/day 24 mcg/day + 24 mcg/day51 mcg/day 24 mcg/day + 27 mcg/day54 mcg/day 27 mcg/day + 27 mcg/day Two pre-filled pens of Yorvipath 420 mcg/1.4 mL57 mcg/day 27 mcg/day + 30 mcg/day (burgundy push button)60 mcg/day 30 mcg/day + 30 mcg/day

*Yorvipath 294 micrograms/0.98 mL delivers doses of 15, 18, or 21 mcg of PTH(1-34) (with orange push button)

**Yorvipath 420 micrograms/1.4 mL delivers doses of 24, 27, or 30 mcg of PTH(1-34) (with burgundy push button)

- Hypersensitivity to the active substance or to any of the excipients listed in section 6.1

- Patients with pseudohypoparathyroidism

Hypercalcaemia

Serious events of hypercalcaemia have been reported with Yorvipath (see section 4.8). The risk ishighest when starting or increasing the dose. During treatment, serum calcium should be measured(see section 4.2) and patients should be monitored for signs and symptoms of hypercalcaemia. Ifsevere hypercalcaemia occurs, treatment should be as per clinical guidelines and dose adjustment of

Yorvipath should be considered (see section 4.2).

Serious events of hypocalcaemia have been reported with Yorvipath (see section 4.8). The risk ishighest when treatment is abruptly discontinued but may occur at any time. During treatment, serumcalcium should be measured and patients should be monitored for signs and symptoms ofhypocalcaemia. If severe hypocalcaemia occurs, treatment should be as per clinical guidelines, doseadjustment of Yorvipath should be considered, and dose adjustment of standing or as needed doses ofactive vitamin D and/or calcium supplements should be considered (see section 4.2).

Concomitant use with cardiac glycosides

Hypercalcaemia of any cause may predispose to digitalis toxicity. In patients using Yorvipathconcomitantly with cardiac glycosides (such as digoxin or digitoxin), serum calcium and cardiacglycoside levels should be monitored and patients should be observed for signs and symptoms ofdigitalis toxicity (see section 4.5).

Severe renal or hepatic disease

No studies have been performed in patients with severe renal impairment and severe hepaticimpairment. Use with caution in these patient populations. Patients with eGFR of < 45 mL/min may bemore susceptible for hypercalcaemic reactions and transient eGFR decrease, particularly wheninitiating treatment. If treatment is initiated in these patients, it is recommended to closely monitorserum calcium levels.

Use in patients at increased risk of osteosarcoma

Yorvipath has not been studied in and should be used with caution in patients;

- with skeletal malignancies and bone metastases

- who are receiving or who have received radiation therapy to the skeleton

- with unexplained elevations of bone-specific alkaline phosphatase

- with metabolic bone diseases who are at increased baseline risk for osteosarcoma (e.g., Paget’sdisease of the bone)

Use in patients with osteoporosis

Screening for and monitoring of osteoporosis should be consistent with local clinical practice for anypatient at increased risk of fragility fractures (see section 4.8).

This medicinal product contains less than 1 mmol sodium (23 mg) per dose, that is to say essentially‘sodium-free’.

No interaction studies have been performed.

Cardiac glycosides (such as digoxin or digitoxin) have a narrow therapeutic index and are affected bycalcium. Patients should be monitored for signs and symptoms of digitalis toxicity when taking

Yorvipath and cardiac glycosides.

Other medicinal products can exert effects on serum calcium and may alter the therapeutic response to

Yorvipath, including but not limited to bisphosphonates, denosumab, romosozumab, thiazide and loopdiuretics, systemic corticosteroids, and lithium. Patients should be monitored for changes in serumcalcium when treated concomitantly with these medicinal products.

There are no or limited amount of data from the use of Yorvipath in pregnant females. Animal studiesdo not indicate direct or indirect harmful effects with respect to reproductive toxicity (see section 5.3).

However, a risk to the pregnant female or developing foetus cannot be excluded. A decision to initiateor discontinue treatment with Yorvipath during pregnancy should take into account the possible risksversus the benefits for the pregnant female. It is recommended to closely monitor maternal serumcalcium levels in pregnant females with hypoparathyroidism, including if treated with Yorvipath.

It is unknown whether palopegteriparatide is excreted in human milk. As palopegteriparatide is notorally absorbed, it is unlikely to adversely affect the breast-fed child. A decision to discontinuebreast-feeding or Yorvipath therapy should take into account the benefit of breast-feeding for the childand the benefit of therapy for the female. It is recommended to closely monitor maternal serumcalcium levels if breast-feeding with hypoparathyroidism, including if treated with Yorvipath.

No studies have been performed on the effects of palopegteriparatide on human fertility. Data fromanimal studies do not indicate that administration of palopegteriparatide impairs fertility (seesection 5.3).

Yorvipath has no or negligible influence on the ability to drive and use machines. However, dizziness,presyncope, syncope and/or orthostatic hypotension was observed in some patients. These patientsshould refrain from driving or the use of machines until symptoms have subsided.

The most frequently reported adverse reactions in clinical trials with palopegteriparatide wereinjection site reactions (21.6%), headache (18.7%), and paraesthesia (13.7%). The most seriousadverse reaction reported in clinical trials was hypercalcaemia (1.40%).

Table 2 presents the adverse reactions for palopegteriparatide-treated patients identified in all phase 2and phase 3 placebo-controlled studies within the MedDRA system organ class. The adverse reactionslisted in the table below are presented by system organ class and frequency categories, defined usingthe following convention: very common (≥ 1/10); common (≥ 1/100 to < 1/10), uncommon (≥ 1/1 000to < 1/100), rare (≥ 1/10 000 to < 1/1 000), very rare (< 1/10 000), and frequency not known (cannotbe estimated from the available data). Within each frequency grouping, adverse reactions are presentedin the order of decreasing seriousness.

Table 2. Frequency of adverse reactions of palopegteriparatide

MedDRA system organ class Frequency Adverse reaction

Metabolism and nutrition disorders Common Hypercalcaemiaa, Hypocalcaemia

Nervous system disorders Very common Headached, Paraesthesiaa

Common Dizzinessa, c, d, Syncoped, Presyncoped

Cardiac disorders Common Palpitationsd, Postural orthostatictachycardia syndromed

Vascular disorders Common Orthostatic hypotensiond

Uncommon Hypertensione

Respiratory, thoracic and mediastinal disorders Common Oropharyngeal pain

Gastrointestinal disorders Very common Nauseaa

Common Diarrhoeaa, Constipation, Vomiting,

Abdominal discomfort, Abdominal pain

Skin and subcutaneous tissue disorders Common Rash, Photosensitivity reaction

Musculoskeletal and connective tissue disorders Common Arthralgia, Myalgia, Muscle twitchingf,

Musculoskeletal painf

Renal and urinary disorders Uncommon Nocturiae

Frequency not Polyuriaeknown

General disorders and administration site Very common Injection site reactionsa, b, Fatigueconditions Common Asthenia, Thirst

Uncommon Chest discomfortf, Chest painf

Investigations Frequency not Bone density decreasedknowna For these adverse reactions, the first occurrence was almost exclusively within the first 3 months of treatment (titrationperiod).b Injection site reactions include injection site reaction, injection site erythema, injection site bruising, injection site pain,injection site haemorrhage, injection site rash, and injection site swelling.c Dizziness includes dizziness and dizziness postural.d Vasodilatory symptoms include dizziness postural, headache, palpitations, Postural orthostatic tachycardia syndrome,orthostatic hypotension, Blood pressure orthostatic decreased and syncope. Vasodilatory symptoms (as identified in clinicaltrials) occurred more frequently in the first 3 months of treatment and constituted a subset of total events reported as adversereactions. A total of 3 events (in 2 patients) considered related to palopegteriparatide occurred within the first 3 months in

TCP-304: dizziness postural (n=1), and headache and palpitations (n=1).e These signs and symptoms are potentially associated with hypercalcaemia, as observed in clinical trials.f These signs and symptoms are potentially associated with hypocalcaemia, as observed in clinical trials.

Hypercalcaemia

Serious events of hypercalcaemia have been reported with Yorvipath. The incidence of hypercalcemiawas greater in patients treated with Yorvipath compared to placebo. During the blinded period,symptomatic hypercalcemia was reported in 8.6% of patients treated with Yorvipath, and all occurredwithin the first 3 months after initiation of Yorvipath.

Patients may develop antibodies to palopegteriparatide. The proportion of patients testing positive forbinding antibodies at any time during treatment was low, with 0.7% having low titre, non-neutralisingantibodies towards PTH and 5% having low titre treatment-emergent antibodies against PEG. In 2.2%of the palopegteriparatide-treated patients with pre-existing PEG antibodies, a transient impact on PK(increased clearance of total PTH, mPEG and decreased PTH concentrations) with decreasing serumcalcium was observed. However, therapeutic effectiveness was maintained by appropriate doseadjustment of palopegteriparatide according to the trial titration algorithm.

Injection site reactions were the most common adverse reactions reported in clinical trials (medianonset was 2.5 days; incidence of 21.6%). The most common injection site reactions were localisederythema (all < 5 cm with the majority 0 to < 2 cm) and were mild or moderate (grade 1 or 2) inseverity with median duration of 72 hours. All injection site reactions resolved without treatment;none were serious or led to discontinuation.

Vasodilatory symptoms

Vasodilatory symptoms have been reported with Yorvipath. These symptoms are usually transient andresolved without treatment; none were serious or led to discontinuation. If symptoms occur, dosing atbedtime while reclining is recommended.

Reporting suspected adverse reactions after authorisation of the medicinal product is important. Itallows continued monitoring of the benefit/risk balance of the medicinal product. Healthcareprofessionals are asked to report any suspected adverse reactions via the national reporting systemlisted in Appendix V.

In the event of overdose, the patient should be carefully monitored by a medical professional.

Overdose can cause hypercalcaemia, the manifestations of which may include dehydration, heartpalpitations, ECG changes, hypotension, nausea, vomiting, dizziness, muscle weakness, andconfusion. Severe hypercalcaemia may require medical care and careful monitoring (see section 4.4).

One instance of accidental overdose of approximately 3-fold the prescribed dose lasting more than7 consecutive days resulted in serum calcium as high as 16.1 mg/dL, the patient was symptomatic andrequired medical intervention. After withholding palopegteriparatide, calcium, and active vitamin D,the patient recovered and restarted on the correct dose.

Pharmacotherapeutic group: Calcium homeostasis, parathyroid hormones and analogues, ATC code:

H05AA05

Endogenous parathyroid hormone (PTH) is secreted by the parathyroid glands as a polypeptide of84 amino acids. PTH exerts its action via cell-surface parathyroid hormone receptors, for example,expressed in bone, kidney and nerve tissue. Activation of PTH1R stimulates bone turnover, increasesrenal calcium reabsorption and phosphate excretion and facilitates synthesis of active vitamin D.

Palopegteriparatide is a prodrug, consisting of PTH(1-34) conjugated to a methoxypolyethylene glycolcarrier (mPEG) via a proprietary TransCon Linker. PTH(1-34) and its main metabolite, PTH(1-33),have similar affinity to and activation of PTH1R as endogenous PTH. At physiological conditions,

PTH is cleaved from palopegteriparatide in a controlled manner to provide a continuous systemicexposure of active PTH.

Study in patients with established hypoparathyroidism

The pivotal phase 3 PaTHway clinical trial (TCP-304) assessed the efficacy and safety of Yorvipath as

PTH replacement therapy for adults with hypoparathyroidism. The 26‑week double-blind,placebo-controlled period of the clinical trial included patients randomised (3:1) to Yorvipath at astarting dose of 18 micrograms/day or placebo, co-administered with conventional therapy (calciumsupplement and active vitamin D). Randomisation was stratified by aetiology of hypoparathyroidism(i.e., postsurgical vs. all other causes). Study treatment (palopegteriparatide or placebo) andconventional therapy were subsequently titrated according to a dosing algorithm guided byalbumin-adjusted serum calcium levels.

Patients’ mean age at recruitment was 49 years (19 to 78 years of age; 12% were ≥ 65 years old), andthe majority of patients were female (78%) and Caucasian (93%). Eighty-five percent (85%) ofpatients had hypoparathyroidism acquired from neck surgery. Of the patients with other aetiologies ofhypoparathyroidism, 7 (8.5%) patients had idiopathic disease, 2 had autoimmune polyglandularsyndrome type 1 (APS-1), 1 had autosomal dominant hypocalcaemia type 1 (ADH1, CaSR mutation),1 had DiGeorge Syndrome, and 1 had hypoparathyroidism, sensorineural deafness and renal dysplasia(HDR) syndrome (GATA3 mutation).

Prior to randomisation, all patients underwent an approximate 4-week screening period in whichcalcium and active vitamin D supplements were adjusted to achieve an albumin-adjusted serumcalcium concentration between 1.95 to 2.64 mmol/L (7.8 to 10.6 mg/dL), a magnesium concentration≥ 0.53 mmol/L (≥ 1.3 mg/dL) and below the upper reference range of normal, and a 25(OH) vitamin Dconcentration between 50 to 200 nmol/L (20 to 80 ng/mL). For conventional therapy, patients weretreated with mean baseline doses of calcium (elemental) of 1 839 mg/day. Mean baseline doses ofactive vitamin D were 0.75 micrograms/day in calcitriol-treated patients (n=70), and2.3 micrograms/day in alfacalcidol-treated patients (n=12). Baseline mean albumin-adjusted serumcalcium and mean 24-hour urine calcium were similar in both treatment groups: mean serum calciumwas 2.2 mmol/L (8.8 mg/dL) and 2.15 mmol/L (8.6 mg/dL) and mean 24-hour urine calcium was392 mg/day and 329 mg/day, for Yorvipath and placebo, respectively.

Primary endpoint

The composite primary efficacy endpoint was defined as the proportion of patients at week 26 whoachieved: serum calcium levels in the normal range (2.07 to 2.64 mmol/L [8.3 to 10.6 mg/dL]),independence from conventional therapy defined as requiring no active vitamin D and ≤ 600 mg/dayof calcium supplementation, and no increase in prescribed study treatment within 4 weeks prior toweek 26. Key secondary endpoints included a subset of Hypoparathyroidism Patient Experience Scale(HPES) domain scores and 36-Item Short Form Survey (SF-36) subscale scores.

The number of patients meeting the composite primary endpoint compared with the placebo group andeach component of the primary endpoint at week 26 is presented in table 3.

Table 3: TCP-304: Response rate based on primary endpoint at week 26

Yorvipath Placebo Response rate(N=61) (N=21) difference(n, %) (n, %) (95% CI)

Response at week 26 48 (78.7%) 1 (4.8%) 74.0%(60.4%, 87.6%)p < 0.0001

Response for each component

Albumin-adjusted serum calcium 49 (80.3%) 10 (47.6%) 32.7%within normal rangea (9.2%, 56.3%)

Independence from active vitamin Db 60 (98.4%) 5 (23.8%) 74.6%(56.1%, 93.1%)

Independence from therapeutic doses 57 (93.4%) 1 (4.8%) 88.7%of calciumc (77.7%, 99.7%)

No dose increase in Yorvipathd 57 (93.4%) 12 (57.1%) 36.4%(14.2%, 58.5%)a The normal range for albumin-adjusted serum calcium was 2.07 to 2.64 mmol/L (8.3 to 10.6 mg/dL).b All daily standing doses of active vitamin D equal to zero AND use of PRN doses for ≤ 7 days within 4 weeks prior toweek 26 visit.c Average daily standing doses of elemental calcium ≤ 600 mg AND use of PRN doses on ≤ 7 days within 4 weeks priorto week 26 visit.d No dose increase in Yorvipath within 4 weeks prior to week 26 visit.

Abbreviations: CI: confidence interval; PRN: pro re nata.

Secondary endpoints

Conventional therapy intake: calcium and active vitamin D doses

In the phase 3 PaTHway trial, at week 26, 93% (57/61) of patients in the Yorvipath group were able todiscontinue conventional therapy (i.e., discontinue active vitamin D and therapeutic doses of calcium).

All patients in the Yorvipath group discontinued active vitamin D by week 8 and had sustainedreduction in therapeutic doses of calcium. There was a significant reduction in conventional therapyintake in the Yorvipath group from baseline to week 26 compared with placebo: active vitamin D(nominal p-value < 0.0001), calcium dose (nominal p-value = 0.0003), and daily pill burden (nominalp-value < 0.0001) (table 4).

Table 4: Secondary endpoints: conventional therapy intake at week 26 - blinded period(ITT population)

Yorvipath Placebo(n/N=60/61)a (n/N=19/21)a Nominal

Baseline Week 26 Baseline Week 26 p-value

Supplemental active vitamin Ddose (mcg), mean (SD) 1.0 (0.7) 0.0 (0.0) 1.0 (0.6) 0.6 (0.7) < 0.0001

Supplemental calcium dose(mg), mean (SD) 1 737 (907) 274 (177) 2 089 (1 448) 1 847 (1 326) 0.0003

Daily pill burden (number ofconventional therapy pills), 6.6 (2.1) 0.5 (1.7) 6.3 (2.8) 5.4 (3.2) < 0.0001mean (SD)

Nominal p-value from testing the differences in change from baseline to week 26 between Yorvipath and placebo.a N is the number of patients in the ITT population; n is the number of patients with data at both baseline and week 26.

Serum biochemistries

Mean serum calcium initially increased and stayed within the normal range in palopegteriparatide-treated patients (figure 2). In placebo patients, serum calcium levels decreased slightly, falling belownormal range at week 2 (mean observed value: 2.06 mmol/L) and at week 26 (mean observed value:2.06 mmol/L). The LS mean treatment difference between Yorvipath and placebo was 0.17 mmol/L(95% CI: 0.100, 0.247; nominal p < 0.0001) at week 26.

Figure 2: Serum calcium (mean ± SE) by visit - blinded period (ITT population)2.51.50 2 4 6 8 10 12 14 16 18 20 22 24 26

Time (weeks)

Palopegteriparatide Placebo

Mean serum phosphate levels for palopegteriparatide-treated patients were in the normal range atbaseline and fell within the normal range through week 26 (Mean change from baseline to week 26was -0.13 mmol/L). Mean serum calcium x phosphate product decreased in patients treated with

Yorvipath and remained stable within the normal range through week 26.

24-hour urine calcium excretion

Yorvipath therapy normalised mean 24-hour urine calcium excretion and showed greater reduction in24-hour urine calcium versus placebo.

The European Medicines Agency has deferred the obligation to submit the results of studies with

Yorvipath in one or more subsets of the paediatric population in hypoparathyroidism, as per paediatricinvestigation plan (PIP) decision, for the indication of treatment of hypoparathyroidism.

Following daily subcutaneous administration, palopegteriparatide releases PTH via autocleavage ofthe TransCon Linker with first-order kinetics, resulting in continuous exposure over 24 hours withinthe estimated normal range (figure 3).

Mean (+/-SE) albumin-adjustedserum calcium (mmol/L)

Figure 3: Mean released PTH* following subcutaneous administration of palopegteriparatide atsteady state in patients with hypoparathyroidism0 4 8 12 16 20 24

Time (hours)

The estimated normal range for PTH(1-34) is approximately 4 to 26 pg/mL. This is calculated based on PTH(1-34)constituting 40% of the molecular weight of PTH(1-84)** and the normal range (10 to 65 pg/mL) for PTH(1-84).

* Mean palopegteriparatide dose (range): 22.3 (12-33) mcg PTH(1-34)/day, n=7, released PTH: sum of PTH(1-34) and

PTH(1-33).

** PTH(1-84) = endogenous parathyroid hormone.

In patients with hypoparathyroidism administered palopegteriparatide corresponding to 18 mcg of

PTH(1-34)/day, the predicted maximum plasma concentration (Cmax) (CV%) of palopegteriparatidewas 5.18 ng/mL (36%) and the predicted Cmax (CV%) for released PTH was 6.9 pg/mL (22%) with amedian time to reach maximum concentrations (Tmax) of 4 hours. The predicted exposure over the24-hour dosing interval (area under the curve, AUC) (CV%) for released PTH was 150 pg*h/mL(22%).

Following multiple subcutaneous doses of palopegteriparatide in the range of 12 to 24 mcg

PTH(1-34)/day, the palopegteriparatide and released PTH concentrations increased in adose-proportional manner reaching steady-state within approximately 10 and 7 days, respectively. Thepeak-to-trough ratio was low, approximately 1.1 and 1.5 over 24 hours at steady state forpalopegteriparatide and released PTH, respectively. Palopegteriparatide accumulated after multipledosing by up to 18-fold for AUC.

The apparent volume of distribution (CV%) of palopegteriparatide is estimated to 4.8 L (50%) and to8.7 L (18%) for released PTH.

PTH released from palopegteriparatide is composed of PTH(1-34) and the metabolite PTH(1-33). PTHis renally metabolised and cleared.

In healthy adults, the clearance (CV%) of palopegteriparatide at steady state is estimated to be0.58 L/day (52%) with a predicted half-life of 70 hours. The apparent half-life of PTH released frompalopegteriparatide is approximately 60 hours. In the liver, most of the PTH is cleaved by cathepsins.

In the kidney, a small amount of PTH binds to PTH1R, but most is excreted by glomerular filtration.

In a pharmacodynamic/pharmacokinetic sub-study in hypoparathyroid patients, daily subcutaneousadministration of palopegteriparatide (mean dose (range): 22.3 (12-33) mcg PTH(1-34)/day) increasedserum calcium levels to within the normal range (see figure 4). The increase in serum calcium levels

Mean (+/-SE)released PTH (pg/mL)occurred in a dose-related manner, supporting the ability to titrate palopegteriparatide according tomeasured serum calcium values in the individual patient.

Figure 4: Mean albumin-adjusted serum calcium concentrations following subcutaneousadministration of palopegteriparatide at steady state in patients with hypoparathyroidism12 311 2.7510 2.59 2.258 27 1.750 4 8 12 16 20 24

Time (hours)

The normal range for albumin-adjusted serum calcium is 2.07 to 2.64 mmol/L (8.3 to 10.6 mg/dL) as denoted by the greyshading. Mean palopegteriparatide dose (range): 22.3 (12-33) mcg PTH(1-34)/day, n=7.

The pharmacokinetics of released PTH was not influenced by sex or body weight. The data for raceand ethnicity did not show any trends indicating differences, but the available data are too limited tomake definitive conclusions.

The pharmacokinetics of released PTH was not influenced by age (19 to 76 years old).

Yorvipath has been administered to patients with hypoparathyroidism with an eGFR of ≥ 30 mL/minin long-term clinical trials without the need for dose adjustment beyond the trial titration algorithm.

No clinical trials were conducted in patients with hypoparathyroidism with severe renal impairment(< 30 mL/min) or on dialysis. In a trial where Yorvipath was administered as a single dose tonon-hypoparathyroid subjects with renal impairment, palopegteriparatide exposure and resultingserum calcium levels were similar in subjects with mild, moderate, and severe renal impairment ascompared to subjects without renal impairment.

No special hazard for humans were revealed in the conventional studies of safety pharmacology,genotoxicity, and local tolerance conducted with palopegteriparatide.

At the highest dose levels in all animal species employed, repeated dosing resulted in adversepersistent hypercalcemia, which in some studies led to premature death/euthanasia, clinical signs,body weight loss and/or soft tissue mineralisation observed mainly in the kidneys. These findings areconsidered results of persistent exaggerated PTH pharmacology and of no relevance in a clinicalsetting where dose adjustments are performed to ensure normalised serum calcium.

In accordance with the expected pharmacological effects, repeated daily administration ofpalopegteriparatide increased bone turnover in rats. At low dose levels (2-fold the maximumrecommended human dose (MRHD), based on exposure to released PTH by AUC) in rats, theincreased bone turnover induced overall net catabolic bone effects. At high dose levels (5-fold the

MRHD, based on exposure to released PTH by AUC) in rats, the increased bone turnover resulted in a

Mean (+/-SE)albumin-adjustedserum calcium (mg/dL)mmol/Lnet anabolic bone effect. Physeal dysplasia was observed at the highest dose level (9-fold the MRHD,based on exposure to released PTH by AUC) in rats. These effects are of no relevance in a clinicalsetting where Yorvipath doses are individually adjusted.

There were no cardiovascular findings in monkeys up to and including the highest dose tested insingle- (3-fold the MRHD, based on exposure to released PTH by Cmax) or repeat-dose studies (0.98-fold the MRHD, based on exposure to released PTH by Cmax).

Increased occurrence of osteosarcomas has been observed in carcinogenicity studies with short-lived

PTH analogues in rats, but there is no evidence of increased risk of osteosarcoma in patients treatedwith short-lived PTH analogues. No carcinogenicity study has been conducted withpalopegteriparatide.

In animal reproduction studies, administration of palopegteriparatide to pregnant rats and rabbitsduring the period of organogenesis resulted in no evidence of embryo-lethality, foetotoxicity ordysmorphogenesis up to and including the highest doses tested (8- and 7-fold, respectively, the

MRHD, based on exposure to released PTH by AUC). Exaggerated PTH pharmacological effects wereobserved at the highest doses tested in the pregnant rats and rabbits (increased serum calcium levels,decreased body weight, decreased food consumption and/or clinical signs). The exposures at the noobserved adverse effect level (NOAEL) for maternal toxicity were 2- and 3- fold the MRHD, based onexposure to released PTH by AUC in pregnant rats and rabbits, respectively.

Palopegteriparatide did not adversely affect pre- and post-natal development in offspring frompregnant and lactating rats up to and including the highest dose tested (4-fold the MRHD, based onexposure to released PTH by Cmax).

Succinic acid

Mannitol

Metacresol

Sodium hydroxide

Hydrochloric acid (for pH adjustment)

Water for injections

In the absence of compatibility studies, this medicinal product must not be mixed with other medicinalproducts.

3 years.

Store below 30 °C.

Keep the pen cap on the pre-filled pen in order to protect from light.

Yorvipath must be discarded after 14 days.

Store in a refrigerator (2 °C - 8 °C).

Do not freeze.

Store in the original package with the pen cap on in order to protect from light.

For storage conditions after first opening of the medicinal product, see section 6.3.

A cartridge (type 1 glass) with a plunger (halobutyl) and a laminate rubber sheet (halobutyl/isoprene)contained in a pre-filled multidose disposable pen made of polypropylene.

Yorvipath is available in pack sizes containing 2 pre-filled pens (with 30 disposable needles or withoutneedles) for 28 days of treatment. Each pre-filled pen is for 14 days of treatment.

Not all pack sizes may be marketed.

Yorvipath 168 micrograms/0.56 mL solution for injection in pre-filled pen

* Each pre-filled pen contains palopegteriparatide equivalent to 168 micrograms of PTH(1-34) in0.56 mL of solvent.

* Pre-filled pen delivering doses of 6, 9, or 12 micrograms

* The strength colour on the outer carton, pen label and push button is blue

Yorvipath 294 micrograms/0.98 mL solution for injection in pre-filled pen

* Each pre-filled pen contains palopegteriparatide equivalent to 294 micrograms of PTH(1-34) in0.98 mL of solvent.

* Pre-filled pen, delivering doses of 15, 18, or 21 micrograms

* The strength colour on the outer carton, pen label and push button is orange

Yorvipath 420 micrograms/1.4 mL solution for injection in pre-filled pen

* Each pre-filled pen contains palopegteriparatide equivalent to 420 micrograms of PTH(1-34) in1.4 mL of solvent.

* Pre-filled pen, delivering doses of 24, 27, or 30 micrograms

* The strength colour on the outer carton, pen label and push button is burgundy

Dose preparation

A new Yorvipath pen should be taken out of the refrigerator 20 minutes before first opening.

The solution should appear clear, colourless and free of visible particles. Do not inject the medicinalproduct if it is cloudy, or contains particulate matter.

Each pre-filled pen is for use by a single patient. A pre-filled pen must never be shared betweenpatients, even if the needle is changed.

If a pre-filled pen has been frozen or exposed to heat, it must be discarded.

Every time a pre-filled pen is prepared for administration, a new needle must be attached.

Needles must not be re-used. This may prevent blocked needles, contamination, infection, leakage ofsolution and inaccurate dosing. The injection needle should be removed after each injection and thepen should be stored without a needle attached. Discard the needles after each injection.

Instructions for the preparation and administration of Yorvipath are given in the package leaflet andinstructions for use.

Any unused medicinal product or waste material should be disposed of in accordance with localrequirements.

Ascendis Pharma Bone Diseases A/S

Tuborg Boulevard 12

DK-2900 Hellerup

Denmark

EU/1/23/1766/001

EU/1/23/1766/002

EU/1/23/1766/003

EU/1/23/1766/004

EU/1/23/1766/005

EU/1/23/1766/006

Date of first authorisation: 17 November 2023

Detailed information on this medicinal product is available on the website of the European Medicines

Agency https://www.ema.europa.eu.