Yorvipath

Pharmacotherapeutic group: Calcium homeostasis, parathyroid hormones and analogues, ATC code: H05AA05 Mechanism of action Endogenous parathyroid hormone (PTH) is secreted by the parathyroid glands as a polypeptide of 84 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, increases renal 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 glycol carrier (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 systemic exposure of active PTH. Clinical efficacy and safety 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 a starting dose of 18 micrograms/day or placebo, co-administered with conventional therapy (calcium supplement and active vitamin D). Randomisation was stratified by aetiology of hypoparathyroidism (i.e., postsurgical vs. all other causes). Study treatment (palopegteriparatide or placebo) and conventional therapy were subsequently titrated according to a dosing algorithm guided by albumin-adjusted serum calcium levels. Patients' mean age at recruitment was 49 years (19 to 78 years of age; 12% were ≥ 65 years old), and the majority of patients were female (78%) and Caucasian (93%). Eighty-five percent (85%) of patients had hypoparathyroidism acquired from neck surgery. Of the patients with other aetiologies of hypoparathyroidism, 7 (8.5%) patients had idiopathic disease, 2 had autoimmune polyglandular syndrome 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 which calcium and active vitamin D supplements were adjusted to achieve an albumin-adjusted serum calcium 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 D concentration between 50 to 200 nmol/L (20 to 80 ng/mL). For conventional therapy, patients were treated with mean baseline doses of calcium (elemental) of 1 839 mg/day. Mean baseline doses of active vitamin D were 0.75 micrograms/day in calcitriol-treated patients (n=70), and 2.3 micrograms/day in alfacalcidol-treated patients (n=12). Baseline mean albumin-adjusted serum calcium and mean 24-hour urine calcium were similar in both treatment groups: mean serum calcium was 2.2 mmol/L (8.8 mg/dL) and 2.15 mmol/L (8.6 mg/dL) and mean 24-hour urine calcium was 392 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 who achieved: 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/day of calcium supplementation, and no increase in prescribed study treatment within 4 weeks prior to week 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 and each 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 (N=61) (n, %) Placebo (N=21) (n, %) Response rate difference (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 within normal range a 49 (80.3%) 10 (47.6%) 32.7% (9.2%, 56.3%) Independence from active vitamin D b 60 (98.4%) 5 (23.8%) 74.6% (56.1%, 93.1%) Independence from therapeutic doses of calcium c 57 (93.4%) 1 (4.8%) 88.7% (77.7%, 99.7%) No dose increase in Yorvipath d 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 to week 26 visit. c Average daily standing doses of elemental calcium ≤ 600 mg AND use of PRN doses on ≤ 7 days within 4 weeks prior to 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 to discontinue 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 sustained reduction in therapeutic doses of calcium. There was a significant reduction in conventional therapy intake 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 (nominal p-value < 0.0001) (table 4). Table 4: Secondary endpoints: conventional therapy intake at week 26 - blinded period (ITT population) Yorvipath (n/N=60/61) a Placebo (n/N=19/21) a Nominal p-value Baseline Week 26 Baseline Week 26 Supplemental active vitamin D dose (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 of conventional therapy pills), mean (SD) 6.6 (2.1) 0.5 (1.7) 6.3 (2.8) 5.4 (3.2) < 0.0001 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 below normal 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) Mean serum phosphate levels for palopegteriparatide-treated patients were in the normal range at baseline and fell within the normal range through week 26 (Mean change from baseline to week 26 was -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 in 24-hour urine calcium versus placebo. Paediatric population 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 paediatric investigation plan (PIP) decision, for the indication of treatment of hypoparathyroidism.